APPLICATION NUMBER · VX-445 Major Human Active Metabolite (M23, VRT -1654549) TK and Safety...

CENTER FOR DRUG EVALUATION AND

RESEARCH

APPLICATION NUMBER:

212273Orig1s000

MULTI-DISCIPLINE REVIEW

Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review

NDA/BLA Multi-disciplinary Review and Evaluation {NDA 212273} {TRIKAFTA, elexacaftor/tezacaftor/ivacaftor}

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NDA/BLA Multi-Disciplinary Review and Evaluation Application Type NDA ( NME)

Application Number(s) 212273 Priority or Standard Priority

Submit Date(s) July 19, 2019 Received Date(s) July 19, 2019

PDUFA Goal Date March 19, 2020 Division/Office DPARP / ODEII

Review Completion Date See stamp date Established/Proper Name elexacaftor/tezacaftor/ivacaftor

(Proposed) Trade Name Trikafta Pharmacologic Class Unclassified / unclassified / Cystic Fibrosis Transmembrane

Conductance Regulatory (CFTR) potentiator Code name VX-445 / VX-661 / VX-770

Applicant Vertex Pharmaceuticals Dosage form tablet

Applicant proposed Dosing Regimen

AM: 2 fixed-dose combination (FDC) tablets containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg, PM: 1 tablet containing 150 mg IVA

Applicant Proposed Indication(s)/Population(s)

Treatment of cystic fibrosis in patients 12 years of age and older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator gene

Applicant Proposed SNOMED CT Indication Disease Term for each

Proposed Indication

190905008/Cystic fibrosis (disorder)

Recommendation on

Regulatory Action Approval

Recommended Indication(s)/Population(s)

(if applicable)

As proposed

Recommended SNOMED CT Indication Disease

Term for each Indication (if applicable)

190905008/Cystic fibrosis (disorder)

Recommended Dosing Regimen

As proposed

Reference ID: 4508780Reference ID: 4508869


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Table of Contents Table of Tables ................................................................................................................................ 5

Table of Figures ............................................................................................................................... 9

Reviewers of Multi-Disciplinary Review and Evaluation .............................................................. 11

Glossary ......................................................................................................................................... 17

1 Executive Summary ............................................................................................................... 19 1.1 Product Introduction ...................................................................................................... 19

1.1 Conclusions on the Substantial Evidence of Effectiveness ............................................ 19

1.1. Benefit-Risk Assessment .................................................................................................... 21

1.2 Patient Experience Data ................................................................................................. 25

2 Therapeutic Context .............................................................................................................. 26 2.1 Analysis of Condition ...................................................................................................... 26

2.2 Analysis of Current Treatment Options ......................................................................... 27

3 Regulatory Background ......................................................................................................... 28 3.1 U.S. Regulatory Actions and Marketing History ............................................................. 28

3.2 Summary of Presubmission/Submission Regulatory Activity ........................................ 29

3.3 Foreign Regulatory Actions and Marketing History ....................................................... 30

4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ................................................................................................................. 31

4.1 Office of Scientific Investigations (OSI) .......................................................................... 31

4.2 Product Quality .............................................................................................................. 31

5 Nonclinical Pharmacology/Toxicology................................................................................... 33 5.1 Executive Summary ........................................................................................................ 33

5.2 Referenced NDAs, BLAs, DMFs ....................................................................................... 34

5.3 Pharmacology ................................................................................................................. 34

5.4 ADME/PK ........................................................................................................................ 37

5.5 Toxicology ....................................................................................................................... 41

5.5.1 General Toxicology .................................................................................................. 41

5.5.2 Genetic Toxicology .................................................................................................. 46

5.5.3 Carcinogenicity ........................................................................................................ 48

5.5.4 Reproductive and Developmental Toxicology ........................................................ 48

5.5.5 Other Toxicology Studies ........................................................................................ 50

5.5.6 Conclusion ............................................................................................................... 51

6 Clinical Pharmacology ............................................................................................................ 52 6.1 Executive Summary ........................................................................................................ 52

6.2 Summary of Clinical Pharmacology Assessment ............................................................ 52



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6.2.1 Pharmacology and Clinical Pharmacokinetics ........................................................ 52

6.2.2 General Dosing and Therapeutic Individualization ................................................. 54

6.3 Comprehensive Clinical Pharmacology Review ............................................................. 57

6.3.1 General Pharmacology and Pharmacokinetic Characteristics ................................ 57

6.3.2 Clinical Pharmacology Questions ............................................................................ 61

7 Sources of Clinical Data and Review Strategy ....................................................................... 75 7.1 Table of Clinical Studies .................................................................................................. 75

7.2 Review Strategy .............................................................................................................. 78

8 Statistical and Clinical and Evaluation ................................................................................... 79 8.1 Review of Individual Trials Used to Support Efficacy ..................................................... 79

8.1.1 VX17-445-102 (Trial 102) Study Design .................................................................. 79

8.1.2 Trial 102 Results ...................................................................................................... 90

8.1.3 VX17-445-103 (Trial 103) Study Design ................................................................ 108

8.1.4 Trial 103 Results .................................................................................................... 112

8.1.5 Assessment of Efficacy Across Trials ..................................................................... 120

8.1.6 Integrated Assessment of Effectiveness ............................................................... 120

8.2 Review of Safety ........................................................................................................... 121

8.2.1 Safety Review Approach ....................................................................................... 121

8.2.2 Review of the Safety Database ............................................................................. 122

8.2.3 Adequacy of Applicant’s Clinical Safety Assessments .......................................... 123

8.2.4 Safety Results ........................................................................................................ 125

8.2.5 Analysis of Submission-Specific Safety Issues ....................................................... 133

8.2.6 Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability ...... 148

8.2.7 Safety Analyses by Demographic Subgroups ........................................................ 149

8.2.8 Specific Safety Studies/Clinical Trials .................................................................... 149

8.2.9 Additional Safety Explorations .............................................................................. 162

8.2.10 Safety in the Postmarket Setting ................................................................... 163

8.2.11 Integrated Assessment of Safety ................................................................... 164

8.3 Statistical Issues ........................................................................................................... 165

8.4 Conclusions and Recommendations ............................................................................ 166

9 Advisory Committee Meeting and Other External Consultations ....................................... 168

10 Pediatrics ............................................................................................................................. 168

11 Labeling Recommendations ................................................................................................ 168

12 Risk Evaluation and Mitigation Strategies (REMS) .............................................................. 169

13 Postmarketing Requirements and Commitment ................................................................ 169

14 Division Director (DPARP) Comments ................................................................................. 170



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15 Appendices ............................................................................................................................. 175 15.1. Financial Disclosure ....................................................................................................... 175

15.2. Nonclinical Pharmacology/Toxicology ........................................................................... 178

15.2.1. Excipients ....................................................................................................... 178

15.2.2. Organic Impurities ......................................................................................... 179

15.2.3. Heavy Metals ................................................................................................. 180

15.2.4. Residual Solvents ........................................................................................... 180

15.2.5. Other Toxicity Studies .................................................................................... 180

15.3. OCP Appendices (Technical Documents Supporting OCP Recommendations) ............. 181

15.3.1. Individual Studies ........................................................................................... 181

15.3.2. Physiologically Based Pharmacokinetic (PBPK) Modeling Review ................ 210

15.3.3. In Vitro Data To Meet Combination Guidance Criteria ................................. 217

15.3.4. Pharmacometrics Review .............................................................................. 223

15.4. Clinical Appendix ............................................................................................................ 233

15.4.1. Supportive Tables, Trial 102 .......................................................................... 233

15.4.2. Supportive Tables, Trial 103 .......................................................................... 238

15.4.3. Supportive Tables, Study 105 ........................................................................ 241



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Table of Tables

Table 1. CFTR Mutation Classes .................................................................................................... 26 Table 2. Treatment Armamentarium Relevant to Proposed CF Indication .................................. 27 Table 3. Approved CFTR Modulators for the Treatment of Cystic Fibrosis .................................. 28 Table 4.Toxicokinetic Studies of VX-445 ....................................................................................... 44 Table 5. VX-445 Major Human Active Metabolite (M23, VRT-1654549) TK and Safety Margins 46 Table 6. VX-445 Toxicokinetics (TK) and Safety Margins .............................................................. 50 Table 7. VX-445 Major Human Active Metabolite (M23, VRT-1654549) TK and Safety Margins 50 Table 8. Dosing Schedule for Concomitant Use of ELX/TEZ/IVA with Moderate and Strong CYP3A Inhibitors ....................................................................................................................................... 55 Table 9. Clinical Pharmacology Studies ........................................................................................ 62 Table 10. Efficacy Results for F/MF Subjects (Study 001, Part D), FAS ......................................... 64 Table 11. Efficacy Results for F/F Subjects (Study 001, Part E), FAS ............................................. 64 Table 12. TEZ/IVA Pharmacokinetic Parameters in Subjects with Moderate Hepatic Impairment Compared with Healthy Subjects ................................................................................................. 65 Table 13. Elexacaftor, Tezacaftor and Ivacaftor Exposure (Mean (SD)) by Age Group (Trials 102 and 103) ........................................................................................................................................ 68 Table 14. Impact of Other Drugs on Systemic Exposure of Elexacaftor, Tezacaftor and/or Ivacaftor ........................................................................................................................................ 69 Table 15. Impact of Elexacaftor/Tezacaftor or Ivacaftor on Other Drugs .................................... 71 Table 16. Bioanalytical Assays Used In Clinical Studies of Elexacaftor ......................................... 73 Table 17. Bioanalytical Assays Used in Clinical Studies of Tezacaftor .......................................... 74 Table 18. Bioanalytical Assays Used in Clinical Studies of Ivacaftor ............................................. 74 Table 19. Clinical Trials Relevant to this NDA ............................................................................... 75 Table 20. Dose and Duration of Treatment .................................................................................. 83 Table 21. Prohibited Medications ................................................................................................. 83 Table 22. Subject Disposition, Trial 102 ........................................................................................ 91 Table 23. Important Protocol Deviations, Trial 102, FAS .............................................................. 92 Table 24. Demographic Characteristics of the Primary Efficacy Analysis, FAS ............................. 93 Table 25. Baseline Characteristics of the Primary Efficacy Analysis, FAS: Trial 102 ..................... 93 Table 26. Genotype Distribution for Mutations Occurring in at Least 6 Subjects, Trial 102, FAS 95 Table 27. Concomitant Medications With Rate Difference of ≥5% Between the ELX/TEZ/IVA and Placebo Arms, Trial 102, FAS ........................................................................................................ 96 Table 28. MMRM Analysis of Absolute Change from Baseline in ppFEV1 (%) at Week 4 (iFAS, Trial 102) ....................................................................................................................................... 96 Table 29. MMRM Analysis of Absolute Change from Baseline in ppFEV1 (%) Through Week 24 (FAS, Trial 102) .............................................................................................................................. 97 Table 30. Negative Binomial Analysis of the Number of Pulmonary Exacerbations During the Pulmonary Exacerbation Analysis Period (FAS, Trial 102) ............................................................ 98 Table 31. MMRM Analysis of Absolute Change from Baseline in Sweat Chloride (mmol/L) Through Week 24 (FAS, Trial 102) ................................................................................................ 99



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Table 32. MMRM Analysis of Absolute Change from Baseline in Cystic Fibrosis Questionnaire-Revised Respiratory Domain Score (Points) Through Week 24 (FAS, Trial 102) .......................... 99 Table 33. MMRM Analysis of Absolute Change from Baseline in BMI (kg/m2) at Week 24 (FAS, Trial 102) ....................................................................................................................................... 99 Table 34. MMRM Analysis of Absolute Change from Baseline in Sweat Chloride (mmol/L) at Week 4 (FAS, Trial 102) ............................................................................................................... 100 Table 35. MMRM Analysis of Absolute Change from Baseline in CFQ-R RD Score (Points) at Week 4 (FAS, Trial 102) ............................................................................................................... 100 Table 36. MMRM Analysis of Absolute Change from Baseline in FEV1 (L) at Week 24 (FAS, Trial 102) ............................................................................................................................................. 104 Table 37. Dose and Duration of Treatment ................................................................................ 109 Table 38. Subject Disposition, Trial 103 ...................................................................................... 112 Table 39. Demographic Characteristics of the Primary Efficacy Analysis, Trial 103, FAS ........... 113 Table 40. Baseline Characteristics of the Primary Efficacy Analysis, FAS: Trial 103 ................... 114 Table 41. MMRM Analysis of Absolute Change from Baseline in ppFEV1 (%) at Week 4 (FAS, Trial 103) ............................................................................................................................................. 115 Table 42. Number and Percentage of Missing Measurements in Primary Endpoint ppFEV1 by Visits (FAS, Trial 102 & Trial 103) ................................................................................................ 116 Table 43. MMRM Analysis of Absolute Change from Baseline in SwCl (mmol/L) at Week 4 (FAS, Trial 103) ..................................................................................................................................... 116 Table 44. MMRM Analysis of Absolute Change from Baseline in CFQ-R RD Score (points) at Week 4 (FAS, Trial 103) ............................................................................................................... 117 Table 45. Safety Database for ELX/TEZ/IVA (N=665) .................................................................. 122 Table 46. Number of Subjects Exposed to ELX/TEZ/IVA, by Duration of Exposure, Trials 102 and 103 .............................................................................................................................................. 122 Table 47. Number of Subjects Exposed to ELX/TEZ/IVA, by Duration of Exposure, Controlled Trials and Open Label Extension ................................................................................................. 123 Table 48. Serious Adverse Events Occurring in at Least 2 Subjects in Any Treatment Arm, by Preferred Term, Trial 102, Safety Set ......................................................................................... 125 Table 49. Treatment Interruptions Due to Adverse Events in at Least 2 Subjects in Any Treatment Arm, Trial 102, Safety Set ......................................................................................... 126 Table 50. Severe (Grade 3) Adverse Events Occurring in At Least 2 Subjects in Any Treatment Arm, Trial 102, Safety Set ............................................................................................................ 127 Table 51. Common Adverse Events With ≥5% Frequency and ≥1% Difference From Placebo in Trial 102, Safety Set .................................................................................................................... 128 Table 52. Common Adverse Events with ≥5% Frequency and Greater Than TEZ/IVA in Trial 103, Safety Set .................................................................................................................................... 129 Table 53. Systolic Blood Pressure, Trial 102, Safety Set ............................................................. 131 Table 54. QTc, Trial 102, Safety Set ............................................................................................ 132 Table 55. Maximum Liver Function Test Elevations During Treatment Emergent Period: Trial 102, Safety Set ............................................................................................................................ 134 Table 56. Hepatobiliary-Related AEs Trial 102, Safety Set ......................................................... 136



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Table 57. Maximum Liver Function Test Elevations During Treatment Emergent Period: Trial 103, Safety Set ............................................................................................................................ 138 Table 58. Incidence of Skin-Related Adverse Events, Trial 102, Safety Set ................................ 139 Table 59. Creatine Kinase Laboratory Data, Trial 102, Safety Set .............................................. 143 Table 60. Muscle-related AEs, Trial 102, Safety Set ................................................................... 144 Table 61. Subject Disposition, Study 105 IA ............................................................................... 151 Table 62. Duration of Exposure, Study 105 IA, OL Safety Set ..................................................... 152 Table 63. Maximum Liver Function Test Elevations During Treatment Emergent Period: Study 105 IA, OL Safety Set ................................................................................................................... 153 Table 64. Hepatobiliary Adverse Events, Study 105 IA, OL Safety Set ....................................... 154 Table 65. Liver Function Test Values: Subject 102- Study 105 ..................................... 155 Table 66. Skin-related Adverse Events, Study 105 IA, Safety Set ............................................... 157 Table 67. Studies Included in Safety Update .............................................................................. 161 Table 68. Quantitative Composition of ELZ/TEZ/IVA Tablet ....................................................... 178 Table 69. Organic Impurity Levels From a 28-Day Mouse Toxicology Study (VX-445-TX-001) .. 179 Table 70. In Vitro Studies (Using Human Biomaterials) of Elexacaftor (VX-445) and Its Major Metabolites ................................................................................................................................. 182 Table 71. Pharmacokinetic Parameters for Unchanged VX-445 and M23-445 in Plasma and Total Radioactivity in Plasma and Whole Blood .................................................................................. 185 Table 72. Mean (CV%) AUC and Cmax Ratios for M23-445 to Unchanged VX-445 in Plasma, Unchanged VX-445 to TRA in Plasma, and TRA in Blood to TRA in Plasma ................................ 186 Table 73. Total Percent of Radioactive Dose as 14C-VX-445 or Metabolites of 14C-VX-445 in Pooled Urine at Specified Times After a Single Oral Administration of 14C-VX-445 to Healthy Male Human Subjects ................................................................................................................. 187 Table 74. Test product, Trial 001 ................................................................................................ 189 Table 75. Summary of the Pharmacokinetic Parameters for ELX Following Single Oral Doses . 191 Table 76. Statistical Analysis of a Food Effect on a VX 445 Tablet Formulation, Part A ............. 192 Table 77. Summary of Selected VX-445 PK Parameters After an IV Infusion, Part A ................. 192 Table 78. Summary of Selected VX-445 PK Parameters Following Multiple Oral Doses for 10 Days, Part B ................................................................................................................................. 195 Table 79. Summary of Selected VX-445 PK Parameters Following Multiple Oral Doses of VX-445 TC for 14 Days, Part C.................................................................................................................. 196 Table 80. Summary of Selected TEZ and IVA PK Parameters Following Multiple Oral Doses of VX-445 TC for 14 Days, Part C ........................................................................................................... 197 Table 81. PK Parameters of VX-445 and M23-445 After Therapeutic (200 mg qd) and Supratherapeutic (400 mg qd) Doses of VX-445 ........................................................................ 199 Table 82. Sampling Schedule, Trial 006 ...................................................................................... 201 Table 83. Geometric Least Squares Mean (GLSM) Ratios and 90% CI for VX-445, TEZ, VX-561, and Their Respective Metabolites With (TP 2) and Without (TP 1) Itraconazole ...................... 201 Table 84. Statistical Analysis of LN and EE Exposures After Administration of LN/EE Alone and After LN/EE+VX-445 TC ............................................................................................................... 204 Table 85. Mean VX-445, TEZ, IVA Exposures after Administration of LN/EE+VX-445 TC ........... 205 Table 86. Trial 005 Design ........................................................................................................... 206


(b) (6)


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Table 87. Test Product VX-561, a Deuterated Isotope of IVA With a Specific Pattern of 9 Substituted Deuteriums .............................................................................................................. 207 Table 88. Relative Bioavailability Assessment of VX-445, TEZ, and VX-561 Exposures After Administration in Part A, Cohort A1 ........................................................................................... 208 Table 89. Relative BA Assessment of VX-445, TEZ, and IVA Exposures After Administration in Part A, Cohort A3 ........................................................................................................................ 208 Table 90. Summary of VX-445, TEZ, and VX-561 PK Parameters After Administration in Part B, Evaluating Food Effect ................................................................................................................ 209 Table 91. Relative BA Assessment of VX-445, TEZ, and VX-561 Exposures as FDC Tablet With a Moderate-fat Meal Compared to Under Fasted Conditions ...................................................... 210 Table 92.Model Input Parameters for VX-445 ............................................................................ 212 Table 93. Human PK Data Used for VX-445 PBPK Model Development and Validation ............ 213 Table 94. Predicted and Observed CmaxR and AUCR for Perpetrator Models Regarding the CYP3A Pathway ........................................................................................................................... 214 Table 95. Summary of Observed (Itraconazole) and Simulated Effects of Strong and Moderate CYP3A Inhibitors on the PK of VX-445 ........................................................................................ 216 Table 96. Summary of Observed and Simulated Mean Steady-State PK of VX-445 in the Presence and Absence of a CYP3A Inhibitor Following Proposed Dose Adjustment Regimens ................ 217 Table 97. Applicant’s Western Blot Data from Report M379 for the Homozygous Donor ........ 219 Table 98. FDA Reanalysis of Effect of Drugs on the Mature Fraction of CFTR in HBE Cells from the F508del/F508del Donor ........................................................................................................ 219 Table 99. FDA Reanalysis of Effect of Drugs on the Mature Fraction of CFTR in HBE Cells From the F508del/G542X Donor .......................................................................................................... 220 Table 100. Potency (EC50) and Efficacy (Maximal Chloride Transport Derived From Fitting Concentration Response Graphs) of ELX Alone and in Combination with TEZ and/or IVA ........ 222 Table 101. Studies Included in Population PK/PD Analysis ........................................................ 223 Table 102. Baseline Demographic Covariates for PK/PD Analysis for ppFEV1 (Upper) and SwCI (Lower) ........................................................................................................................................ 224 Table 103. Elexacaftor Population Pharmacokinetic Final Model Parameter Estimates for Healthy Subjects (Left) and CF Subjects (Right) .......................................................................... 227 Table 104. Studies Included in Population PK Analysis .............................................................. 231 Table 105. Trial 102, Study Assessments: Treatment Period and Safety Follow-up Visit .......... 233 Table 106. Eligible CFTR Mutations, Trial 102 ............................................................................ 236 Table 107. Liver Function Test Values for Subject 102- ................................................ 237 Table 108. Liver Function Test Values for Subject 102- ................................................ 237 Table 109. Summary of Respiratory-related Adverse Events: Trial 102, Safety Set ................... 238 Table 110. Study Assessments, Trial 103 .................................................................................... 238 Table 111. Respiratory-related Adverse Events, Trial 103, Safety Set ....................................... 241 Table 112. Study 105 Schedule of Assessments ......................................................................... 241


(b) (6)

(b) (6)


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Table of Figures

Figure 1. Dosing Recommendations for Patients 12 Years and Older .......................................... 54 Figure 2. Molecular Structure of Elexacaftor, Tezacaftor and Ivacaftor ...................................... 57 Figure 3. Covariate Effect on Steady State ELX Exposure Based on Post Hoc Analysis in Patients Who Provided PK Data in the ELX popPK Dataset. ....................................................................... 67 Figure 4. ELX (VX-445) and M23-445 Exposure (AUC0-24h) in Adult and Adolescent Patients with Cystic Fibrosis in Phase 3 Studies (Studies 102 and 103) ............................................................. 68 Figure 5. Design of Trial 102 ......................................................................................................... 80 Figure 6. MMRM Analysis of Absolute Change from Baseline in ppFEV1 (%) by Visit (FAS, Trial 102) ............................................................................................................................................... 98 Figure 7. Absolute Change from Baseline in SwCl by Visit, Trial 102 (FAS) ................................ 101 Figure 8. Absolute Change from Baseline in CFQ-R RD Score by Visit, Trial 102 (FAS) .............. 102 Figure 9. Absolute Change from Baseline in BMI by Visit, Trial 102 (FAS) ................................. 103 Figure 10. MMRM Analysis of Absolute Change from Baseline in FEV1 by Visit (FAS, Trial 102)..................................................................................................................................................... 104 Figure 11. Least Squares Mean Difference Between Treatments With 95% CI for Change From Baseline in ppFEV1 at Week 4 by Subgroup (iFAS, Trial 102) ..................................................... 105 Figure 12. Least Squares Mean Difference Between Treatments With 95% CI for Change From Baseline in ppFEV1 at Week 4 by Subgroup Using Bayesian Shrinkage Subgroup Analysis (iFAS, Trial 102) ..................................................................................................................................... 107 Figure 13. Design of Trial 103 ..................................................................................................... 109 Figure 14. Least Squares Mean Difference Between Treatments With 95% CI for Change From Baseline in ppFEV1 at Week 4 by Subgroup (FAS, Trial 103) ...................................................... 118 Figure 15. Least Squares Mean Difference Between Treatments With 95% CI for Change From Baseline in ppFEV1 at Week 4 by Subgroup Using Bayesian Shrinkage Subgroup Analysis (FAS, Trial 103) ..................................................................................................................................... 119 Figure 16. Study Design, Open Label Extension Study 105 ........................................................ 150 Figure 17. Mean (±SD) Cumulative Percent of Radioactive Dose Recovered in Urine and Feces at Specified Intervals After a Single 200-mg (200-μCi) Oral Dose of 14C-VX-445 to Healthy Male Subjects ....................................................................................................................................... 184 Figure 18. Mean Concentration-Time Profiles of Unchanged VX-445 and M23-445 in Plasma and Total Radioactivity in Plasma and Whole Blood at Semi-Log (Lower) Scales ............................. 185 Figure 19. Mean VX-445 Plasma Concentration-Time Profiles Following Single Dose Administration of VX-445, Part A (Log-linear Scale) ................................................................... 191 Figure 20. Mean VX-445 Plasma Concentration-Time Profiles on Day 10 Following Multiple Oral Doses for 10 Days, Part B (Log-linear) ........................................................................................ 193 Figure 21. Mean VX-445 Trough Plasma Concentration-Time Profiles Following Multiple Oral Doses for 10 Days (Part B) and 14 Days (Part C) ......................................................................... 194 Figure 22. Mean VX-445 Plasma Concentration Versus Time After Therapeutic (200 mg qd) and Supratherapeutic (400 mg qd) Doses of VX-445 for 7 Days ....................................................... 199 Figure 23. VX18-445-006 Part A Study Design ............................................................................ 200



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Figure 24. Study Design Scheme ................................................................................................. 202 Figure 25. Mean EE Plasma Concentration Time Profiles After Administration of LN/EE Alone (Day 21) and After LN/EE+VX-445 TC (Day 31) ........................................................................... 203 Figure 26. Mean LN Plasma Concentration Time Profiles After Administration of LN/EE Alone (Day 21) and After LN/EE+VX-445 TC (Day 31) ........................................................................... 204 Figure 27. Simulated and Observed VX-445 PK Parameters (A) Cmax (B) AUC of SAD and MAD Studies ......................................................................................................................................... 215 Figure 28. Concentration-Response Graphs in F508del/F508del and F508del/MF HBE Cells Treated With ELX, TEX, and/or IVA. Data Shown as Mean ± Sem, and Handled Using Naïve Pooling Approach Without Accounting for Donor or Recording Plate Differences ................... 221 Figure 29. Comparison of TEZ Exposure in the Presence or Absence of ELX From the F/F Triple Combination Cohort ................................................................................................................... 228 Figure 30. Comparison of IVA Exposure in the Presence or Absence of ELX from the F/F Triple Combination Cohort. .................................................................................................................. 229 Figure 31. Dose-Response Simulations for ppFEV1 .................................................................... 230 Figure 32. Dose-Response Simulations for Sweat Chloride ........................................................ 230



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Reviewers of Multi-Disciplinary Review and Evaluation

Regulatory Project Manager Angela Ramsey Nonclinical Reviewer Dong Zhao, PhD, DABT Nonclinical Supervisor Andrew Goodwin, PhD Nonclinical ODE Associate Director Timothy McGovern, PhD Division of Clinical Pharmacology 2 Reviewer Jianmeng Chen, MD, PhD Division of Clinical Pharmacology 2 Team Leader Bhawana (Bavna) Saluja, PhD Division of Pharmacometrics Reviewer Junshan Qiu Division of Pharmacometrics Team Leader Jingyu (Jerry) Yu, PhD Genomics and Targeted Therapies Reviewer Hobart Rogers Genomics and Targeted Therapies Team Leader Christian Grimstein PBPK Reviewer Xinyuan Zhang, PhD PBPK Team Leader Yuching Yang, PhD DARS Reviewer Wendy Wu, PhD DARS Team Leader James Weaver, PhD Clinical Reviewer Courtney McGuire, MD Clinical Team Leader Stacy Chin, MD Statistical Reviewer Mingyu Xi, PhD Statistical Team Leader Yongman Kim, PhD Cross-Disciplinary Team Leader Stacy Chin, MD Division Director (OCP) Chandrahas Sahajwalla Division Director (OB) Mark Rothmann, PhD Division Director (DPARP) Sally Seymour, MD Office Director (ODE II) Mary Thanh-Hai, MD



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Additional Reviewers of Application OPQ RBPM Florence Aisida Co-Application Technical Lead (ATL) Craig Bertha Emerging Technologies Team (ETT) Lead and co-ATL Sharmista Chatterjee Drug Substance Reviewer (primary) Paresma Patel Drug Substance Reviewer (secondary) Donna Christner Drug Product Reviewer (primary) Venkateswara Pavuluri Drug Product Reviewer (secondary) Julia C. Pinto CMC Branch Chief Julia C. Pinto Primary Manufacturing Assessor Pratibha Bhat Secondary Manufacturing Assessor Yong Hu Process Analytical Technology Assessor Hong Yang Biopharmaceutics Reviewer (primary) Kalpana Paudel Biopharmaceutics Reviewer (secondary) Haritha Mandula Biopharmaceutics Reviewer (tertiary) Sandra Suarez ORA Lead Zhihao Peter Qui OPDP Kyle Snyder OSE/DMEPA Lissa Owens, Idalia Rychlik, Michael

Sinks DMPP Maria Nguyen DRISK Robert Pratt

OB=Office of Biostatistics OCP=Office of Clinical Pharmacology ODE 2=Office of Drug Evaluation 2 OPQ=Office of Pharmaceutical Quality OPDP=Office of Prescription Drug Promotion OSI=Office of Scientific Investigations OSE= Office of Surveillance and Epidemiology DEPI= Division of Epidemiology DMEPA=Division of Medication Error Prevention and Analysis DPARP=Division of Pulmonary Allergy and Rheumatology Products DRISK=Division of Risk Management



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Signatures

DISCIPLINE REVIEWER OFFICE/DIVISION SECTIONS AUTHORED/ APPROVED

AUTHORED/ APPROVED

Nonclinical Reviewer

Dong Zhao OND/ODE2/DPARP Sections: 5, 15.2

Select one: _X_ Authored

___ Approved

Signature:

Nonclinical Supervisor

Andrew Goodwin OND/ODE2/DPARP Sections: 5, 15.2

Select one: _X__ Authored

_X__ Approved

Signature:

Nonclinical Tertiary Reviewer

Timothy McGovern OND/IO Sections: 5, 15.2

Select one: ___ Authored

_X_ Approved Signature:

Clinical Pharmacology Reviewer

Jianmeng Chen OTS/OCP/DCP II Sections: 6, OCP appendices 15.3.1

Select one: X Authored

___ Approved

Signature:



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AUTHORED/ APPROVED

Clinical Pharmacology Team Leader

Bavna Saluja OTS/OCP/DCP II Section: 6, OCP appendices 15.3


_ X_ Approved Signature:

Pharmacometrics Reviewer

Junshan Qiu OTS/OCP/DPM Section: OCP appendices 15.3.4


___ Approved

Signature:

Pharmacometrics Team Leader

Jerry Yu OTS/OCP/DPM Section: OCP appendices 15.3.4


___ Approved

Signature:

Physiologically Based Pharmacokinetic (PBPK) Modeling Reviewer

Xinyuan Zhang OTS/OCP/DPM Section: OCP appendices 15.3.2

Select one: X Authored

___ Approved

Signature:

PBPK Modeling Team Leader

Yuching Yang OTS/OCP/DPM Section: OCP appendices 15.3.2


_ X Approved

Signature:

Division of Applied Regulatory Science (DARS) Reviewer

Wendy Wu OTS/OCP/DARS Section: OCP appendices 15.3.3

Select one: _X__Authored

Approved

Signature:



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Division of Applied Regulatory Science (DARS) Reviewer

James Weaver OTS/OCP/DARS Section: OCP appendices 15.3.3

Select one: _X_ Authored

Approved

Signature:

Division Director (OCP)

Chandrahas Sahajwalla OTS/OCP/DCP II Section: 6, OCP

appendices 15.3


_X_ Approved

Signature:

Clinical Reviewer

Courtney McGuire, MD OND/ODE2/DPARP

Sections: 1, 2, 3, 4, 7, 8, 9, 10, 11, 12, 13, Appendices 15.1, 15.4

Select one: x_ Authored

___ Approved

Signature:



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AUTHORED/ APPROVED

Clinical Team Leader / CDTL

Stacy Chin, MD OND/ODE2/DPARP Sections: 1-13, Appendix 15


_X__Approved

Signature:

Division Director (Clinical)

Sally Seymour, MD OND/ODE2/DPARP

Section: 14 Sections: All

Select one: _X__ Authored

__X_ Approved Signature:

Statistical Reviewer

Mingyu Xi, PhD OTS/OB/DBII Sections: 8

Select one: _x_ Authored

___ Approved

Signature:

Statistical Team Leader

Yongman Kim, PhD OTS/OB/DBII Sections: 8


_x__ Approved

Signature:

Division Director (OB)

Mark Rothmann, PhD

OTS/OB/DBII Sections: 8


_ X_ Approved

Signature:

Office Director (ODE2)

Mary Thahn-Hai OND/ODE2 Sections: All


_X__ Approved

Signature:



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Glossary

ADME absorption, distribution, metabolism, excretion AE adverse event AESI adverse events of special interest ALP alkaline phosphatase ALT alanine transaminase AR adverse reaction AST aspartate transaminase BA bioavailability BMI body mass index CFR Code of Federal Regulations CFTR cystic fibrosis transmembrane conductance regulator CFQ-R RD Cystic Fibrosis Questionnaire-Revised Respiratory Domain CK creatinine kinase CMC chemistry, manufacturing, and controls CSR clinical study report DDI drug-drug interaction ECG electrocardiogram EE ethinyl estradiol EFD embryo-fetal development ELX elexacaftor ELX/TEZ/IVA elexacaftor/tezacaftor/ivacaftor FDA Food and Drug Administration FDC fixed-dose combination GGT gamma-glutamyl transferase HBE human bronchial epithelial IA interim analysis ICH International Conference on Harmonisation IND Investigational New Drug INR international normalized ratio IPD important protocol deviation IVA ivacaftor LFT liver function test LUM/IVA lumacaftor/ivacaftor MMRM model for repeated measures MedDRA Medical Dictionary for Regulatory Activities NDA new drug application NOAEL no observed adverse effect levels PBPK physiologically based pharmacokinetic PD pharmacodynamics PI prescribing information



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PK pharmacokinetics PMC postmarketing commitment PMR postmarketing requirement PREA Pediatric Research Equity Act QD once a day REMS risk evaluation and mitigation strategy SAE serious adverse event SAP statistical analysis plan SBP systolic blood pressure SOC System Organ Class SwCl sweat chloride TEAE treatment emergent adverse event TE treatment emergent TEZ tezacaftor TEZ/IVA tezacaftor/ivacaftor TRA total radioactivity WB western blot



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1 Executive Summary

1.1 Product Introduction

The Applicant, Vertex Pharmaceuticals Incorporated (Vertex) submitted a 505(b)(1) New Drug Application (NDA) for TRIKAFTA (elexacaftor (ELX)/tezacaftor(TEZ)/ivacaftor(IVA)) combination therapy for the treatment of cystic fibrosis (CF) in patients 12 years of age and older who have at least one deletion of phenylalanine 508 mutation (F508del) in the CF transmembrane conductance regulator gene (CFTR). IVA monotherapy (Kalydeco) was first approved for the treatment of CF patients with a G551D mutation in the CFTR gene on January 31, 2012. The indication was expanded over time to include treatment of CF in patients aged 2 years and older who have one mutation in the CFTR gene that is responsive to IVA based on clinical and/or in vitro assay data. A combination product consisting of IVA and a second CFTR modulator, tezacaftor (TEZ/IVA, trade name Symdeko) was approved on February 5, 2018 for the treatment of CF patients 12 years and older who are homozygous for the F508del mutation or who have at least one mutation in the CFTR gene that is responsive to TEZ/IVA based on in vitro data and/or clinical evidence. The indication was expanded to include treatment of CF in patients aged 6 and older on June 21, 2019. While approved CFTR modulator therapies exist for CF patients who have homozygous F508del mutations, “gating” mutations, and “residual function” mutations in the CFTR gene, there are no approved CFTR modulators for patients with “minimal function” (MF) mutations, defined as class I mutations resulting in no to minimal amounts of CFTR protein or mutations lacking an in vitro response to available therapies. Neither IVA nor TEZ/IVA demonstrated efficacy in CF patients heterozygous for F508del and a MF mutation. For this application, the Applicant combined TEZ/IVA with a different CFTR modulator, ELX, for the purpose of increasing the delivery and amount of functional CFTR protein at the cell surface, resulting in enhanced chloride ion transport.

1.1 Conclusions on the Substantial Evidence of Effectiveness

The recommended regulatory action is approval for orally administered elexacaftor 200 mg/tezacaftor 100mg/ivacaftor 150 mg qAM and ivacaftor 150 mg qPM1 for the treatment of CF patients aged 12 years and older with at least one F508del mutation. To support ELX/TEZ/IVA for this indication, the Applicant completed two phase 3 efficacy and safety trials in two different CFTR mutation populations. These trials demonstrated substantial evidence of efficacy for ELX/TEZ/IVA in CF patients who are heterozygous for the F508del mutation and a second MF2 mutation (Trial 102), and in those who are homozygous for the 1 Hereafter, referred to as ELX/TEZ/IVA. 2 This subpopulation includes patients heterozygous for F508del and a second CFTR mutation that make either no CFTR protein (i.e., class I mutation) or for which in vitro data suggest the CFTR protein is not responsive to present therapies (i.e., IVA and TEZ/IVA). For purpose of this application, the Applicant grouped these patients into the category “minimal function.”



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F508del mutation (Trial 103). The determination of efficacy was primarily based on a clinically and statistically significant improvement in the primary endpoint of absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) and supported by key secondary endpoints showing benefits in the Cystic Fibrosis Questionnaire-Revised Respiratory Domain (CFQ-R RD) score, body mass index (BMI), sweat chloride (SwCl) and reduction in number of pulmonary exacerbations (PEx). Clinical data demonstrated that ELX/TEZ/IVA was superior to TEZ/IVA (F/F population, Trial 103), supporting the added benefit of ELX to ELX/TEZ/IVA. Evaluation of in vitro data from western blot (WB) and Ussing chamber electrophysiology experiments show greater activity for the triple drug combination, ELX/TEZ/IVA, compared to the monocomponents and dual combinations.



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1.1. Benefit-Risk Assessment

Benefit-Risk Summary and Assessment CF is a rare, progressive, usually fatal autosomal recessive genetic disease. While approximately 2000 disease-causing mutations in the CFTR gene have been identified, most CF patients in the United States carry at least one allele with the F508del CFTR mutation.3 Three other approved therapies exist for the proposed subpopulation of CF patients who are either homozygous for F508del or heterozygous for F508del and a second missense or noncanonical splice mutation allele predicted to be responsive to TEZ/IVA therapy. However, there are no approved therapies for certain subpopulations of CF patients that are heterozygous for F508del. The Applicant evaluated the efficacy and safety of ELX/TEZ/IVA in two adequate and well-controlled phase 3 trials in two CFTR mutation subgroup populations. In CF patients with F508del and a second MF mutation, 24 weeks of ELX/TEZ/IVA treatment as compared to placebo resulted in clinically and statistically significant improvements in ppFEV1, CFQ-R RD score (a well-established disease-specific quality of life measure), SwCl and BMI, as well as reduction in number of PEx. In F508del homozygous (F/F) patients, ELX/TEZ/IVA treatment for 4 weeks versus TEZ/IVA resulted in clinically and statistically significant improvements in ppFEV1, SwCl, and CFQ-R RD scores. In addition to clinical data, in vitro assay data in human bronchial epithelial (HBE) cells showed greater chloride transport activity for the triple combination (ELX/TEZ/IVA) versus the dual combinations (ELX/TEZ, ELX/IVA and TEZ/IVA). The assessment of safety focused on known safety risks associated with IVA and TEZ/IVA therapy , including liver function test (LFT) elevations, creatine kinase (CK) elevation, rash, increased blood pressure, and cataracts. No safety issues arose with the addition of ELX that offset the efficacy benefits provided by the ELX/TEZ/IVA combination. The potential safety risks identified with ELX/TEZ/IVA may be managed through labeling. In general, efficacy and safety results across various demographic and baseline disease characteristic subgroups were consistent with the overall findings. The review recommends approval of ELX/TEZ/IVA for the treatment of CF patients aged 12 years and older who have at least one F508del mutation. Efficacy data in the F/F and the F/MF populations, including CF patients with CFTR mutations that make no functional CFTR protein (i.e. Class I mutations), support the proposed indication. While the ELX/TEZ/IVA clinical program did not specially evaluate all mutations covered under the broader indication of “CF with at least one F508del mutation”, the Agency expects a similar treatment benefit for other CF mutations not studied in this program (e.g. patients heterozygous for F508del and a second gating/residual function mutation). The premise for

3 United States Cystic Fibrosis Foundation, Johns Hopkins University, The Hospital for Sick Children, The Clinical and Functional Translation of CFTR (CFTR2). Accessed at http://cftr2.org on September 6, 2019


(b) (4)


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this expectation is that the safety and effectiveness of IVA monotherapy and/or TEZ/IVA combination therapy have been demonstrated in clinical trials of other mutations (e.g., gating, residual function). Barring evidence to suggest that ELX interacts with TEZ or IVA to reduce efficacy or alter safety, the triple combination should also be safe and effective in these subpopulations. However, to provide additional clinical efficacy data that may be used to inform prescribers, the review team recommends a post-marketing commitment (PMC) to evaluate the efficacy of ELX/TEZ/IVA in CF patients heterozygous for F508del and a second gating/residual function mutation. In addition, the review team recommends a PMC for the ongoing open-label extension (Study 105) to provide additional long-term safety data. No safety concerns were identified that should preclude approval or require a REMS. The combination rule has been addressed through clinical trial data demonstrating the added benefit of ELX to the TEZ/IVA combination in this program, and the contribution of TEZ to TEZ/IVA was previously demonstrated in the TEZ/IVA development program. While the clinical trials did not include an ELX/IVA treatment arm to assess the contribution of TEZ to the triple combination, in vitro data from a well-established assay in HBE cells showed increased chloride transport of the triple combination compared to each of the monocomponents and dual combinations.

Dimension Evidence and Uncertainties Conclusions and Reasons

Analysis of Condition

• CF is a rare, progressive, and usually fatal autosomal recessive genetic disease that affects approximately 30,000 children and adults in the United States. CF results from mutations to the CFTR gene that lead to decreased or dysfunctional CFTR protein which aids in the regulation of salt and water absorption and secretion throughout the body. Lack of properly functioning CFTR causes the clinical sequelae of CF disease: malabsorption of nutrients, inability to mobilize tenacious respiratory secretions, recurrent pulmonary infection, irreversible lung damage, and ultimately respiratory failure. The median age of survival for a patient with CF is in the mid-to-late 30’s.

• The most common CFTR mutation is F508del – in the United States, approximately 86% of CF patients carry at least one allele and 45.3% are homozygous (carry two alleles).

• However, over 2,000 different disease-causing mutations in the CFTR gene have been identified.

CF is a rare, progressive, and usually fatal genetic disease. The CFTR mutation included in the proposed indication represents most patients with CF in the United States.



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Current Treatment

Options

• While no cure exists, there are three approved CFTR modulator therapies aimed at the cause of CF (i.e., absent or defective CFTR ion channel at the cell surface) in a subset of CF patients with the following mutations in the CFTR gene:

o Gating mutations (e.g., G551D, S549N) o Conduction mutations (e.g., D1152H, R117H) o F508del/F508del homozygous mutations o Missense or non-canonical splice mutations predicted to be

responsive based on clinical and/or in vitro assay data • However, there remain subpopulations of CF patients possessing

mutations for which there are no approved CFTR modulator therapies.

• Other medications are used to treat the signs and symptoms of CF, but not the underlying cause of CF.

There is an unmet medical need in those subpopulations not covered by any existing CFTR modulator therapy. While there are three approved therapies for specific subpopulations of CF patients, the treatment effect in some mutations (e.g. homozygous F508del) are modest. In these populations, there remains an unmet medical need for treatment options that may afford a greater treatment effect.

Benefit

• The Applicant demonstrated substantial evidence of efficacy for the ELX/TEZ/IVA combination in CF patients who have at least one F508del mutation clinical trials evaluating improvement in lung function (change from baseline in ppFEV1), and other clinically meaningful endpoints such as pulmonary exacerbation rate, CFQ-R RD and BMI.

• In the study evaluating CF patients heterozygous for F508del and a second MF mutation (Trial 102), clinical data demonstrated that ELX/TEZ/IVA was superior to placebo with respect to change from baseline in ppFEV1 as well as all key secondary endpoints inclusive of improvement in CFQ-R RD score, SwCl, reduction in number in PEx, and increase in BMI. Historical data from a previously conducted trial in the MF population evaluating TEZ/IVA vs placebo showed minimal treatment response and was terminated early for

ELX/TEZ/IVA provides a clinically relevant, robust treatment benefit in CF patients with at least one F508del CFTR mutation. While the clinical program did not include a full factorial evaluation of the combination product, the totality of clinical data from this program as well as IVA and TEZ/IVA programs and in vitro data support the contribution of each component to the triple combination product. ELX/TEZ/IVA addresses an unmet medical need for a rare, life-threatening orphan disease by providing a new therapeutic option for a number of patients with mutations not covered by approved CFTR modulators and a



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futility, and thus supports the added benefit of ELX to the combination.

• In the study evaluating patients homozygous for the F508del mutation (Trial 103), clinical data demonstrated that ELX/TEZ/IVA was superior to TEZ/IVA with respect to change from baseline in ppFEV1, SwCl, as well as CFQ-R RD score. Data from this trial also demonstrates the contribution of ELX to the TEZ/IVA combination.

• While neither trial evaluated the dual combination of ELX/IVA, the in vitro data from WB and Ussing chamber electrophysiology experiments showed greater activity for the triple drug combination versus the monocomponents and dual combinations.

more effective treatment option for F508del homozygous patients, who represent the majority of CF patients.

Risk and Risk Management

• The safety program for ELX/TEZ/IVA demonstrated potential risks that have been associated with IVA monotherapy, TEZ/IVA dual therapy, and/or other CFTR modulators: LFT elevation, drug-drug interactions, and increased blood pressure.

• Cataracts are a potential risk identified with the IVA monotherapy • The ELX/TEZ/IVA combination demonstrated new safety signals of CK

elevation and rash. • No REMS is proposed.

The potential risks of LFT elevation, rash, CK elevation, cataracts, increased blood pressure, and drug-drug interactions can be managed through labeling and routine pharmacovigilance; a REMS is not required. No substantial safety findings were identified in the clinical development program that outweigh the potential benefit.



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1.2 Patient Experience Data

Patient Experience Data Relevant to this Application (check all that apply) X The patient experience data that were submitted as part of the

application include: Section of review where discussed, if applicable

X Clinical outcome assessment (COA) data, such as

X Patient reported outcome (PRO) 8.1.1, 8.1.2, 8.2.6 □ Observer reported outcome (ObsRO) □ Clinician reported outcome (ClinRO) □ Performance outcome (PerfO) □ Qualitative studies (e.g., individual patient/caregiver

interviews, focus group interviews, expert interviews, Delphi Panel, etc.)

□ Patient-focused drug development or other stakeholder meeting summary reports

□ Observational survey studies designed to capture patient experience data

□ Natural history studies □ Patient preference studies (e.g., submitted studies or

scientific publications)

x Other: (Please specify): Cystic Fibrosis Foundation Patient

Registry, Annual Data Report 2017

x Patient experience data that were not submitted in the application, but were considered in this review:

x Input informed from participation in meetings with patient stakeholders

□ Patient-focused drug development or other stakeholder meeting summary reports

□ Observational survey studies designed to capture patient experience data

x Other: (Please specify): Cystic Fibrosis Foundation

□ Patient experience data was not submitted as part of this application.



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2 Therapeutic Context

2.1 Analysis of Condition

CF is an autosomal recessive, progressive, and usually fatal genetic disease most common in the Caucasian population. In the United States, CF is an orphan disease which occurs in approximately one out of every 3,500 children born and affects roughly 30,000 children and adults. CF results from mutations in the CFTR gene that lead to decreased or dysfunctional CFTR protein which aids in the regulation of salt and water absorption and secretion throughout the body. Lack of properly functioning CFTR ion channel is responsible for the clinical sequelae of CF, including malabsorption of nutrients, and the presence of tenacious respiratory secretions. Tenacious secretions are difficult to mobilize, leading to recurrent/chronic pneumonia, progressive lung damage, and ultimately respiratory failure which is the primary cause of death. Over 2,000 different mutations in the CFTR gene have been identified, though not all are associated with disease causation.4 The most prevalent CF-causing mutation is F508del; in the US Cystic Fibrosis Foundation Patient Registry, approximately 86% of CF patients carry at least one allele and 45.3% are homozygous for F508del (F/F). Historically, CFTR mutations have been categorized according to their functional impact on CFTR protein synthesis or function:

Table 1. CFTR Mutation Classes Class Description Prevalence1 Class I (protein production mutations) No functional CFTR created 22%

Class II (protein processing mutations)

CFTR protein created, but misfolded, keeping it from reaching the cell surface 88%

Class III (gating mutations)

CFTR protein created and reaches cell surface, but does not function properly 6%

Class IV (conduction mutations)

Opening in CFTR protein ion channel is faulty 6%

Class V (insufficient protein mutations)

CFTR created in insufficient quantities. 5%

1 Percent of people with CF who have at least one mutation in that class. Source. Adapted from https://www.cff.org/What-is-CF/Genetics/Types-of-CFTR-Mutations/ and https://www.cff.org/What-is-CF/Genetics/Types-of-CFTR-Mutations/. Accessed on September 6, 2019. This classification system can help understand the CFTR protein and potential disease severity, but may be oversimplified. While not widely adapted, there is increasing interest in classifying mutations according to response to available therapies.5 4 United States Cystic Fibrosis Foundation, Johns Hopkins University, The Hospital for Sick Children, The Clinical and Functional Translation of CFTR (CFTR2). Accessed at http://cftr2.org on September 6, 2019 5 Cystic Fibrosis Foundation Patient Registry 2017 Annual Data Report



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There is no cure for CF and, except for mutation-based subpopulations demonstrated to be responsive to IVA, lumacaftor (LUM)/IVA, or TEZ/IVA, treatment is limited to alleviation of symptoms and treatment of complications. Over the past several decades, life expectancy among patients with CF has increased with improved care. However, it remains well below the national average with the median predicted age of survival in the mid-forties.5 Current therapies used by patients with CF to help manage their disease are listed in Table 2 below.

2.2 Analysis of Current Treatment Options

Medications used to treat CF include drugs targeting the symptoms and sequelae of disease as well as those directed at the cause of CF, i.e. CFTR modulators. The FDA-approved CFTR modulators are only available for a subset of CFTR mutation subpopulations covered in the proposed indication. Table 2 summarizes the current treatment armamentarium for CF patients.

Table 2. Treatment Armamentarium Relevant to Proposed CF Indication Active Ingredient Trade Name FDA-approved for CF Indication? CFTR modulator Ivacaftor Kalydeco Yes: one mutation in the CFTR gene that

is responsive to ivacaftor potentiation based on clinical and/or in vitro assay

a Lumacaftor/Ivacaftor Orkambi Yes: F508del homozygous mutations Tezacaftor/Ivacaftor Symdeko Yes: F508del homozygous mutations and

one mutation in the CFTR gene that is responsive to ivacaftor potentiation based on clinical and/or in vitro assayb

Inhaled Antibiotics for the Treatment of Pseudomonas aeruginosa Tobramycin (nebulized) TOBI Yes Tobramycin (dry powder) TIP Yes Aztreonam (nebulized) Cayston Yes Polymyxin E (IV form given via nebulizer)

Colistin

No

Inhaled Treatments used as Mucolytics Dornase alpha (DNase) Pulmozyme Yes Hypertonic Saline (7%) ---- No Oral Pancreatic Enzyme Supplementation Pancrease, pancrelipase Creon, Pancreaze,

Zenpep, Pancrelipase, Pertzye, Viokace, Ultresa

Yes

Inhaled Bronchodilators Albuterol sulfate Pro-Air, Ventolin,

Proventil, Albuterol, etc. Approved as bronchodilator

Levalbuterol hydrochloride Xopenex Approved as bronchodilator



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Active Ingredient Trade Name FDA-approved for CF Indication? Anti-Inflammatory Agents Oral azithromycin Zithromax No Oral high-dose Ibuprofen Motrin, Advil, etc. No

a Includes E56K, P67L, R74W, D110E, D110H, R117C, R117H, G178R, E193K, L206W, R347H, R352Q, A455E, S549N, S549R, G551D, G551S, D579G, 711+3A→G, E831X, S945L, S977F, F1052V, K1060T, A1067T, G1069R, R1070Q, R1070W, F1074L, D1152H, G1244E, S1251N, S1255P, D1270N. G1349D, 2789+5G→A, 3272-26A→G, 3849+10kbC→T mutations b Includes E56K, R117C, A455E, S945L, R1070W, 3272-26A→G, P67L, E193K, F508del, S977F, F1074L, 3849+10kbC→T, R74W, L206W, D579G, F1052V, D1152H, D110E, R347H, 711+3A→G, K1060T, D1270N, D110H, R352Q, E831X, A1067T, 2789+5G→A mutations. F508del must be present in two copies or with at least one copy of these above-mentioned mutations to be indicated. Source: Approved labeling data from [email protected] (accessed on September 29, 2019)

3 Regulatory Background

3.1 U.S. Regulatory Actions and Marketing History

Neither ELX nor ELX/TEZ/IVA are approved nor marketed in the United States for any other indication. However, components of the proposed triple combination product (IVA monotherapy and IVA in combination with TEZ or LUM) are FDA-approved for the treatment of CF patients with specific CFTR mutations. Regulatory actions for related products also owned by the Applicant include:

Table 3. Approved CFTR Modulators for the Treatment of Cystic Fibrosis Drug CFTR population Age / Approval date TEZ/IVA (Symdeko®) NDA 210491

Homozygous F508del mutation Missense and splice mutationsa

• 12 years and old, 2/12/2018

• 6 to 11 years, 6/21/2019

LUM/IVA (Orkambi®) NDA 206038

Homozygous F508del mutation • 12 years and old, 7/2/2015

• 6 to 11 years, 9/28/2016

IVA (Kalydeco®) NDA 207925 and 203188

Gating and conduction mutationsb • 6 years and older, 1/31/2012

• 2 years to 6 years, 2/8/2017

• 12 months to 2 years, 8/15/2018

• 6 months to 12 months, 4/29/2019

a Referred to as “residual function” mutations in the development program and defined as responsive or predicted to be responsive to TEZ/IVA based on clinical and/or in vitro assay data b One mutation in the CFTR gene that is responsive to IVA based on clinical and/or in vitro assay data; includes some Class V mutations For complete list of indicated mutations refer to Table 1



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3.2 Summary of Presubmission/Submission Regulatory Activity

ELX and the ELX/TEZ/IVA combination was developed under Investigational New Drug (IND) 132,547, which was opened on December 12, 2016. ELX/TEZ/IVA was granted Fast Track Designation on February 8, 2017, Breakthrough Therapy Designation on May 15, 2018, Orphan Drug Designation (ODD 18-6476) on August 29, 2018, and Priority Review designation on August 14, 2019. A summary of topics related to the clinical development program that were discussed during key interactions between the Applicant and the FDA is provided below. Additional Chemistry Manufacturing and Controls (CMC) meetings between the Applicant and the FDA were held on separate occasions and are not included. November 28, 2017: Teleconference, Type B Phase 2 meeting

• Discussion of proposed efficacy and safety data to support an initial NDA in F/MF population.

• The Division stated that early timing of the efficacy assessment (at Week 4) and small size of safety database (both size and length of exposure) introduces regulatory risk. The adequacy of the safety database would be a review issue. To reduce regulatory risk, the Division recommended including additional safety data from other CF populations with the initial submission.

• A ppFEV1 endpoint would likely support a traditional approval program. • Agreement that additional safety data in other populations would be required to support a

broader indication. February 20, 2018: Type B, End of Phase 2 Meeting (IND 132547)

• Conceptually, the Division agreed with the proposed approach to submit the initial NDA for the more limited indication in the F/MF population prior to seeking a broader indication. However, the Division reiterated that the early timing of the primary efficacy analysis (i.e. Week 4) and abbreviated safety database introduce regulatory risk. For the supplemental application to support a broader indication, the Division recommended a development program more consistent with other approved CFTR modulators in terms of assessed efficacy endpoints, treatment duration, and safety database size.

• The Division recommended including a third treatment arm (ELX/IVA) to demonstrate the contribution of TEZ.

• The Division recommended against the use of SwCl as a primary endpoint in any study intended to support efficacy.

•

• For the triple combination, in vitro data may be used to support rare CFTR mutations that

were not directly evaluated in the clinical trial.


(b) (4)


30

June 6, 2018: Teleconference, Type B meeting

• The Division reiterated that a 4-week controlled treatment period in the proposed studies evaluating F/F and heterozygous F508del entails regulatory risk, and recommended a longer treatment period to assess additional clinically meaningful endpoints (i.e., exacerbations, BMI, and CFQ-R RD) and to provide a larger safety database. The Division recommended 1 year of exposure to support an expanded indication in additional patient populations (F/F, gating and residual function).

• In the F/MF population, the overall risk/benefit assessment will be a review issue that considers unmet need and availability of other therapies at the time of the initial NDA submission.

June 11, 2018: Request for Feedback

• The Division agreed to the submission of the 2-year rat carcinogenicity study with ELX as a Post-Marketing Requirement (PMR)

June 26, 2019: Type B, Pre-NDA meeting

• The proposed broad indication for at least one F508del mutation would be a review issue. • The Division requested justification for the contribution of the monocomponents to the

combination. • The Division does not anticipate an Advisory Committee meeting.

3.3 Foreign Regulatory Actions and Marketing History

Neither ELX nor ELX/TEZ/IVA are approved for marketing in any country outside the United States.


(b) (4)


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4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety

4.1 Office of Scientific Investigations (OSI)

Due to the Agency’s experience with the Applicant, including the recent approval of TEZ/IVA (Symdeko®) and quality of the datasets as judged by the clinical and statistical review teams, and the unmet medical need for the rare, life-threatening disease, Office of Scientific Investigations audits were deemed unnecessary for this submission. The small number of patients at each site made it unlikely that issues at any one site would substantially impact the efficacy or safety findings.

4.2 Product Quality

The drug product is a triple fixed-dose combination (FDC) immediate release (IR) tablet containing three drugs (VX-445 or elexacaftor or ELX, tezacaftor or TEZ, and ivacaftor or IVA). ELX is a new molecular entity, which is formulated with the previously approved tezacaftor/ivacaftor active pharmaceutical ingredients (APIs) that were in the double FDC Symdeko® Tablet drug product of NDA 210491. Tezacaftor is class II and ivacaftor is class II or IV as per the Biopharmaceutics Classification System (BCS), so they are both poorly soluble molecules. ELX is also poorly soluble and is class II or IV as per the BCS. As such, the physicochemical properties of the drugs/formulation components are important to control, as they potentially impact the bioavailability of each API. ELX is manufactured through Sufficient detail was provided outlining the control of input materials, reaction times, process parameters and in-process controls. Starting material specifications include sufficient impurity controls that are adequately justified to minimize any impact on the purity of the final drug substance. The Applicant provided adequate characterization data for the drug substance and specified impurities and sufficient data to demonstrate adequate control of potentially mutagenic impurities through the manufacturing process, as per ICH M7. The overall control strategy is based on the manufacturer’s process understanding gained during development, and includes specifications for starting materials, reagents, solvents, catalysts, and for the drug substance itself. Together, these provide sufficient controls for identity, purity, strength, and quality of elexacaftor API. Clinical and registration drug substance batch data were provided and all of these were within specification acceptance criteria. The long term and accelerated stability data provided show little or no changes to the quality attributes of elexacaftor, thus the proposed retest period of months is supported. As the current triple fixed-dose combination (FDC) tablet dosage form of ELX/TEZ/IVA is similar to the previously approved double FDC tablet dosage form containing TEZ/IVA (comparable formulation with analogous continuous manufacturing process), Vertex built on their knowledge of the double FDC tablet by the addition of the ELX NME that is added as


(b) (4)

(b) (4)

(b) (4)

(b) (4)


32

crystalline API. For the triple FDC, the stability studies revealed that degradation products formed were below the reporting threshold up to 6 months at accelerated (40°C/75% relative humidity [RH]) conditions and 12 months at long-term storage (25°C/60% RH) conditions, in blister packs proposed for commercialization, with no changes reported in physical form or chiral purity of the drugs. The Applicant provided data supporting their control strategy for elemental impurities in the drug product, following ICH Q3D. The Agency laboratory has found the method for assay and quantification of degradants in the drug product to be suitable for regulatory purposes. The stability data provided in the application support the proposed 24 month expiry for the FDC tablets when packaged in foil-foil blisters and stored at controlled room temperature. The review concluded that the three dissolution methods and associated acceptance criteria were acceptable considering that the Applicant has tightened the in-process acceptance criterion and has provided two post-marketing commitments (PMCs) regarding improvements to the control of both ELX and PSDs. The biopharmaceutics team (with input from the biostatistics team) did not agree with the Applicant’s

The ETT concluded that the process controls

currently proposed along with those to be implemented based on PMCs for ELX and PSDs, would be adequate in reducing manufacturing variation that could lead to variable drug dissolution. The Office of New Drug Products Division Director has considered these positions regarding and has concluded that the Applicant’s mitigation strategies for addressing factors potentially impacting drug dissolution and their understanding of and experience with approved continuous manufacturing processes and their controls, was acceptable as proposed by the Applicant. Furthermore, it was concluded that the clinical need and substantial benefit that this drug product will provide for CF patients, outweighs the risks of accepting the Applicant’s proposal. The drug product is manufactured using a continuous manufacturing (CM) process. During manufacturing, the applicant uses process analytical technology (PAT) for in-process control. Specifically,

The drug product is released based on more typical end-product testing for all pertinent parameters, as opposed to real-time-release testing, which Vertex has used for some previous applications that utilized CM.


(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)


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The Office of Process and Facilities has performed a pre-approval inspection of , a manufacturer of a starting material/intermediate of the ELX synthesis, as this site had not been inspected by the Agency previously. The Vertex, Boston drug product manufacturing site had been inspected recently for the approval of Symdeko of NDA 210491, a double FDC IR tablet that is similar to the current triple FDC IR tablet except that it does not contain ELX. Because of this, the shortened review period, and the high benefit/risk ratio, it was decided that post-approval inspection of Vertex, Boston would be an acceptable plan. In conclusion, all CMC sub-disciplines (API, drug product, process & facilities, and biopharmaceutics) recommend an Approval action for this NDA. Refer to the Integrated Quality Assessment in Panorama.

5 Nonclinical Pharmacology/Toxicology

5.1 Executive Summary

The Applicant has conducted a comprehensive program of pharmacology, pharmacokinetics (PK) and toxicology studies to support clinical development and the NDA submission. Nonclinical studies were conducted with either elexacaftor alone (to qualify the new drug component of TRIKAFTA) and/or elexacaftor combined with tezacaftor and ivacaftor (to assess the proposed triple combination). All pivotal toxicity studies have been submitted and reviewed previously under IND 132547. The key findings from the nonclinical studies are cited and summarized in this review to support the approval of NDA 212273. The pharmacological, pharmacokinetic, and absorption, distribution, metabolism and excretion (ADME) studies are reviewed in this review.

The Applicant has also assessed the pharmacological and toxicological profile of the major human metabolite of elexacaftor, M23-445. The safety qualification of M23-445 is also evaluated in this review.

Pharmacological studies demonstrated that elexacaftor binds to CFTR. Alone and in combination with tezacaftor and ivacaftor, elexacaftor facilitates processing and trafficking of CFTR leading to increased chloride transport in HBE cells collected from CF patients. Toxicological studies indicated that elexacaftor was negative in mutagenicity and clastogenicity tests, negative in teratogenicity and carcinogenicity assays (based on the 6-month study in mouse only; the 2-year carcinogenicity study in rat will be completed as a post-marketing requirement). Elexacaftor related toxicities were identified mainly in the gastrointestinal tract, comprised of ulceration/erosion in esophagus, stomach and/or duodenum, and in testis comprised of germ cell/seminiferous tubule degeneration. These findings were observed at plasma exposures around 7-fold in rats or >10-fold in dogs compared to the human exposure at the recommended dose. No additional toxicities were identified when combined with


(b) (4)


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tezacaftor and/or ivacaftor. To conclude, NDA 212273 is recommended for approval from the nonclinical perspective.

Throughout this section, study reports and associated discussion generally refer to elexacaftor as VX-445 or VX-1651445 and M23-445 as M23 or VRT-1654548.

The pharmacological and toxicological properties of ivacaftor, tezacaftor, and the ivacaftor-tezacaftor dual combination have been reviewed under previous NDAs and are not discussed extensively in this review.

5.2 Referenced NDAs, BLAs, DMFs

NDA 203188, Kalydeco (ivacaftor) tablets NDA 207925, Kalydeco (ivacaftor) granules NDA 206038, Orkambi (ivacaftor, lumacaftor) tablets NDA 210491, Symdeko (ivacaftor, tezacaftor) tablets NDA 211358, Orkambi (ivacaftor, lumacaftor) granules

5.3 Pharmacology

As listed in the following tables, multiple in vitro pharmacological studies have been conducted identifying the mechanism of action and activity of VX-445 (elexacaftor). As the activities of ivacaftor (IVA) and/or tezacaftor (TEZ) have been demonstrated in the previous applications listed in Section 5.2., the studies under the current submission addressed the contribution of VX-445 when administered alone and in combination with the other two molecules. None of the primary or secondary pharmacology studies were conducted in compliance with GLP. In the opinion of the nonclinical reviewer, this is a typical approach in drug research and does not affect the integrity of the application.

Primary Pharmacology

Primary Pharmacology Study Report Number Effect of VX-445 on chloride transport in bronchial epithelial cells isolated from CF donors homozygous or heterozygous for the F508del-CFTR mutation

M378

The effect of VX-445 on the processing and trafficking of F508del-CFTR in F508del-HBE cells

M379

Effect of VX-445 metabolite VRT-1654548 (M23) on chloride transport in F508del/3905insT-CFTR human bronchial epithelial cells

O084

Effects of VX-445 Alone and in Combination With TEZ and/or IVA on the Channel Gating Properties of F508del-CFTR

O232

Binding of VX-445 to CFTR alone and in combination with tezacaftor O377

In Study O377, the binding of VX-445 to a thermostable form of human CFTR (TS-CFTR) was measured by LC/MS/MS detection following separation of free compound from protein-bound compound by size exclusion chromatography (SEC). The results indicated that VX-445 binds to TS-CFTR with a Kd,apparent of 72 ± 47 nM, and TEZ binds to TS-CFTR with a Kd,apparent of 127 ± 59 nM. The binding of VX-445 is not disrupted in the presence of 500 nM TEZ binding, suggesting that VX-445 and TEZ are able to bind to TS-CFTR simultaneously at different binding sites.



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In Study O232, Fisher Rat Thyroid cells recombinantly expressing F508del-CFTR were treated with VX-445 (1 μM) either alone or in combination with 3 μM TEZ for 18-24 hours. Channel gating was determined in excised membrane patches in patch clamp experiments. VX-445-corrected channels showed a baseline open probability (Po) of 0.039 ± 0.033 after phosphorylation with PKA (75 nM), which remained unaffected by acute readdition of 1 μM VX-445 (Po = 0.049 ± 0.019). Potentiation with 1 μM IVA increased Po to 0.89 ± 0.019. When cells were corrected with 1 μM VX-445 in combination with 3 μM TEZ, baseline Po was 0.093 ± 0.049 which remained unchanged by acute readdition of VX-445/TEZ (Po = 0.113 ± 0.086). Further addition of IVA increased Po to 0.86 ± 0.024. These data suggested that both the VX-445-corrected and the VX-445/TEZ-corrected F508del-CFTR minimally improved gating defect compared to uncorrected F508del-CFTR (Po = 0.028 ± 0.031). However, subsequent addition of IVA improved F508del-CFTR gating to levels well above wild-type CFTR (Po = 0.46 ± 0.065).

Evidence indicated that VX-445 alone and in combination with IVA/TEZ promoted chloride transport (Study M378, by Ussing chamber electrophysiology) and CFTR protein processing and trafficking (Study M379, by WB) in HBE cells from CF donors with F508del-CFTR homozygous and compound heterozygous mutations. Those studies are reviewed in detail by OCP in Appendix 18.4.3. In addition, the results from Study O084 suggested that VRT-1654548, a major human metabolite (M23) of VX-445, when administered in combination with TEZ/IVA, could also enhance the chloride transport with close to 1/3 of activity (EC50, VRT1654548 = 0.44 μM) relative to that in parent molecule (VX-445, EC50, VX-445 = 0.16 μM ) in mutated HBE cells.

Secondary Pharmacology

Secondary Pharmacology Study Report Number The effect of VX-445 on misfolded proteins other than CFTR M402

Radioligand binding assays with VRT-1651445-1 VRT-1651445-TX-028

Radioligand binding assays with VRT-1651445-12 VRT-1651445-TX-029

Cellular and tissue assays of the activity of VRT-1651445-12 VRT-1651445-TX-030

Electrophysiological assays for activities on the ion channels using the Ion Flux HT electrophysiological platform

VRT-1651445-TX-031

In Study M402, 3 μM VX-445 was incubated with a few other mutated proteins including the G601S-human ether-a-go-go (G601S-hERG) cardiac K+ channel, G268V-P-glycoprotein (G268V-PgP), α1-antitrypsin Z (zAAT), N370S-β- glucosidase, and mutant HTT protein with a 145 glutamine expansion (mHTT Q145). These represent proteins that either utilize similar trafficking pathways as CFTR (G601S-hERG), are from the same superfamily as CFTR (G268V-Pgp), are other endoplasmic reticulum-arrested misfolded proteins (zAAT and N370S-β-glucosidase), or an unrelated protein that misfolds and forms nuclear and cytoplasmic aggregates (mHTT Q145). The results indicated that VX-445 did not facilitate the processing and trafficking, alter the immature form, or affect total protein levels of the those mutant proteins studied, suggesting that VX-445 selectively affects CFTR relative to other misfolded protein classes.

Ligand-binding assays and/or functional assays (Studies VRT-1651445-TX-028, -029, -030, and -031) of VX-445 with a panel of 179 proteins showed limited off-target binding at 10 μM. Follow-



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up functional studies conducted for a small number of hits demonstrated very low activities with IC50 in micro-molar ranges, suggesting low risk of off-target activities of VX-445 at the proposed clinical dose.

Safety Pharmacology

The following in vitro and in vivo safety pharmacology studies were conducted in compliance of GLP. All of the studies have been reviewed previously under IND 132547 (DARRTS Reference ID: 4040659).

Safety Pharmacology Study Report Number GLP Effects on hERG channel 0, 10, and 30 μM, IC50> 30 μM

VRT-1651445-TX-011 Yes

Effects on central nervous system in rats 0, 5, 15, or 30 mg/kg, PO, 10 females/group

VRT-1651445-TX-008 Yes

Effects on respiratory system in rats 0, 5, 15, or 30 mg/kg, PO, 8 females/group

VRT-1651445-TX-010 Yes

Effects on cardiovascular system in dogs 0, 10, and 50 mg/kg, PO

VRT-1651445-TX-002 No

Effects on cardiovascular system in dogs 0, 2, 12.5 and 25 mg/kg, PO

VRT-1651445-TX-009 Yes

In Study VRT-1651445-TX-011, VX-445 concentrations up to 30 μM were tested with patch clamp in HEK293 cells stably expressing the human ether-a-go-go-related gene (hERG) protein. VX-445 inhibited potassium hERG channel by only 31.2 ± 2.4% at 30 μM, suggesting a low risk for QT prolongation at clinical relevant plasma concentrations.

In studies VRT-1651445-TX-008 and VRT-1651445-TX-010, up to 30 mg/kg single dose of VX-445 showed no effect on the CNS or respiratory functions in rats.

In the single-dose, cardiovascular, telemetered-dog, non-GLP study (Study VRT-1651445-TX-002), a single dose of 50 mg/kg resulted in a decrease in blood pressure compared to vehicle-treated dogs. These changes included: decreases in systolic pressure of ~6 to 10 mmHg (5% to 7%) from 5 to 17 hours postdose, the peak decrease occurring between 7 to 8 hours postdose (~18 to 19 mmHg, 14%); relatively slight decreases in mean arterial pressure even at 7 to 8 hours postdose (~6 to 9 mmHg, 7% to 9%); and minimal to no decrease in diastolic pressure. The decreases in blood pressure were accompanied by increases in heart rate (up to ~11 to 13 beats/minute; 14% to 21%), heart rate-influenced decreases in electrocardiogram (ECG) intervals (i.e., RR, PR and uncorrected QT intervals), and decrease in QTc.

In the GLP cardiovascular study in telemetered dogs (Study VRT-1651445-TX-009), single dosing of VX-445 at 24.78 mg/kg did not result in any changes in body temperature, blood pressure, pulse pressure, heart rate, or ECGs. Therefore, the NOEL was determined to be 24.78 mg/kg. Additionally, there were no noteworthy cardiovascular and/or ECG changes recorded in the 7-day and 28-day repeat dosing studies in dogs with dose levels up to 50 mg/kg/day.



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5.4 ADME/PK

The Applicant has characterized the absorption, distribution, metabolism, excretion, and PK of VX-445 in a comprehensive program of studies in vitro using cells, subcellular fractions, and recombinantly expressed enzymes and transporters, and in vivo after single and multiple IV/PO doses of VX-445 administered to male and female animals. None of the studies were compliant with GLP regulations, but all were conducted in compliance with laboratory SOPs and current industry practice standards based on the relevant FDA Guidance recommendations. The results of the PK studies were consistent with those obtained from the GLP-compliant toxicology studies.

Absorption

The results of major absorption studies are summarized in the following table. The key absorption and PK results are summarized below:

• VX-445 as a moderate to highly permeable molecule, has good oral bioavailability in rats and dogs. Rat and dog were selected as the nonclinical species.

• VX-445 exposures tended to accumulate in the repeat dosing study. • There was no difference in exposure between sexes. • Systemic exposures to VX-445, TEZ, and IVA (and respective metabolites) in combination

studies in rats and dogs were similar to the exposures observed when these compounds were dosed individually (See Sections 5.5.3 and 5.5.4).

Type of Study Major Findings Absorption M262: PK of VRT-1651445 in Male Cynomolgus Monkeys following administration of single IV or oral dose (3 mg/kg)

IV AUC = 25.2 μg*hr/mL Bioavailability: 67.6% Volume of distribution: 0.302 L/kg Oral Tmax: 3.3 hours Oral t ½: 3.7 hours

M263: PK of VRT-1651445 in Male Beagle Dogs following administration of single IV or oral dose (3 mg/kg)

IV AUC = 236 μg*hr/mL Bioavailability: 87.7% Volume of distribution: 0.277 L/kg Oral Tmax: 4.7 hours Oral t ½: 12.3 hours

M128: Toxicokinetics of VRT-1651445 in Beagle Dogs Following Once Daily Oral Gavage Dosing for Seven Days 0, 2, 10, and 50 mg/kg/day; 2/sex/group

VX-445 exposure increased more than dose proportionally; The Day 7 AUC levels were higher than Day 1 with accumulation ratios ranging from 1.4 to 3; No sex difference in exposures.

M274: PK of VRT-1651445 in Male SD Rats following administration of single IV or oral dose (3 mg/kg)

IV AUC = 30.4 μg*hr/mL Bioavailability: 84.3% Volume of distribution: 0.622 L/kg Oral Tmax: 3.3 hours Oral t ½: 4.9 hours

M388: In Vitro Study to Assess the Passive Permeability of VRT- 1651445 and whether it is a Substrate of P-glycoprotein in MDCK cells and Caco-2 cells

VX-445 is a substrate for the efflux transporter P-glycoprotein (P-gp) and is classified as a moderately (in MDCK) or highly (in Caco-2) permeable compound



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Type of Study Major Findings N053: A 3-day PK of VX-445 in Female Long Evans rats by oral administration of VX-445 at 10, 25, and 100 mg/kg

VX-445 exposure increased dose-proportionally on Day 1 and more than dose-proportionally on Day 3; The Day 3 AUC levels were higher than Day 1

O286: Pharmacokinetics of VRT-1651445 Following Single Oral Administration in Fed and Fasted Male Beagle Dogs. 10 mg/kg

No food effect

O297: Pharmacokinetics of VRT-1651445 Following Intravenous Administration to Male CD-1 Mice. 2 mg/kg

AUC = 37.1 μg*hr/mL Volume of distribution = 0.317 L/kg

Distribution and Excretion

The results of the major VX-445 distribution studies are summarized in the following table. There is no significant species difference in plasma protein binding, tissue distribution, or excretion for VX-445. The key findings are listed below:

• VX-445 can cross the blood-brain barrier, placenta, and also be secreted through milk to some extent.

• VX-445 is mainly excreted through bile. • VX-445 and/or its active metabolite M23 are highly bound to rat, dog, monkey and

human plasma proteins (mainly serum albumin), in HBE media, and in liver microsomes. • VX-445 does not selectively partition into red blood cells.

Type of Study Major Findings Distribution 8385613: Placental Transfer, Tissue Distribution, and Lacteal Excretion of 14C-VX-445 Following Administration of a Single Oral Dose to Pregnant and Lactating Rats. 10 mg/kg, 100 μCi/kg, PO to female pregnant or lactating SD rats

VX-445 was widely distributed in all tissues. Tissues with the highest 14C-VX-445-derived radioactivity were the liver, adrenal gland, renal cortex, kidney, myocardium, stomach mucosa, and harderian gland; Tissues of the non-circumventricular central nervous system had quantifiable radioactivity, indicating 14C-VX-445-related radioactivity crossed the blood-brain barrier; 14C-VX-445-derived radioactivity was quantifiable through 48 hours postdose in fetus, suggesting the capability of VX-445 transfer across placenta. VX-445 could transfer to milk with a ratio of milk/plasma concentration = 36%

8385911: Radioanalysis in Support of Clinical Protocol VX18-445-003 (A Phase 1, Open-label, Mass Balance Study to Investigate the Absorption, Distribution, Metabolism, and Excretion of 14C-VX-445 Following Single Oral Administration in Healthy Subjects 200 mg (200-µCi)

Mean blood/plasma concentration ratios in human ranged from 0.581 to 0.723; Tmax = 6-12 hours 87.3% recovered in feces,

M253: Tissue Distribution of VRT-1651445 in Male Sprague Dawley Rats Following Oral Administration at 3, 10, 30 mg/kg

At Tmax, tissue to plasma ratios in brain, lung, heart, and kidney ranged from 0.185 to 1.37; liver to plasma ratios were 5.30, 4.18 and 2.88 at 3, 10 and 30 mg/kg, respectively



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Type of Study Major Findings M268: In Vitro Binding of VRT-1651445 to Proteins in Rat, Dog, Monkey, and Human Plasma

In rat, dog, monkey and human plasma, the binding of VX-445 to proteins were 99.68%, 99.51%, 99.33%, and 99.63%, respectively.

M275: In Vitro Blood:Plasma Partitioning of VRT-1651445 in Human

Blood:plasma ratio in human following in vitro incubation at 1 μM was 0.501

O062: In Vitro Binding of VRT-1651445 and its Metabolite VRT-1654548 to Plasma Proteins

The average VX-445 free fraction in mouse, rat, dog, monkey and human plasma was 0.00476, 0.00637, 0.00819, 0.0111 and 0.00704, respectively; corresponding VRT-1654548 (M23) free fraction was 0.00276, 0.00525, 0.00680, 0.00762 and 0.00405, respectively

O097: In Vitro Blood-Plasma Partitioning of VRT-1651445 in Rat, Dog, and Monkey

Blood : plasma ratio of VX-445 at 1µM was 0.581 for rat, 0.587 for dog, and 0.677 for monkey

O111: In Vitro Binding of VRT-1651445 To Liver Microsome Proteins

The average percent bound for VRT-1651445 in rat, dog, monkey and human liver microsomes was 81.7%, 74.8%, 80.8%, and 75.1%, respectively

O130: In Vitro Binding of VRT-1651445 and its metabolite VRT-1654548 To Proteins in HBE Medium Containing 20% Human Serum

The average percent bound value for VX-445 and M23 was 96.8% and 97.6% in HBE medium with 20% human serum, respectively

O131: In Vitro Binding of VRT-1651445 To Hepatocyte Proteins

The average percent bound for VX-445 ranged from 23.2% to 43.8% in hepatocytes across the species

RPT04494: Mass Balance and Biliary Excretion Following a Single Oral or Intravenous Dose of [14C]VRT-1651445 in Male Sprague Dawley Rats and Tissue Distribution Using Quantitative Whole Body Autoradiography (QWBA) Following a Single Oral Dose of [14C]VRT-1651445 in Male Long-Evans and Sprague Dawley Rats 3 mg/kg

The main route of excretion was through bile; The endocrine and metabolic/excretory tissues, as well as the tissues of the gastrointestinal tract contained the highest VX-445 distribution; VX-445 distribution did not preferentially associate with melanin

RPT04562: Human Dosimetry Prediction for Oral [14C]VRT-1651445

After administration of 100 µCi 14C-VX-445, the effective dose (ED) to the whole body was far below the single dose limit of 3000 mrem, therefore, dosing 14C-VX-445 around this dose is safe to human

Metabolism

The results of the major VX-445 metabolism studies are summarized in the following table. In summary, VX-445 after oral administration in all the species tested, was mainly oxidated by CYP3A4/CYP3A5 in liver. Its metabolic products were then excreted through bile. No human specific metabolite was identified. M23 was the major human metabolite in human, but its exposures in animals were generally lower than 10 %.

Type of Study Major Findings Metabolism M281: The In Vitro Stability of VRT-1651445 in Human Recombinant CYP Isozymes

CYP3A4 and CYP3A5 were likely to be the major isozymes involved in VX-445 metabolism



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Type of Study Major Findings M291: Characterization of VRT-1651445 Metabolites In Vitro in Human, Rat, Dog, and Monkey and In Vivo in Rat, Dog, and Monkey

CYP3A4/5 were the metabolic enzymes for VX-445 In vitro metabolite profiles were qualitatively similar across human, rat, dog, and monkey No human-specific metabolites were observed in vitro

O033: Characterization of VRT-1651445 Metabolites in Mouse and Human Liver Microsome

Metabolic pathways observed in human and mouse liver microsome: pyrrolidine methyl oxidation, left hand side methyl oxidation, pyrazole methyl oxidation, pyrazole oxidation, pyrazole N-demethylation, amide hydrolysis with pyrrolidine cyclization and pyrrolidine cyclization.

O241: Metabolic Stability of VRT-1651445 In Liver Microsomes From Human, Monkey, Dog, and Rat

The hepatic clearance values for VX-445 were monkey>human>rat>dog, but are all predicted to be low (<15% hepatic blood flow)

O229: Metabolite Profile and Identification of Metabolites in Plasma and Feces from Healthy Male Human Subjects after A Single Oral Administration of [14C]VX-445

M23 was identified as the major metabolite in human plasma (~17%)

O278: Metabolite Profile and Identification of Metabolites in Plasma, Bile, and Feces from Male Rats after A Single Oral or Intravenous Administration of [14C]VX-445

None of the circulating metabolite accounted for >10% of total exposure in rats

Drug-drug interaction

The effects of VX-445 on CYPs and transporters are summarized in the following table. The results are not always consistent among different studies. Most of the effects of VX-445 on CYPs and transporters are also noted with TEZ and IVA. The key findings are listed below:

• As CYP3A4/CYP3A5 are the major isozymes involved in VX-445 metabolism, co-administration of inhibitors or inducers of this enzyme with VX-445 may change the exposures of VX-445 and its metabolites.

• VX-445 at the clinically relevant concentrations may have low potential to cause DDIs via CYP inhibition,

• VX-445 and M23 are potentially weak inhibitors but unlikely to be the substrates for multiple efflux transporters including P-gp and OATP1B1/1B3. As VX-445 is highly permeable and has high oral bioavailability, its oral absorption is not expected to be limited by efflux transporters.

Type of Study Major Findings PK drug interaction M292: In Vitro Assessment of VRT-1651445 as an Inhibitor of OATP1B1

VX-445 has the potential to inhibit OATP1B1 activity

M295: In Vitro Inhibition of Human Cytochrome P450 Enzymes by VRT-1651445

VX-445 was not a potent inhibitor of CYPs. Weak inhibition of CYP2C9 and CYP 2C8 was noted with IC50 of 10.9 and 16.7 µM, respectively



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Type of Study Major Findings M299: In Vitro Assessment of VRT-1651445 as an Inhibitor of P-glycoprotein

VX-445 had a weak potential to inhibit the P-gp mediated active transport with IC50 of 23.8 µM in MDCK-MDR1 assays

M307: Evaluation of VRT-1651445 as an Inducer of CYP3A4, CYP2B6, and CYP1A2 using Primary Cryopreserved Human Hepatocytes

VX-445 at concentrations ranging from 0.1-60 µM had no impact to CYP mRNA expression or protein activity

O063: In Vitro Inhibition of Human Cytochrome P450 Enzymes by VRT-1654548

VX-445 appeared to be a weak inhibitor of CYP2C8, 2C9, and 2C19 with respective IC50s of 20.8, 20.7, and 25.5 µM

O094: In Vitro Assessment of VRT-1651445 and VRT-1654548 as Inhibitors of OATP1B3

VX-445 and M23 potentially inhibit efflux transporter OATP1B3 in OATP1B3 transfected HEK293 cells

O195: In Vitro Assessment of VRT-1654548 as an Inhibitor of OATP1B1

VX-445 potentially inhibits efflux transporter OATP1B1 in OATP1B1 transfected HEK293 cells

O211: In Vitro Assessment of VRT-1654548 as an Inhibitor of P-glycoprotein

VX-445 potentially inhibits P-gp activity with an IC50 of 25.6 µM with MDCK-MDR1 assays

O212: In Vitro Assessment of VRT-1654548 as a Substrate of OATP1B1

M23 does not affect OATP1B1 activity in OATP1B1 transfected HEK293 cells

O225: In Vitro Assessment of VRT-1651445 and VRT-1654548 as Substrates of OATP1B3

VX-445 and M23 are not uptake substrates of OATP1B3

O271: Evaluation of VRT-1654548 as an Inducer of CYP3A4/5, CYP2B6, and CYP1A2 using Primary Cryopreserved Human Hepatocytes

VX-445 at the range of concentrations between 0.1-60 µM has a low potential to induce CYP3A4/5, CYP2B6, and CYP1A2 in cryopreserved human hepatocytes

O287: In Vitro Assessment of VX-445 as a Substrate of OATP1B1

VX-445 is a not a substrate of OATP1B1 in transfected HEK293 cells

O288: In Vitro Assessment of VRT-1654548 for Passive Permeability and as a Substrate of P-glycoprotein

VX-445 is a substrate of human P-gp, and its passive permeability is low to moderate

O354: Potential Clinical Impact of VX-445 Reversible Inhibition on CYP2C9 and CYP2C8 Based on R1 Value and Net Effect Model

VX-445 has low potential to inhibit CYP2C9 or CYP2C8 in vivo

5.5 Toxicology

5.5.1 General Toxicology

As listed in the following table, general toxicity studies with either VX-445 alone or in combination with tezacaftor (VX-661) and ivacaftor (VX-770) were conducted in rats, mice, and dogs with dosing durations up to 6 months in rodents and 9 months in non-rodents. All of the pivotal studies have been reviewed previously under IND 132547 (DARRTS Reference ID: 4040659, 4248432, 4283062, and 4404180). Key findings discussed in the previous reviews are accurately summarized below.

General Toxicology Study GLP Report Number

Rats

VX-445: A 7-day Oral (Gavage) Toxicity and Toxicokinetic Study in Rats Doses: 0, 15, 50 or 100 mg/kg/day, Female/5 per group Doses: 0, 2, or 4 mg/kg/day, Female/5 per group

No VRT-1651445-TX-001 VRT-1651445-TX-015



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General Toxicology Study GLP Report Number

VX-445: A 28-Day Oral (Gavage) Toxicity and Toxicokinetic Study in Rats Followed by a 28-Day Recovery Period Doses: 0 (vehicle), 10, 25, or 50 mg/kg/day in males; and 0, 5, 15 or 30 mg/kg/day in females; 15/sex/group

Yes VRT-1651445-TX-006

VX-445/VX-661/VX-770: A 28-Day Oral (Gavage) Combination Toxicity and Toxicokinetic Study in Rats Doses: VX-445: 0, 20, 40, or 150 mg/kg/day in males, 0, 7.5, 15, or 60 mg/kg/day in females VX-660: 45 mg/kg/day VX-770: 30 mg/kg/day

Yes VRT-1651445-TX-021

VX-445/VX-661/VX-770/CTP-656: A 13-week Oral (Gavage) Toxicity and Toxicokinetics Study in Sprague Dawley Rats Doses: VX-445: 0, 4, 7.5, 20, or 35 mg/kg/day in males; 0, 2, 4, 8, or 12.5 mg/kg/day in females; 10/sex/group VX-661: 40 or 45 mg/kg/day in males; 35 or 40 mg/kg/day in females VX-770: 30 mg/kg/day VX-561: 25 mg/kg/day

Yes VX-445 TX 007

VX-445: A 26-week Oral (Gavage) Toxicity Study in Sprague Dawley Rats Followed by a 6-week Recovery Period Doses: 0, 7.5, 15, 40, and 75 mg/kg/day in males; 0, 4, 7.5, 15 and 30 mg/kg/day in females, 15/sex/group

Yes VX-445-TX-005

Dogs

VX:445: A 7-day Oral (Gavage) Toxicity and Toxicokinetic Study in Beagle Dogs Doses: 0, 2, 10, or 50 mg/kg/day; 2/sex/group

No VRT-1651445-TX-003

28-day Oral (Gavage) Toxicity and Toxicokinetic Study in Beagle Dogs Doses: 0, 2, 12.5, or 30 mg/kg/day; 4/sex/group

Yes VRT-1651445-TX-007

28-day Oral (Gavage) Combination Toxicity and Toxicokinetic Study in Beagle Dogs Doses: 0, 3.5, or 15 mg/kg/day VX-445 co-administered with 50/10 mg/kg/day VX-661/770; 4/sex/group

Yes VRT-1651445-TX-022

VX-445: A 39-week Oral (Gavage) Toxicity and Toxicokinetic Study in Beagle Dogs With a 26-week Interim Sacrifice and 6-week Recovery Period Doses: 0, 2.5, 6 or 14 mg/kg/day, 4/sex/group each for Day 183 and Day 273, main; 2/sex/group, recovery (control and HD)

Yes VX-445-TX-006

Mice

VX-445: 28-day Repeated Dose Oral Toxicity and Toxicokinetic Study in CByB6F1 Mice With a Preliminary 5-day Range-finding Toxicity Study Doses: 0, 50, 100, 300, 600, 1000, or 1500 mg/kg/day , 3/sex/group, for 5-day phase 50, 100, and 150 mg/kg/day, 10/sex/group, for 28-day phase

Yes VX-445-TX-011

Repeat dosing toxicities with VX-445 alone in rats When VX-445 was administered alone, dose limiting toxicities/mortalities were only identified in the initial 7-day dose-range-finding studies at 100 mg/kg/day in female rats. Microscopic changes consisted of minimal to marked erosion/ulceration in stomach and/or duodenum. Additionally, the gastric mucosal changes were accompanied with transmural inflammation and evidence of vascular injury (submucosal/serosal arterial necrosis/hemorrhage). All those



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changes are considered to be adverse and directly related to VX-445. As a consequence, the high dose was limited to 50 and 30 mg/kg/day for the male and female rats, respectively, in the 28-day study in rat (VRT-1651445-TX-006). However, there were no VX-445-related adverse changes identified and the No Observed Adverse Effect Levels (NOAEL) were determined to be 50 and 30 mg/kg/day for males and females, respectively.

When VX-445 was administered to rats chronically (VX-445-TX-005), it was not tolerated at ≥40 mg/kg/day in male or 30 mg/kg/day in female. Multiple deaths/euthanasia were noted in those animals with the findings of decreased food intake leading to lower body weight and declining clinical condition with erosion of the glandular mucosa of the stomach. There was no adverse changes identified at 15 mg/kg/day; this dose level was considered as the NOAEL corresponding to AUC values 4 (males) or 12 (females) times the recommended human dose. The exposure of VX-445 accumulated continuously in all dose levels in both male and female animals over the 26-week dosing period.

Repeat dosing toxicities with VX-445 in combination with VX-661 and VX-770 in rats Relative to VX-445 mono-administration, the identified toxicities were generally consistent when VX-445 was administered in combination with tezacaftor (VX-661) and ivacaftor (VX-770) or its deuterated form (VX-561 or CTP-656) in the 1-month or 3-month studies in rats. In the 1-month study (VRT-1651445-TX-021), VX-445 at 60 and 150 mg/kg/day was not tolerated. All males at 150 mg/kg/day and all females at 60 mg/kg/day were euthanized in extremis within 2 weeks after the dosing started. Gastrointestinal erosion/ulceration of the glandular stomach (pylorus and/or fundus) and/or proximal duodenum was considered the cause of morbidity in most animals euthanized in extremis. Additional test item-related findings consisted of decreased hematopoietic cellularity in the bone marrow (femur, sternum), seminiferous tubule degeneration/atrophy in the testes, increased germ cell debris and/or oligospermia in the epididymides. Most of these changes were present at mono-treatment groups at 150 mg/kg/day in males and at 60 mg/kg/day in females with limited involvement of the 75 mg/kg/day dose level in males. The NOAEL of the VX-445/VX-661/VX-770 triple combination was deemed to be 20/45/30 mg/kg/day in males, and 15/45/30 mg/kg/day in females.

In the 3-month triple combination study in rats (VX-445-TX-007), multiple deaths in high dose triple combinations might be test item related. Test item related adverse microscopic findings were limited to high dose males including testicular germ cell degeneration, and seminiferous tubular degeneration/atrophy; increased germ cell debris with or without oligospermia in epididymides; stomach glandular erosion; and hemorrhage in brain and spinal cord. The NOAEL for the VX-445 in the triple combination groups was determined as 7.5 mg/kg/day in males and 12.5 mg/kg/day in females. The lower NOAEL noted in males was due to the lower mid-dose selected in this study.

Repeat dosing toxicities with VX-445 alone in dogs When VX-445 was administered alone for 7 days in dogs (VRT-1651445-TX-003), adverse changes were limited to the highest dose of 50 mg/kg/day, which included clinical findings of skin cold to touch, decreased activity and thinness in both males and females; body weight loss



44

(up to 13% in males and up to 10% in females when compared to individual Day 1 levels) accompanied by decreased food consumption; and mild, locally extensive epithelial erosion with small areas of focal ulceration in the distal esophagus noted in both males. Consequently, the high dose was limited to 30 mg/kg/day in the 28-day study in dog (VRT-1651445-TX-007). There were no VX-445-related adverse changes identified and the NOAEL was deemed to be 30 mg/kg/day.

When VX-445 was administered alone chronically (up to 39-week) in dogs (VX-445-TX-006), test item-related microscopic changes were noted at 14 mg/kg/day including hepatocellular hypertrophy, epithelium vacuolation in gallbladder, and testicular seminiferous tubule atrophy/degeneration. The testicular changes were not fully reversible and were adverse. In conclusion, 6 mg/kg/day was the NOAEL of this study, corresponding to AUC values 6 times the recommended human dose.

Repeat dosing toxicities with VX-445 in combination with VX-661 and VX-770 in dogs In the 1-month triple combination study in dogs (VRT-1651445-TX-022), all animals survived until the end of dosing. No adverse findings were identified with up to 15 mg/kg/day of VX-445 co-administered with VX-661/VX-770. Therefore, the high dose was deemed to be the NOAEL of this study.

Repeat dosing toxicities with VX-445 alone in mice VX-445 toxicity was assessed in a 4-week study in Tg.RasH2 wildtype mice (VX-445-TX-011) determining the dose levels for the 6-month carcinogenicity study. Animals did not tolerate administration of VX-445 at ≥ 300 mg/kg/day for 5 days or at 150 mg/kg/day for about 2 weeks due to mortality and/or severe clinical signs (body weight loss, hypothermia, decreased motor activity, hunched/prostrate posture, ataxia and/or ruffled fur). 50 mg/kg/day was selected as the high dose for the carcinogenicity study because of test item related non-adverse microscopic changes in adrenal gland at 100 mg/kg/day as well as the narrow exposure difference between 100 mg/kg/day and the lethal dose.

VX-445 Toxicokinetics (TK) and Safety Margins Adequate safety margins of VX-445 were obtained supporting the corresponding clinical studies during the development.

Table 4.Toxicokinetic Studies of VX-445 Study Species NOAEL

(mg/kg) M/F VX-445 AUC0-

24h (µg.h/mL)

VX-445 Exposure Margin

4-week toxicity Dog 2 52.3 0.3 12.5 704 3.9 30 1730 9.5

4-week combo toxicity

VX-445/770 15/7.5 1920 11 VX-445/661/770

3.5/50/10 493 2.7

VX-445/661/770 15/50/10

2290 13

2.5 341 1.9



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VX-445 NOAELs and the corresponding margins are labeled in red. Clinical exposure of VX-445 in CF subjects at a VX-445/661/770 triple combination treatment with VX-445 dose of 200 mg qd at the steady state on Day 14 (VX16-445- 001, part C: AUC0-24hr = 166 μg·h/mL) *exposure level on Dosing Day 1 (vs. Day 27 for 50 and 100 mg/kg/day) a. Extrapolated based on the exposure of 50 mg/kg/day from the 4-week rat study, the exposure of 45 mg/kg/day after 3-month of dosing is expected to be >1380, based on the 3-month triple combination study in rat. b. Extrapolated based on the exposure from the 4-week rat study

39-week toxicity 6 1130 6.2 14 3040 17

4-week toxicity Mouse 50 1940 11.7 100 4330 26

150* 2510 15 4-week toxicity Rat 10/5 33.4/26.7 0.2/0.15

25/15 107/182 0.6/1 50/30 290/416 1.6/2.3

26-week toxicity 7.5/4 356/268 2/1.5 15/7.5 633/593 3.5/3.3 40/15 1370/2140 7.5/12 75/30 1560/2260 8.6/12


VX445/661/770 20/45/30 (M)

608 3.3

VX445/661/770 40/45/30 (M)

1250 6.9

VX445/661/770 7.5/45/30

288 1.6

VX445/661/770 15/45/30

1380 7.6


VX445/661/770 4/40/30 (M)

90.9 0.5

VX445/661/770 7.5/40/30 (M)

208 1.1

VX445/661/770 20/45/30 (M)

613 3.4

VX445/661/770 35/45/30 (M)

1330 7.3

VX445/661/770 2/35/30 (F)

87.6 0.5

VX445/661/770 4/40/30 (F)

231 1.3

VX445/661/770 8/40/30 (F)

649 3.6

VX445/661/770 12.5/40/30 (F)

1090 6



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Table 5. VX-445 Major Human Active Metabolite (M23, VRT-1654549) TK and Safety Margins Study Species NOAEL

(mg/kg) M/F M23 AUC0-24h

(µg.h/mL) M23

Exposure Margin

39-week toxicity Dog 2.5 11.4 0.1 6 72.1 0.9

14 201 2.4 4-week toxicity Mouse 5 8.9 0.1

15 26.8 0.3 50 89.4 1 100 206 2.5

26-week toxicity Rat 7.5/4 16.3/20a 0.2/0.2 15/7.5 31.4/43.3 0.4/0.5 40/15 106/227 1.3/2.7


VX445/661/770 4/40/30 (M)

4.38 0.05

VX445/661/770 7.5/40/30 (M)

11.1 0.1

VX445/661/770 20/45/30 (M)

38.1 0.5

VX445/661/770 35/45/30 (M)

122 1.5

VX445/661/770 2/35/30 (F)

4.8 0.06

VX445/661/770 4/40/30 (F)

15.4 0.2

VX445/661/770 8/40/30 (F)

50.3 0.6

VX445/661/770 12.5/40/30 (F)

99.9 1.2

VX-445 NOAELs and the corresponsive margins are labeled in red. Clinical exposure of VRT-1654548 (M23, VX-445 metabolite) in CF subjects at a VX- 445/661/770 triple combination treatment with VX-445 dose of 200 mg qd at the steady state on Day 14 (VX16-445-001, part C: AUC0-24hr = 83.1 μg·h/mL)

5.5.2 Genetic Toxicology

A standard battery of in vitro and in vivo genotoxicity studies with VX-445 were submitted and reviewed previously (DARRTS Reference ID 4040659 and 4404180). The results are briefly summarized in this section. All studies listed below were conducted in compliance with GLP and considered valid. VX-445 exhibited no potential for genetic toxicity. Genetic Toxicity Study Report Number Bacterial Reverse Mutation Assay VRT-1651445-TX-

012

VRT-1651445: In vitro Mammalian Cell Micronucleus Assay in TK6 Cells VRT-1651445-TX-013

VRT-1651445: In Vivo Mammalian Erythrocyte Micronucleus Assay in Rats VRT-1651445-TX-014



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Genetic Toxicity Study Report Number In Silico Analysis of Process Intermediates and Impurities in the Synthesis of VX-445 for Mutagenic Potential

VX-445-TX-023

In Vitro Reverse Mutation Assay in Bacterial Cells (Ames, VRT-1651445-TX-012) VX-445 was tested in the Ames Reverse Mutation Assays at concentrations of 6.67 to 5000 μg/plate in several strains of Salmonella typhimurium (TA98, TA100, TA1535, TA1537) and Escherichia coli strain WP2 uvrA in the presence and absence of an exogenous metabolic activation system.

In the preliminary toxicity assay with and without Aroclor-induced rat liver S9, VX-445 was tested at concentration levels of 6.67, 10.0, 33.3, 66.7, 100, 333, 667, 1000, 3333 and 5000 μg per plate. Precipitate was observed at ≥1000 μg/ plate. No toxicity was observed at any dose level.

In the definitive mutagenicity assay with and without S9, VX-445 was tested at concentration levels of 0.0, 150, 500, 1500 and 5000 μg per plate. No toxicity was observed at any concentration. Precipitate was observed at ≥1500 μg/plate. No positive mutagenic responses were observed with any of the tester strains in either the presence or absence of S9 activation. All positive and vehicle control values were within acceptable ranges, and all criteria for a valid study was met. Under the conditions of the study, VX-445 was concluded to be negative in the bacterial reverse mutation assay when tested up to maximum limit of 5000 μg/plate.

In Vitro Micronucleus Assays in TK6 Mammalian Cells (VRT-1651445-TX-013) VX-445 concentrations from 0.05 to 500 μg/mL were tested in the preliminary assay. Based on the precipitation and the cytotoxicity observed, 10 to 100 μg/mL VX-445 were tested in the definitive assay with 4-hour incubation in the presence and absence of S9 activation. In addition, 5-50 μg/mL VX-445 were tested in the nonactivated 27-hour exposure group. No significant or dose-related increases in micronuclei induction were observed in any of the treatment groups. Therefore, VX-445 was negative for the induction of micronuclei under the conditions of the assay. In Vivo Clastogenicity Assay in Rats (Micronucleus Assay, VRT-1651445-TX-014) 2000 mg/kg of VX-445 was selected as the maximal tolerated dose based on the clinical signs (piloerection and lethargy) in the preliminary test. In the definitive test, single oral doses of 500-2000 mg/kg VX-445 in female rats caused no increase in the incidence of MnPCEs relative to the vehicle control groups. However, cyclophophamide, the positive control, induced a significant increase in the incidence of micronucleated polychromatic erythrocytes (MnPCEs). In conclusion, VX-445 was negative for the induction of clastogenicity when dosed orally in female rats up to 2000 mg/kg (AUC 3180 ug*hr/mL). Other Genetic Toxicity Studies Vertex Pharma assessed the mutagenic potential of process intermediates and impurities during the production of VX-445 via in silico analysis. The results are discussed in Appendix 18.3.2.



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5.5.3 Carcinogenicity

The 6-month carcinogenicity study with oral administration of up to 50 mg/kg/day of VX-445 in in TgRas.H2 mice has been submitted and reviewed previously (DARRTS Reference ID 4489328). VX-445 was determined to be non-carcinogenic based on no VX-445 related neoplastic changes identified. Non-neoplastic lesions consisted of atrophy, infarcts, cysts and interstitial inflammation noted in kidney of males at 10 mg/kg/day and females ≥5 mg/kg/day, even though not clearly dose related, were deemed to be related to the administration of VX- 445 and adverse. At the high-dose of 50 mg/kg/day, mean VX-445 and M23 exposures were 1720 and 78.5 ug*hr/mL, respectively. The reviewer notes that transgenic carcinogenicity studies are considered suitable for hazard identification only (Jacobs and Brown. 2016. Toxicologic Pathology. 43: 605-610); therefore, exposure comparisons will not be included in the product label.

Carcinogenicity Study Report Number Review Reference ID 26-week oral (gavage) oncogenicity study in CByB6F1-Tg(HRAS)2 (hemizygous) [RasH2] mice Doses: 0, 5, 10 and 50 mg/kg/day; 25/sex/group

VX-445-TX-012 4489328

2-year oral (gavage) oncogenicity study in Sprague-Dawley rats Doses: 0, 1, 3, 10 mg/kg/day; 70 /sex/group

VX-445-TX-015 Ongoing

A 2-year carcinogenicity study in rats (Study VX-445-TX-015) is ongoing and the division agreed that this study could be completed as a Post-Marketing Requirement based on the unmet medical need in the proposed indication (communication dated Jun 28, 2018).

5.5.4 Reproductive and Developmental Toxicology

The following GLP studies were submitted and reviewed previously (DARRTS Reference ID 4404180 and 4489328). Reproductive and Developmental Toxicology Studies Report Number Review Reference ID Definitive study of EFD in pregnant rats Doses: 0, 15, 25, or 40 mg/kg/day (oral) ; 25 females/group

VRT-1651445-TX-026

4404180

Dose-range-finding EFD study in pregnant rabbits VRT-1651445-TX-025

4404180

Definitive EFD study in pregnant rabbits Doses: 0, 50, 100, and 125 mg/kg/day (oral) ; 22 females/group

VRT-1651445-TX-027

4404180

Fertility and early embryonic development study Doses: 0, 45, 55, 75 mg/kg/day in males; 0, 15, 25, 35 mg/kg/day in females (oral) ; 25/sex/group

VX-445-TX-010 4404180

VX-445: An Oral (Gavage) Study of the Effects on Pre- and Postnatal Development, Including Maternal Function in Sprague Dawley Rats Doses: 0, 5, 7.5 or 10 mg/kg/day (oral); 24 females/group

VX-445-TX-014 4489328



49

Fertility and Early Embryonic Development (VX-445-TX-010) A few breeding pairs with males at 75 mg/kg/day did not produce a litter, which led to lower fertility and copulation indices relative to controls. The values were below the minimum mean values in the test facility historical control data and was considered adverse. No test item related effect on male reproductive performance were noted in males at 45 or 55 mg/kg/day. No test item-related effects were observed on male mating indices or sperm analysis in males at any dose level.

The female fertility index and conception index at 35 mg/kg/day were lower than the respective controls and below the lower margin of the historical control data from the test facility. These findings were probably caused by the nongravid females in that group and were considered adverse. There were no VX-445 related effect on female reproductive performance at the mid- and low-dose groups.

In conclusion, the NOAEL for reproductive toxicity was determined to be 55 mg/kg/day in males and 25 mg/kg/day in females based on lower male and female fertility, male copulation, and female conception indices at 75 mg/kg/day (males) and 35 mg/kg/day (females). The reviewer notes that the study design (treated males mated with treated females) did not allow for a determination of whether the adverse effects observed were due to male and/or female-mediated effects.

Embryo-Fetal Development (EFD) Study in Rats (VRT-1651445-TX-026) Maternal toxicities consisting of mortalities and decreased body weight gains were noted in animals at 40 mg/kg/day. This correlated to the decreased fetal body weight (-16.4%) and was considered adverse. Decreased fetal weight (-9.8%) was also noted in the 25 mg/kg/day group but was not considered to be adverse since the mean level was still within the historical control range. No test article-related fetal malformations were observed at any dose. In conclusion, the NOAEL for VX-445 maternal and embryo/fetal toxicities was deemed to be 25 mg/kg/day. EFD Study in Rabbits (VRT-1651445-TX-027) Due to the clinical signs and body weight loss, two of 22 females at 125 mg/kg/day were euthanized during the study which indicated maternal toxicity of VX-445. However, there were no fetal changes at any VX-445 treated groups relative to controls. The NOAEL for maternal toxicity was 100 mg/kg/day and the NOAEL for embryo/fetal development was 125 mg/kg/day. Prenatal and Postnatal Development Study (VX-445-TX-014) There were no VX-445 related adverse findings identified in this study. Test item related non-adverse changes were only noted in the rates of body weight gains during a couple of intervals of preweaning and post-weaning phases in F1 animals. 10 mg/kg/day was deemed to be the NOAEL in this study. Other Development Studies Vertex submitted juvenile toxicity studies in rats with VX-445 or VX-661. The results of those studies are not discussed in this review since they are not needed to support approval of the proposed indication in CF patients 12 years of age and older under the current application.



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Table 6. VX-445 Toxicokinetics (TK) and Safety Margins

Study Species NOAEL (mg/kg) M/F

VX-445 AUC0-24h

(µg.h/mL) VX-445

Exposure Margin

Fertility and early embryonic development (FEED) study Rat

45/15 290a/182b 1.7/1.1 55/25 - - 75/35 - -

Embryofetal development (EFD) studies

Rat 15 451 2.5 25 782 4.3 40 1920 10.

5

Rabbit 50 225 1.2

100 853 4.7 125 571 3.1

Pre- and post-natal development study Rat

5 78.8 0.5 7.5 169 1 10 298 1.8

VX-445 NOAELs and the corresponsive margins are labeled in red. Clinical exposure of VX-445 in CF subjects at a VX-445/661/770 triple combination treatment with VX-445 dose of 200 mg qd at the steady state on Day 14 (VX16-445- 001, part C: AUC0-24hr = 166 μg·h/mL) Extrapolated based on the exposure of 50 mg/kg/day from the 4-week rat study, the exposure of 45 mg/kg/day after 3-month of dosing is expected to be >1380, based on the 3-month triple combination study in rat. Extrapolated based on the exposure from the 4-week rat study

Table 7. VX-445 Major Human Active Metabolite (M23, VRT-1654549) TK and Safety Margins Study Species NOAEL

(mg/kg) M/F

M23 AUC0-24h (µg.h/mL)

M23 Exposure Margin

EFD studyc Rat 15 227 2.7

25 227 2.7 40 227 2.7

FEED studyc 45/15 100/227 1.2/2.7 55/25 90/227 1/2.7 75/35 80/227 1/2.7

PPND study 5 4.4 0.05

7.5 10.5 0.1 10 22.2 0.3

VX-445 NOAELs and the corresponding margins are labeled in red. Clinical exposure of VRT-1654548 (M23, VX-445 metabolite) in CF subjects at a VX-445/661/770 triple combination treatment with VX-445 dose of 200 mg qd at the steady-state on Day 14 (VX16-445-001, part C: AUC0-24hr = 83.1 μg·h/mL). AUCs of M23 in the rat EFD and fertility studies are extrapolated based on the levels from the 26-week rat study and the 3-month combination study and might not be accurate due to the difference in dosing duration (VX-445/M23 exposure increased over time) and lack of comparable dose levels tested in the general toxicity study.

5.5.5 Other Toxicology Studies

Refer to Appendix 18.3 for nonclinical assessment of excipients, organic impurities, heavy metals, residual solvents, photosafety, local tolerance, and environmental impact. No safety concerns were identified in any of these studies.



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5.5.6 Conclusion

The Applicant has characterized VX-445 in genetic toxicology, general toxicology, developmental/reproductive toxicology, and carcinogenicity studies. Adequate safety margins for VX-445 were obtained in all species and studies based on exposures at the NOAELs that exceed the human exposures at the recommended human dose. No novel or synergistic toxicities were observed in triple combination studies with ivacaftor and tezacaftor. M23 (VRT-1654548) has been identified as a major human metabolite, with exposures up to 50% that of the parent in clinical studies. In vitro studies indicate that M23 is pharmacologically active, though to a lesser extent than VX-445. No standalone toxicology studies with the metabolite were submitted in the NDA, but M23 levels were quantified in many of the VX-445 toxicology studies. Levels of M23 formed in nonclinical species were generally lower than in humans, resulting in relatively low exposure margins in some cases. Based on the relevant guidance documents including M3(R2) [2010], M3(R2) Questions and Answers [2011], and Safety Testing of Drug Metabolites, 2016), metabolite exposure margins of at least 0.5x compared to the clinical exposure are recommended in at least one species. Safety margins at the NOAELs in the general toxicology (rat, dog, and mouse), FEED (rat), and EFD (rat) studies exceeded this level. The exposure margin for M23 at the NOAEL in the rat Prenatal and Postnatal Development study was slightly lower (0.3x) based upon high-dose selection in that study. No standalone genetic toxicology studies with M23 were submitted, but metabolite exposures at or above those at the recommended clinical dose were represented in the rat micronucleus assay (based on cross-study TK comparison) and in the 6-month transgenic mouse carcinogenicity study. Overall, the safety qualification of M23 was considered adequate, particularly in the context of the unmet medical need for the proposed cystic fibrosis indication. Dose comparisons in the product labeling are based on the summed AUCs of VX-445 and M23 (with the exception of the rabbit EFD study). This approach is consistent with the labeling language describing nonclinical studies conducted with ivacaftor and tezacaftor. In conclusion, there are no outstanding pharmacology-toxicology issues. The NDA is recommended for approval from the nonclinical perspective.



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6 Clinical Pharmacology

6.1 Executive Summary

The Applicant, Vertex Pharmaceuticals Incorporated, submitted a 505(b)(1) NDA 212273 seeking the marketing approval for elexacaftor (ELX)/ tezacaftor (TEZ)/ivacaftor (IVA) combination therapy (TRIKAFTA) for “the treatment of cystic fibrosis (CF) in patients aged 12 years and older who have at least one F508del mutation in the CFTR gene.” TRIKAFTA is tablet formulation of a fixed-dose combination (FDC) of ELX, TEZ and IVA. The proposed dose is two ELX 100 mg/TEZ 50 mg/IVA 75 mg tablets in the morning and one IVA 150 mg tablet in the evening, approximately 12 hours apart. TRIKAFTA should be taken with fat-containing food. NDA 212273 consists of 9 clinical and clinical pharmacology studies, including 6 clinical pharmacology studies in healthy subjects (Table 4), and 3 clinical studies (2 pivotal phase 3 studies 102 and 103; one open-label rollover study 105) to demonstrate the efficacy and safety of ELX/TEZ/IVA. The majority of the clinical pharmacology studies for TEZ and IVA have been reviewed previously under NDA 203188 (KALYDECO review by Dr. Lokesh Jain archived on January 18, 2012) and NDA 210491(SYMDEKO by Dr. Jianmeng Chen archived on February 2, 2018). In addition to the clinical studies, the Applicant also submitted results from several in vitro studies to support the contribution of TEZ component to the fixed-dose combination efficacy. The western blot assays demonstrate an additive effect for the combination of tezacaftor and ELX on CFTR mature fraction. The Ussing chamber electrophysiology experiments showed that ELX enhances chloride transport in F508del/F508del-HBE and F508del/MF-HBE cells in a concentration-dependent manner. Further, ELX+IVA+TEZ combination treatment is more potent and efficacious than effects due to TEZ alone, IVA alone, and TEZ+IVA combined, and ELX+IVA combined (Figure 28, Table 100). OCP recommends the application be approved from clinical pharmacology perspective with revisions to labeling.

6.2 Summary of Clinical Pharmacology Assessment

6.2.1 Pharmacology and Clinical Pharmacokinetics

Elexacaftor and tezacaftor bind to different sites on the CFTR protein and have an additive effect in facilitating the cellular processing and trafficking of F508del-CFTR to increase the amount of CFTR protein delivered to the cell surface compared to either molecule alone. Ivacaftor potentiates the channel-open probability (or gating) of the CFTR protein at the cell surface. The following is a summary of the clinical PK of ELX/TEZ/IVA:



53

Absorption: The absolute bioavailability of elexacaftor is approximately 80% when administered orally in the fed state. Following administration of the ELX/TEZ/IVA FDC tablet in the fed state, VX-445 was absorbed with a median time [range] to maximum concentration (Tmax) of 6 [4 to 12] hours. The median Tmax was 3 [2 to 4] hours for TEZ and 4 [3 to 6] hours for IVA. When a single dose of ELX/TEZ/IVA was administered with fat-containing foods, the systemic exposure (AUC) of elexacaftor increased approximately 1.9- to 2.5-fold, tezacaftor exposure was similar and ivacaftor exposure was approximately 2.5- to 4-fold higher than when taken in a fasting state (Study 005). Distribution: Elexacaftor and tezacaftor are approximately 99% bound to plasma proteins; in both cases primarily to albumin. Ivacaftor is approximately 99% bound to plasma proteins; primarily to albumin, and also to alpha 1-acid glycoprotein and human gamma-globulin. After oral administration of ELX/TEZ/IVA, the mean (±SD) apparent volume of distribution for elexacaftor, tezacaftor and ivacaftor was 53.7 L (17.7), 82.0 L (22.3) and 293 L (89.8), respectively. Elexacaftor, tezacaftor and ivacaftor do not partition preferentially into human red blood cells. Metabolism: ELX, TEZ, and IVA are all extensively metabolized in humans, primarily by CYP3A4/5. ELX has 1 major metabolite, M23-445, circulating in plasma with a mean metabolite-to-parent AUC ratio of approximately 35% to 50% at steady-state. M23-445 has similar potency to ELX in F/MF-HBE cells and is considered pharmacologically active. TEZ has 3 major circulating metabolites in humans, M1-TEZ, M2-TEZ, and M5-TEZ. M1-TEZ has a similar potency to that of TEZ and is considered pharmacologically active. M2-TEZ is much less pharmacologically active than TEZ or M1-TEZ, and M5-TEZ is not considered pharmacologically active. Another minor circulating metabolite, M3-TEZ, is formed by direct glucuronidation of TEZ. IVA has 2 major circulating metabolites in humans, M1-IVA and M6-IVA. M1-IVA has approximately one-sixth the potency of IVA and is considered pharmacologically active. M6-IVA is not considered pharmacologically active. Excretion: After oral administration of 14C-ELX, the majority of radioactivity was recovered in feces (87.3%), with minimal renal excretion (approximately 0.23% radioactivity in urine). The concentrations of unchanged radiolabeled ELX in urine were generally below the limit of quantification, indicating that renal clearance of ELX is negligible in humans. The mean (SD) elimination t½ of ELX following administration of ELX/TEZ/IVA FDC tablets was 24.7 (4.87) hours.



54

Following oral administration of 14C-TEZ, the majority of radioactivity was excreted in the feces (72%; unchanged or as M2-TEZ) and about 14% was recovered in urine (mostly as M2-TEZ). Renal excretion of TEZ is negligible in humans. The mean (SD) elimination t½ of TEZ following administration of the ELX/TEZ/IVA FDC tablets was 60.3 (15.7) hours. Following oral administration of ivacaftor alone, the majority of ivacaftor (87.8%) is eliminated in the feces after metabolic conversion. There was minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine), and there was negligible urinary excretion of ivacaftor as unchanged drug. The mean (SD) elimination t½ of IVA following administration of the ELX/TEZ/IVA FDC tablets was 13.1 (2.98) hours. Drug interaction between ELX and TEZ/IVA: There is no significant drug-drug interaction (DDI) between the 3 compounds. ELX exposure was similar following administration of ELX monotherapy or when dosed in combination with TEZ/IVA. TEZ and IVA exposures in the FDC were generally consistent with historical data from the TEZ/IVA and IVA programs. In addition, population pharmacokinetics (popPK) analyses indicated that ELX has minimal impact on TEZ/IVA PK.

6.2.2 General Dosing and Therapeutic Individualization

General Dosing Dosing recommendations are shown in Figure 1 below:

Figure 1. Dosing Recommendations for Patients 12 Years and Older

(Source: Figure 2, clinical overview)

The regimen of ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h was selected for Phase 3 studies based on exposure-response (E-R) analyses for efficacy from study 001 (Part D/E). Analyses of the E-R relationships for ppFEV1 and SwCl indicated that the 200-mg ELX dose provides >90% of maximal benefit, with numerically better improvements in lung and CFTR function than the lower doses (See Section 6.3.2). The doses of TEZ and IVA are the approved doses for TEZ/IVA and IVA for patients aged 12 years and older.



55

Efficacy/safety data from the pivotal Phase 3 studies support the recommended dosing regimen of ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for the proposed indications. Therapeutic Individualization Hepatic impairment: Elexacaftor alone or in combination with tezacaftor and ivacaftor has not been studied in subjects with hepatic impairment. Similar to tezacaftor and ivacaftor, higher exposure of elexacaftor is expected in patients with moderate (Child-Pugh Class B, score 7 to 9) and severe hepatic impairment (Child-Pugh Class B, score 10-15). Therefore, patients with severe hepatic impairment should not be treated with ELX/TEZ/IVA. Use of ELX/TEZ/IVA is not recommended in patients with moderate hepatic impairment and

However, recognizing that physicians and patients may choose to use ELX/TEZ/IVA because of the robust efficacy in spite of the presence of moderate hepatic impairment, the label will include language advising against its use in this patient subgroup unless the benefit exceeds the risk. If used in patients with moderate hepatic impairment, ELX/TEZ/IVA should be used with caution and the ivacaftor dose should be reduced by half. Liver function tests should be closely monitored. No dose adjustment is recommended for patients with mild hepatic impairment. Strong CYP3A inhibitors: Co-administration with itraconazole, a strong CYP3A inhibitor, increased elexacaftor exposure (AUC) by 2.8 fold, tezacaftor by 4.5 fold and D-ivacaftor by 11 fold (study 006). Therefore, when co-administered with strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin), the dose should be reduced Table 8) Moderate CYP3A inhibitors: Physiologically-based pharmacokinetic modeling suggested co-administration with fluconazole, a moderate CYP3A inhibitor, may increase elexacaftor and tezacaftor exposure (AUC) by approximately 1.9-2.3- fold and 2.1- fold, respectively. In a previous study, co-administration of fluconazole increased ivacaftor exposure (AUC) by 3.0 fold. When co-administered with moderate CYP3A inhibitors, the dose of ELX/TEZ/IVA should be reduced (Table 8).

Table 8. Dosing Schedule for Concomitant Use of ELX/TEZ/IVA with Moderate and Strong CYP3A Inhibitors

Moderate CYP3A Inhibitors Day 1 Day 2 Day 3 Day 4* Morning Dose

Two elexacaftor/tezacaftor/ivacaftor tablets

One ivacaftor tablet


One ivacaftor tablet

Evening Dose^

No dose

* Continue dosing with two elexacaftor/tezacaftor/ivacaftor tablets and one ivacaftor tablet on alternate days. ^ The evening dose of ivacaftor should not be taken.


(b) (4)


56

Strong CYP3A Inhibitors Day 1 Day 2 Day 3 Day 4# Morning Dose


No dose No dose Two elexacaftor/tezacaftor/ivacaftor tablets

Evening Dose^

No dose

# Continue dosing with two elexacaftor/tezacaftor/ivacaftor tablets twice a week, approximately 3 to 4 days apart. ^ The evening dose of ivacaftor tablet should not be taken.

CYP3A inducers: Concomitant use of CYP3A inducers may result in reduced exposures of ELX, TEZ, and IVA, and thus reduced efficacy. Therefore, co-administration of ELX/TEZ/IVA with strong CYP3A inducers, such as rifampin, is not recommended. Outstanding issues The Office of Clinical Pharmacology recommends one PMR study: Evaluate the impact of hepatic impairment on elexacaftor PK; consequently, update the approved TRIKAFTA labeling with recommendations for appropriate use of TRIKAFTA in patients with hepatic impairment. In the absence of this information, the Prescribing Information (PI) will recommend the following:

“TRIKAFTA has not been studied in patients with moderate or severe hepatic impairment. Patients with severe hepatic impairment should not be treated with TRIKAFTA. Use of TRIKAFTA is not recommended in patients with moderate hepatic impairment unless the benefit exceeds the risk. If used in patients with moderate hepatic impairment, TRIKAFTA should be used with caution and at a reduced dose (see Table 1). Liver function tests should be closely monitored [see Warnings and Precautions (5.1)].”

No dose adjustment is recommended for patients with mild hepatic impairment. Table 1: Dose adjustment of TRIKAFTA in patients with hepatic impairment Mild (Child-Pugh

Class A) Moderate (Child-Pugh Class B)* Severe

(Child-Pugh Class C)

Morning No dose adjustment Two tablets of elexacaftor/tezacaftor/ivacaftor

Should not be used

Evening No dose adjustment No ivacaftor dose Should not be used

* Use not recommended unless the benefit exceeds the risk



57

6.3 Comprehensive Clinical Pharmacology Review

6.3.1 General Pharmacology and Pharmacokinetic Characteristics

Product: Elexacaftor is a small molecule drug. Its structure is shown in Figure 2.

Figure 2. Molecular Structure of Elexacaftor, Tezacaftor and Ivacaftor

The proposed medicinal product is a combination of 3 orally bioavailable small molecules, elexacaftor (ELX), tezacaftor (TEZ) and ivacaftor (IVA). Morning dose: The ELX/TEZ/IVA fixed-dose combination tablet is available as an orange, capsule shaped, film-coated tablet containing 100 mg of elexacaftor, 50 mg of tezacaftor, 75 mg of ivacaftor. Evening dose: The ivacaftor tablet is available as a light blue, capsule shaped, film-coated tablet containing 150 mg of ivacaftor. Summary of Clinical Pharmacology and Pharmacokinetics

Review Issue Recommendations and Comments Pharmacology

Mechanism of Action ELX and TEZ bind directly to CFTR at different sites to facilitate the processing and trafficking of F508del-CFTR. The F508del-

Elexacaftor



58

Review Issue Recommendations and Comments CFTR delivered to the cell surface by ELX and TEZ has defective channel gating activity that can be potentiated by IVA.

QT Prolongation

The effect of multiple doses of elexacaftor 200 mg and 400 mg once daily on QTc interval was evaluated in a double-blind, randomized, placebo and active-controlled, thorough QT/QTc study in healthy subjects (Study # VX18-445-009). At a dose 2 times the maximum recommended dose, elexacaftor does not prolong the QT interval to any clinically relevant extent. The largest upper bound of the 2-sided 90% CI for the mean difference between elexacaftor and placebo was below 10 ms. In separate studies of TEZ and IVA evaluating doses up to 3 times the maximum approved dose, TEZ and IVA did not prolong the QT interval to any clinically relevant extent.

General Information

Bioanalysis ELX, TEZ and IVA plasma concentrations were measured using validated liquid chromatography with tandem mass spectrometric detection (MS/MS).

Healthy Subjects vs. Patients

The pharmacokinetics of ELX is similar between healthy adult volunteers and patients with CF. Following administration of ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h, the mean ELX AUC at steady-state was 166 h*μg/mL in (Study 001 Part C), 186 h*μg/mL (Study 009), 226 h*μg/mL (Study 002) in healthy subjects, and 161 h*μg/ml (Trial 102), 164 h*μg/ml (Trial 103), 173-175 h*μg/ml (Study 001 part D and E) in patients with CF.

Drug exposure at steady-state following the therapeutic dosing regimen

The population PK (PopPK) model estimated mean Cmax,ss and AUCτ,ss were 8.66 μg/mL and 162 μg*h/mL, respectively, for ELX, 6.77μg/mL and 93.4 μg*h/mL, respectively, for TEZ, and 1.24 μg/mL and 11.7 μg*h/mL, respectively, for IVA, following ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h dosing regimen in CF patients.

Dose-Proportionality

Exposures of ELX (administered alone or in combination with ivacaftor) increased in an approximately dose-proportional manner with increasing doses from 60 mg to 400 mg once daily (Study 001, 009).

Accumulation

ELX and M23-445 achieved steady-state within approximately 14 days of dosing. The mean accumulation ratio (AR) is 2.3 for elexacaftor, 1.6 for tezacaftor and 2.4 for ivacaftor. The mean accumulation ratio (AR) is similar to previously reported in the STMDEKO program (See clinical pharmacology review for NDA210491). Additionally, the steady state AUC of



59

Review Issue Recommendations and Comments TEZ and IVA are similar in CF patients taking TRIKAFTA or SYMDEKO.

Absorption

Bioavailability [oral]

The absolute bioavailability of ELX when administered orally in the fed state is approximately 80%. The relative bioavailability of ELX, TEZ, and IVA, and their metabolites, with the FDC formulation compared to the separate tablet formulations of ELX and IVA was approximately 1 (study 005).

Tmax [oral] The median Tmax for TEZ was 4h (2-6h). The median Tmax for IVA was 6 h (3-10h). (study 005).

Food effect (moderate-fat) GMR (fed/fasted, 90% CI) (Study 005)

AUC0-inf Cmax

ELX 1.89 (1.60, 2.25) 3.87 (3.35, 4.46) TEZ 1.05 (0.99, 1.11) 1.02 (0.93, 1.12) IVA* 3.08 (2.45, 3.87) 4.32 (3.01, 6.18) *based on Study VX13-661-004 Distribution

Volume of Distribution

After oral administration of ELX/TEZ/IVA, the mean (±SD) apparent volume of distribution of elexacaftor, tezacaftor and ivacaftor was 53.7 L (17.7), 82.0 L (22.3) and 293 L (89.8), respectively.

Plasma protein binding

Both elexacaftor and tezacaftor are approximately 99% bound to plasma proteins, primarily to albumin. Ivacaftor is approximately 99% bound to plasma proteins, primarily to albumin, and also to alpha 1-acid glycoprotein and human gamma-globulin.

Blood-to-plasma ratio

Elexacaftor, tezacaftor and ivacaftor do not partition preferentially into human red blood cells. For ELX, the blood:plasma partitioning ratio in human following in vitro incubation was 0.501. In the mass balance study (study 003), the mean blood-to-plasma ratio of total radioactivity was approximately 60%, indicating no appreciable accumulation of radioactivity in blood cells.

Substrate transporter systems [in vitro]

Based on in vitro results, both ELX and M23-445 are substrates for P-glycoprotein (P-gp), however, they are not substrates for the uptake transporters OATP1B1 or OATP1B3.



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Review Issue Recommendations and Comments TEZ is a substrate for the uptake transporter OATP1B1, and efflux transporters P-gp and BCRP. TEZ is not a substrate for OATP1B3. Ivacaftor is not a substrate for OATP1B1, OATP1B3, or P-gp.

Elimination

Effective half-life After steady-state dosing of ELX/TEZ/IVA in CF patients, the effective half-lives of ELX, TEZ and IVA were approximately 29.8 (10.6), 17.4 (3.66), and 15.0 (3.92) hours, respectively.

Metabolism

Primary metabolic pathway(s) [in vitro] and active moieties

In vitro data suggested that ELX is metabolized mainly by CYP3A4 and CYP3A5. M23-445 (N-demethylation) was identified as the only major metabolite circulating in the plasma and accounted for 17.3% of the total circulating radioactivity based on metabolite profiling in study 003. The mean metabolite-to-parent (M23-445/ELX) AUC ratio in plasma after a single dose was 26% (Study 003, See appendix 18.4.1). At steady-state, the mean metabolite to parent (M23-445/ELX) AUC ratio is 0.350 to 0.504 on Day 14. M23-445 is pharmacologically active with similar potency to ELX in F/MF human bronchial epithelial cells. In vitro data suggested that TEZ is metabolized mainly by CYP3A4 and CYP3A5. M1, M2, and M5 were the 3 major circulating metabolites of TEZ in humans. M1 has the similar potency to that of TEZ and is considered pharmacologically active. M2 is much less pharmacologically active than TEZ or M1, and M5 is not considered pharmacologically active. Another minor circulating metabolite, M3, is formed by direct glucuronidation of TEZ. IVA is also metabolized extensively in humans. In vitro and in vivo data indicate that ivacaftor is metabolized primarily by CYP3A4 and CYP3A5. M1 and M6 are the two major metabolites of ivacaftor in humans. M1 has approximately one-sixth the potency of IVA and is considered pharmacologically active. M6 is not considered pharmacologically active.

Excretion

Primary excretion pathway

ELX is eliminated primarily by biliary/fecal excretion. After a single oral dose of 200 mg (200 μCi) 14C-ELX in healthy male subjects, the majority of radioactivity was recovered in feces (87.3%), with minimal renal excretion (approximately 0.23% radioactivity in urine) (Study 003). The concentrations of



61

Review Issue Recommendations and Comments unchanged ELX in urine were generally below the limit of quantification, indicating that renal excretion of ELX is negligible in humans. TEZ is eliminated primarily by biliary/fecal excretion. Following oral administration of 14C TEZ, the majority of the dose (72%) was excreted in feces (unchanged or as the M2 metabolite) and about 14% was recovered in urine (mostly as M2 metabolite). Less than 1% of the administered dose was excreted in urine as unchanged TEZ, suggesting that renal excretion is not the major pathway for TEZ elimination in humans. Following oral administration of IVA alone, the majority of administered dose (87.8%) was eliminated in feces after metabolic conversion. There was minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine), and there was negligible urinary excretion of ivacaftor as unchanged drug.

DDI between ELX and TEZ/IVA Impact of TEZ/IVA on ELX PK No significant impact (study 001).

Impact of ELX on TEZ/IVA PK

TEZ, IVA, and metabolite exposures in Part C of Study 001 were consistent with historical data, indicating no effect of ELX on TEZ or IVA PK. Additionally, popPK analyses of TEZ and IVA data from Study 001 indicate steady-state exposures of TEZ and IVA are similar in the absence or presence of ELX in CF subjects (see appendix 18.4.4). Therefore, doses of TEZ and IVA were not adjusted for the TC regimen and are consistent with the approved doses of TEZ/IVA and IVA.

6.3.2 Clinical Pharmacology Questions

Does the clinical pharmacology program provide supportive evidence of effectiveness? This submission consisted of nine clinical and clinical pharmacology studies, including 6 clinical pharmacology studies in healthy subjects (Table 9), and three clinical studies (two pivotal phase 3 studies 102 and 103; one open-label rollover study 105). The proposed indication of ELX/TEZ/IVA was based on the two pivotal Phase 3 studies 102 and 103 (see Sections 7 and 8).



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Table 9. Clinical Pharmacology Studies

Majority of the clinical pharmacology studies for TEZ and IVA have been reviewed previously under NDA 203188 (refer to the clinical pharmacology review by Dr. Lokesh Jain archived on January 18, 2012) and NDA 210491(refer to the clinical pharmacology review by Dr. Jianmeng Chen archived on 02/02/2018). See Appendix 15.3.1 for individual study reviews for clinical pharmacology studies. Contribution of individual components to efficacy (heterozygous and homozygous F508del mutations) The Applicant designed and executed in vitro assays to evaluate the effect of each drug alone, all double combinations and the triple combination on CFTR maturation and chloride transport. The WB assays demonstrated an additive effect for the combination of tezacaftor and ELX on CFTR mature fraction. Ivacaftor had a small and consistently negative but not statistically significant effect on CFTR mature fraction. The Ussing chamber electrophysiology experiments showed that ELX concentration-dependently enhances chloride transport in F508del/F508del-HBE and F508del/MF-HBE cells, and that this effect is larger than that achieved by TEZ alone, IVA alone, and TEZ+IVA combined. Further, ELX+IVA+TEZ combination treatment is more potent and efficacious than effects due to TEZ alone, IVA alone, TEZ+IVA combined, and ELX+IVA combined. Overall, the Applicant performed in vitro WB experiments and Ussing chamber electrophysiology experiments using single drugs, all possible pairwise combinations as well as the full triple combination. See Section 15.3.3 for the full analysis of these experiments. Efficacy in patients with at least one F508del mutation (heterozygous and homozygous F508del mutations) ELX/TEZ/IVA is indicated for the treatment of cystic fibrosis (CF) in patients aged 12 years and older who have at least one F508del mutation in the CFTR gene. The pivotal Phase 3 studies support the efficacy of ELX/TEZ/IVA in CF patients aged 12 years and older with F/F (Trial 103) or F/MF (Trial 102) mutations (see Sections 7 and 8).



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Trial 102 enrolled F/MF subjects who had an F508del mutation on one CFTR allele, and an MF mutation on the other allele resulting in either no CFTR protein or a protein that does not respond to IVA and TEZ/IVA in vitro. The majority of F/MF subjects that were enrolled (~78%) had a second allele with a Class I mutation, which are mutations that produce no CFTR protein. Thus, the clinical effects of ELX/TEZ/IVA treatment in these patients were driven solely by the responsiveness of a single F508del allele. As the second allele is not expected to interfere with the efficacy of ELX/TEZ/IVA, the proposed indication of CF with at least one F508del mutation is reasonable. Is the proposed dosing regimen appropriate for the general patient population for which the indication is being sought? Yes, the proposed dosing is reasonable from a clinical pharmacology perspective. The basis for dose selection and findings from phase 2 studies is discussed below: Dose/exposure-response for efficacy: The dosing regimen of ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h was selected for Phase 3 studies based on results of dose-ranging in Study 001 Part D (F/MF) and Part E (F/F). Elexacaftor dose: In a phase 2 study (study 001), a range of ELX doses (50 mg, 100 mg, 200 mg QD) were administered in combination with TEZ 100 mg QD/IVA 150 mg BID in subjects 18 years of age or older with the F/MF genotype (part D). ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h was also compared to TEZ 100 mg qd/IVA 150 mg q12h in adult F/F subjects (part E). The dosing regimen of ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for Phase 3 studies was supported by the population PK/PD analyses of Study 001 part D and E. In F/MF and F/F subjects 18 years of age and older, treatment with ELX/TEZ/IVA for 4 weeks resulted in significant improvements in ppFEV1 compared to baseline and robust improvements in CFQ-R RD scores and SwCl concentrations (i.e., reductions) compared to baseline (Table 10, Table 11). In combination with TEZ 100 mg QD/IVA 150 mg BID, treatment with ELX 200 mg resulted in a numerically greater improvement in ppFEV1 and SwCl compared to the two lower doses in F/MF subjects (Table 10). Efficacy and safety data from the pivotal Phase 3 studies support the recommended dosing regimen of ELX 200 mg once a day (qd) in combination with TEZ 100 mg qd/IVA 150 mg q12h in CF patients with F/F (Trial 103) or F/MF (Trial 102) mutation (see Sections 7 and 8).



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Table 10. Efficacy Results for F/MF Subjects (Study 001, Part D), FAS

Source: Table 5, summary of clin efficacy

Table 11. Efficacy Results for F/F Subjects (Study 001, Part E), FAS

Source: Table 6, summary of clin efficacy



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Tezacaftor/ivacaftor dose: A range of doses for TEZ/IVA in combination therapy was not studied. The proposed TEZ/IVA dose is the currently approved dose of SYMDEKO in cystic fibrosis patients with responsive mutations.

Is an alternative dosing regimen or management strategy required for subpopulations based on intrinsic patient factors? Use of TRIKAFTA is not recommended in patients with severe hepatic impairment. Use of TRIKAFTA is not recommended in patients with moderate hepatic impairment unless the benefit exceeds the risk (see below). There is no dose adjustment based on renal function, age, weight, or other intrinsic factors. See below for the data submitted by the Applicant and the reviewer’s comments. Patients with Hepatic Impairment Hepatic metabolism and/or excretion are major route of elimination for ELX, TEZ and IVA. Impact of moderate hepatic impairment on TEZ/IVA PK was assessed in a non-randomized, open-label, multiple dose study (Study 009) and has been reviewed previously under NDA 210491 (Table 12). In another study (study 770-013), subjects with moderately impaired hepatic function had approximately two-fold increase in ivacaftor AUCinf. Therefore, dose adjustment (from 150 mg q12h to 150 mg qd) is recommended based on the largest change in IVA exposure observed in studies with moderate hepatic impairment subjects, and no dose adjustment for TEZ is necessary for patients with mild or moderate hepatic impairment. ELX has not yet been studied in subjects with hepatic impairment. An increase in exposure of ELX is expected in patients with moderate or severe hepatic impairment. Therefore, patients with severe hepatic impairment should not be treated with ELX/TEZ/IVA. Use of ELX/TEZ/IVA is not recommended in patients with moderate hepatic impairment, and

. However, recognizing that physicians and patients may choose to use ELX/TEZ/IVA because of the robust efficacy in spite of the presence of moderate hepatic impairment, the label will include language advising against its use in this patient subgroup unless the benefit exceeds the risk. If used in patients with moderate hepatic impairment, ELX/TEZ/IVA should be used with caution and the ivacaftor dose should be reduced by half. Liver function tests should be closely monitored. Graphical evaluation of liver enzyme levels (AST and ALT) on the PK for ELX did not show any trend, and no dose modification is recommended for patients with mild hepatic impairment.

Table 12. TEZ/IVA Pharmacokinetic Parameters in Subjects with Moderate Hepatic Impairment Compared with Healthy Subjects

Day Analyte Parameter Group comparison Mean Ratio 90% CI of the ratio

Day 10 TEZ AUCτ (ng.h/mL)

Moderate hepatic impairment/healthy

66397/48791 1.36 (1.17, 1.58)


(b) (4)


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Source: Table 11-6, Table 11-7, Study 009 report)

Reviewer comment: As elexacaftor is primarily eliminated by hepatic metabolism and biliary excretion, hepatic impairment is likely to increase the systemic exposure of elexacaftor. However, the current clinical development program contains limited information to inform dosing of elexacaftor in patients with hepatic impairment. Patients with Child Pugh B and C hepatic impairment were likely excluded in the phase 2 and 3 studies because these clinical studies excluded patients with AST, ALT, GGT, or ALP greater than 3 x ULN. In addition, patients with total bilirubin greater than 2x ULN were also excluded. Therefore, a systematic evaluation of pharmacokinetics (PK) for elexacaftor in subjects with hepatic impairment is needed to help guide dosing decision for elexacaftor. Accordingly, a PMR is being issued to characterize the PK for elexacaftor in subjects with hepatic impairment.

Before the PK data of ELX is available in the patients with moderate hepatic impairment from the PMR study, a dose recommendation for this specific population cannot be made for ELX. Based on internal discussion with the clinical team, there may be situations in which ELX/TEZ/IVA is prescribed to patients with moderate hepatic impairment despite labeling recommendations due to the robust treatment effect on numerous clinically meaningful endpoints (see 8.1.6). In the case that a physician and patient determine that the potential benefit of ELX/TEZ/IVA use exceeds the potential risk of worsening liver disease, language will be included in the PI stating that the IVA dose should be reduced and the evening dose should not be given. In addition, liver function tests (AST, ALT, bilirubin) should be closely monitored.

Patients with renal impairment Renal excretion is not a major pathway for ELX elimination. Therefore, the Applicant did not conduct a dedicated study in patients with renal impairment. Based on population PK analysis, the reviewer’s analysis confirmed a lack of clinically meaningful effect on ELX PK for patients with mild or moderate renal impairment based on estimated glomerular filtration rate (Figure 3). The median steady state AUC values were 156, 164, and 197 μg*hr/mL, in patients with normal renal function, mild renal impairment, or moderate renal impairment, respectively. No data were collected for patients with baseline eGFR≤ 50ml/min/1.73 m2, as these patients were excluded from the Phase 2/3 studies.

Cmax (ng/mL)


4277/3873 1.10 (0.952, 1.28)

IVA AUCτ (ng.h/mL)


17262/11351 1.52 (1.13, 2.04)

Cmax (ng/mL)


1084/1028 1.05 (0.806, 1.38)



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Figure 3. Covariate Effect on Steady State ELX Exposure Based on Post Hoc Analysis in Patients Who Provided PK Data in the ELX popPK Dataset.

Source: o303_PopPK repsort Figure 5-6 Panel A

Reviewer comment: Renal clearance likely plays a minimal role in the elimination of ELX, TEZ and IVA, and no dose adjustment is necessary for patients with mild to moderate renal impairment. Caution is recommended when administering ELX, TEZ and IVA combination therapy to patients with severe renal impairment (creatinine clearance less than or equal to 30mL/min) or with end-stage renal disease. These recommendations are consistent with the approved labeling for IVA monotherapy (KALYDECO) and TEZ/IVA (SYMDEKO).

Pediatrics CF is a congenital disorder that affects children from birth. During the EOP2 communication dated February 20, 2018 (IND 132547), the Agency and the Applicant reached an agreement that phase 3 studies would enroll patients 12 years and older. The adolescent patients would be administered the same dosing regimen as adults. This is based on the similar disease and predicted similar drug exposure in adult and adolescent patients. The proposed dose is reasonable from a clinical pharmacology perspective as the exposures achieved in pediatric patients aged 12-17 years is similar to adults (Table 13). In the phase 3 trials (Trials 102 and 103), pediatric patients accounted for approximately 29% of the patients enrolled in each arm. The systemic exposure for the three active components were similar between adolescent and adult patient population in the Phase 3 trials (Table 13) . Additionally, the efficacy in adolescents was similar to adults and the adverse events (AEs) were generally comparable between the two groups (see Section 8).



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Table 13. Elexacaftor, Tezacaftor and Ivacaftor Exposure (Mean (SD)) by Age Group (Trials 102 and 103)

Age

Groups (years)

PK ELX TEZ IVA

Cmax (ng/ml)

Cmin (ng/ml)

AUC τ * (ng*h/ml)

Cmax (ng/ml)

Cmin (ng/ml)

AUC τ * (ng*h/ml)

Cmax (ng/ml)

Cmin (ng/ml)

AUCτ * (ng*h/ml)

12 to < 18

8400 (1750)

4048 (2076)

149000 (38700)

7000 (1650)

2100 (816)

96000 (23400)

1150 (288)

626 (263)

10600 (3350)

≥ 18 8770 (2160)

5488 (2652)

167000 (50500)

6690 (1390)

2050 (810)

92400 (23800)

1270 (353)

750 (334)

12100 (4170)

*AUC0 24h for elexacaftor and AUC0 12h for ivacaftor Source: Reviewer’s Analysis

Figure 4. ELX (VX-445) and M23-445 Exposure (AUC0-24h) in Adult and Adolescent Patients with Cystic Fibrosis in Phase 3 Studies (Studies 102 and 103)

Source: Figure 8, summary clin pharm

Are there clinically relevant food-drug or drug-drug interactions, and what is the appropriate management strategy?

Food effect The systemic exposure of ELX increased by approximately 1.5-fold and 1.9-fold when administered with a low-fat meal and moderate-fat meal, respectively, compared to administration under fasted conditions. The exposure of IVA increased by approximately 2.5- to 4-fold when administered with fat-containing meals relative to fasted conditions, while food had no clinically relevant effect on the exposure of TEZ. In the Phase 3 studies, subjects were instructed to administer study drug with fat-containing food. Therefore, consistent with dosing recommendations for TEZ/IVA and IVA, ELX/TEZ/IVA FDC (morning dose) and IVA tablet (evening dose) should be administered with fat-containing food.



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Potential for other drugs to affect ELX/TEZ/IVA In vitro studies showed that ELX, TEZ and IVA are all extensively metabolized by CYP3A. Therefore, ELX, IVA and TEZ exposures are expected to be reduced by concomitant CYP3A inducers and increased by concomitant CYP3A inhibitors. In vitro studies showed that ELX and TEZ are substrates for the efflux transporter P-gp, but ivacaftor is not. Due to the high permeability (colorectal adenocarcinoma (Caco-2) cell study M388, Table 70) of ELX, inhibition of P-gp is not expected to impact its absorption. ELX and IVA are not substrates for OATP1B1 or OATP1B3; tezacaftor is a substrate for OATP1B1, but not OATP1B3. TEZ is a substrate for BCRP. The effects of co-administered drugs on the systemic exposure of elexacaftor, tezacaftor and/or ivacaftor are shown in Table 14.

Table 14. Impact of Other Drugs on Systemic Exposure of Elexacaftor, Tezacaftor and/or Ivacaftor

Co-administered drug

Effect on PK AUCinfrR CmaxR Dosing recommendation

Strong CYP3A inhibitor: itraconazole

↑ TEZ 4.51 1.48 Two tablets of ELX/TEZ/IVA twice a week, taken approximately 3 to 4 days apart. The evening dose of ivacaftor 150 mg should not be taken. This is consistent with the labeling of SYMDEKO (TEZ/IVA). ↑ ELX 2.83 1.05

Moderate CYP3A inhibitor ELX 1.9-2.3* 1.07-

1.08*

Dose adjustment based on PBPK. Overall, dose is reduced by half for ELX/TEZ/IVA. This is consistent with the labeling of SYMDEKO (TEZ/IVA).

CYP3A inducer: rifampin

ELX (expected ↓)

NA NA Co-administration not recommended. This is consistent with the labeling of SYMDEKO (TEZ/IVA).

DDI studies conducted previously and reviewed under NDA 210491 and NDA 203188

Strong CYP3A inhibitor: itraconazole

↑ TEZ 4.02 2.83 One tablet of TEZ 100 mg/IVA 150 mg twice a week, taken approximately 3 to 4 days apart. The evening dose of ivacaftor 150 mg should not be taken. Overall, TEZ dose is reduced to 1/3.5, and IVA dose is reduced to 1/7 for SYMDEKO. ↑ IVA 15.6 8.60

Moderate CYP3A inhibitor: fluconazole

TEZ 2.1** 1.7**

Dose adjustment based on PBPK. Overall, dose is reduced by half for TEZ and IVA. ↑ IVA 2.95 2.47

↔ TEZ 1.08 1.05 No dose adjustment for TEZ and IVA.



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Co-administered drug

Effect on PK AUCinfrR CmaxR Dosing recommendation

ciprofloxacin ↔IVA 1.17 1.18

CYP3A inducer: rifampin

TEZ (expected ↓)

NA NA Co-administration not recommended for SYMDEKO.

↓ IVA 0.114 0.2

↑- Increase, ↔ - no change *Range is based on PBPK simulations with moderate inhibitors fluconazole, verapamil, and erythromycin (PBPK report O318); ** PBPK report N032

Reviewer comment:

1. When administered with a strong CYP3A inhibitor, itraconazole, the systemic exposure of ELX increased by 2.8-fold, compared to the 4.5-fold and 15.6-fold increase for TEZ and IVA, respectively. The proposed dosing regimen in the presence of strong CYP3A inhibitors is to reduce ELX/ TEZ/IVA dosing to 200/100/150 mg twice weekly.

With a 3.5-fold dose reduction for ELX and TEZ in presence of strong CYP3A inhibitors, the steady-state ELX and TEZ exposures are predicted to be at similar levels as those observed under normal dosing conditions. Therefore, a 3.5-fold dose reduction in ELX/TEZ dose, when co-administered with a strong CYP3A inhibitor (such as itraconazole), is not expected to significantly impact efficacy of the triple combination.

Based on study 006, a 7-fold dose reduction for IVA in the presence of itraconazole will lead to exposures equivalent to a 300 mg bid IVA dose in the absence of itraconazole. In a separate DDI study with ivacaftor and ketoconazole, ivacaftor exposure was increased by 8.45-fold. The dose reduction recommendations are consistent with the labeling for IVA monotherapy. Overall, the proposed dose adjustment for TRIKAFTA when co-administered with strong CYP3A inhibitor is reasonable considering the efficacy and safety of ELX/TEZ/IVA. These recommendations are consistent with the approved labeling for IVA monotherapy (KALYDECO) and TEZ/IVA (SYMDEKO).

2. In a DDI study, a moderate CYP3A inhibitor, fluconazole, increased the systemic exposure of ivacaftor by 3-fold. The PBPK model predicted a 2.1-fold increase in TEZ exposure and a 1.9-2.3-fold increase in ELX exposure when co-administered with fluconazole (See Appendix 18.4.2). Therefore, when co-administered with moderate CYP3A inhibitors, the dose of TRIKAFTA should be reduced by half (Table 8). These recommendations are consistent with the approved labeling for IVA monotherapy (KALYDECO) and TEZ/IVA (SYMDEKO).

3. No significant change in exposure (AUC and Cmax) of TEZ and IVA was observed following co-administration with ciprofloxacin. As IVA is considered to be a sensitive substrate, the effect of ciprofloxacin on the PK of ELX is not expected to be larger than its effect on IVA.



71

Therefore, no dose adjustment of TRIKAFTA is recommended when co-administered with ciprofloxacin. These recommendations are consistent with the approved labeling for IVA monotherapy (KALYDECO) and TEZ/IVA (SYMDEKO).

4. Co-administration with rifampin significantly reduced the AUC and Cmax of IVA by ∼89% and 80%, respectively. Rifampin is an inducer for CYP3A4 and is also expected to reduce the exposure of ELX and TEZ. These lower exposures will result in inefficacious concentrations. Therefore, co-administration of TRIKAFTA with rifampicin or other CYP3A inducers is not recommended. These recommendations are consistent with the approved labeling for IVA monotherapy (KALYDECO) and TEZ/IVA (SYMDEKO).

5. ELX is a substrate for P-gp. Due to the high permeability, inhibition of P-gp is not expected to impact absorption of ELX.

Potential for ELX/TEZ/IVA to affect other drugs: Overall, ELX/TEZ/IVA are not inhibitors or inducers for the CYP enzymes evaluated (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). Based on the in vitro results, ELX, TEZ, IVA, and their major metabolites do not inhibit the CYP enzymes evaluated in human liver microsomes, except for IVA and M1-IVA which showed potential to inhibit CYP2C8, CYP2C9, and CYP3A4. A clinical study with midazolam showed that the combination regimen of TEZ/IVA is not an inhibitor of CYP3A. Clinical studies (with rosiglitazone and desipramine) showed that IVA is not an inhibitor of CYP2C8 or CYP2D6. Based on the in vitro results, ELX and M23-445 may inhibit OATP1B1 and OATP1B3 uptake, and IVA has the potential to inhibit P-gp. Co-administration of TEZ/IVA with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold. Based on the in vitro results, ELX/TEZ/IVA does not have significant inhibition/induction effect on other transporters evaluated (i.e., P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, or OAT3). The effects of ELX, TEZ and/or IVA on the exposure of co-administered drugs are shown in Table 15.

Table 15. Impact of Elexacaftor/Tezacaftor or Ivacaftor on Other Drugs Drug Dose and

Schedule TEZ/IVA or IVA

Effect on Drug PK

Mean Ratio (90% CI) of Elexacaftor and Ivacaftor

No Effect=1.0

Dosing recommendation

AUC Cmax Oral

Contraceptive Ethinyl

estradiol 30 µg/Levonor

gestrel 150 µg qd

ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg

q12h

↑ Ethinyl estradiol (EE)

1.33 (1.20, 1.49)

1.26 (1.14, 1.39)

No dose adjustment

↑ Levonorgestrel

(LN)

1.23 (1.10, 1.37)

1.10 (0.985, 1.23)

DDI studies conducted previously and reviewed under NDA 210491 Midazolam

(CYP3A substrate)

TEZ 100 mg/IVA 150 mg every morning + IVA

↔ Midazolam 1.12 (1.01, 1.25)

1.13 (1.01, 1.25)

No dose adjustment



72

Drug Dose and Schedule

TEZ/IVA or IVA

Effect on Drug PK

Mean Ratio (90% CI) of Elexacaftor and Ivacaftor

No Effect=1.0

Dosing recommendation

AUC Cmax 150 mg every

evening Digoxin (P-gp

substrate)

TEZ 100 mg/IVA 150 mg every morning + IVA 150 mg every

evening

↑ Digoxin 1.30 (1.17, 1.45)

1.32 (1.07, 164)

When used concomitantly with digoxin or other

substrates of P gp with a narrow therapeutic index

such as cyclosporine, everolimus, sirolimus, and

tacrolimus, caution and appropriate monitoring

should be used Oral

Contraceptive TEZ 100 mg/IVA

150 mg every morning + IVA 150 mg every

evening

↔ Ethinyl estradiol

1.12 (1.03, 1.22)

1.15 (0.99, 1.33)

No dose adjustment

↔ Norethindrone

1.05 (0.98, 1.12)

1.01 (0.87, 1.19)

DDI studies conducted previously and reviewed under NDA 203188 Rosiglitazone

(CYP2C8 substrate)

IVA 150 mg twice daily

↔ Rosiglitazone

0.975 (0.897, 1.06)

0.928 (0.858, 1.00)

No dose adjustment

Desipramine (CYP2D6 substrate)


↔ Desipramine

1.04 (0.985, 1.10)

1.00 (0.939; 1.07)

No dose adjustment

Midazolam (CYP3A4

probe substrate)


↑ Midazolam 1.54 (1.39, 1.69)

1.38 (1.26, 1.52)

Use with caution and monitor for

benzodiazepine-related side effects during

coadministration with Kalydeco.

Oral Contraceptive


↔ Ethinyl estradiol

1.07 (1.00, 1.14)

1.22 (1.10, 1.36)

No dose adjustment

↔ Norethindrone

1.05 (0.99, 1.12)

1.09 (1.01, 1.19)

↑ = increase, ↓ = decrease, ↔ = no change. CI = Confidence interval;

Reviewer comment: Ivacaftor is a weak inhibitor of CYP3A, and co-administration of ivacaftor with midazolam increased midazolam exposure by ~50% in a previously conducted study (Study 770-010). Based on in vitro studies, TEZ has a low potential to inhibit CYP3A4 and a low potential to induce CYP3A. The net effect of TEZ/IVA on CYP3A was assessed in a dedicated DDI study and co-administration of TEZ/IVA and midazolam did not affect midazolam exposure.

When ELX/TEZ/IVA was studied in combination with oral contraceptive LN/EE, a CYP3A substrate, there was a small increase in the exposures of LN and EE, but the magnitude of these increases is not considered to be clinically relevant. ELX/TEZ/IVA is not expected to impact the efficacy or safety of hormonal contraceptives and no dose adjustment of CYP3A substrates is required when co-administered with ELX/TEZ/IVA.

the Applicant mentioned that the elevated bilirubin observed in Trial 102 may be due to OATP1B1 and OATP1B3 inhibition by ELX and M23-ELX. If bilirubin elevation is


(b) (4)

(b) (4)


73

not observed within the 4-week study (Trial 103), then the bilirubin elevation is not likely due to transporter inhibition, and more likely due to liver toxicity. In addition, liver enzyme elevations were observed with bilirubin elevation, also consistent with liver toxicity (see Sections 7 and 8).

What is the Bioanalytical Method for ELX? The summary of bioanalytical method used for the pivotal studies is listed in Table 16, Table 17 and Table 18. Analytical method for ELX and its major metabolites: report # O068 An analytical method was developed and validated for the determination of VX-445 and M23-445 in K2 EDTA human plasma samples via LC-MS/MS Detection, and was used in the majority of clinical studies. The method was precise, accurate, sensitive, and selective with a calibration range of 10.0 to 10000 ng/mL for VX-445 and 5.0 to 5000 ng/mL for M23-445. The analytes were stable under laboratory analysis conditions. The long-term stability was 336 days (-20oC and -70oC) for VX-445 and M23-445. Analytical method for TEZ, IVA and the major metabolites: report # O162 An analytical method was developed and validated for the determination of ivacaftor, M1-ivacaftor, TEZ, and M1-TEZ in K2 EDTA human plasma samples via LC-MS/MS Detection, and was used in the majority of clinical studies. The method was precise, accurate, sensitive, and selective with calibration ranges of 10.00 to 10000 ng/mL for TEZ and M1-TEZ and 2.00 to 2000 ng/mL for IVA and M1-IVA. The analytes were stable under laboratory analysis conditions. The long-term stability of TEZ, M1-TEZ, IVA, and M1-IVA was 248 days (-25oC and -80oC).

Table 16. Bioanalytical Assays Used In Clinical Studies of Elexacaftor

Source: Table 4, summary of biopharm


(b) (4)


74

Table 17. Bioanalytical Assays Used in Clinical Studies of Tezacaftor


Table 18. Bioanalytical Assays Used in Clinical Studies of Ivacaftor




75

7 Sources of Clinical Data and Review Strategy

7.1 Table of Clinical Studies

Table 19. Clinical Trials Relevant to this NDA

Trial Identity (Dates) NCT no.

Trial Design Regimen/schedule/route Study Endpoints

Treatment Duration/Follow

Up No.

enrolled Study

Population No. of Centers and Countries

Controlled Studies to Support Efficacy and Safety VX17-445-102

(6/15/18 to

4/24/19)

03525444 R, DB, PC, PG

• ELX 200 mg/TEZ 100 mg/IVA 150 mg qAM + IVA 150 qPM • Placebo BID

-Absolute Δ ppFEV1 at Wk 4 -Absolute Δ ppFEV1 through Wk 24 - # PEx through Wk 24 - Absolute Δ SwCl through Wk 24 - Absolute Δ CFQ-R RD through Wk 24 - Absolute Δ BMI at Wk 24 - Absolute Δ SwCl at Wk 4 - Absolute Δ CFQ-R RD at Wk 4

24 wks Follow-up: 4 wks or open-label extension

R: 405 Tx: 403 C: 400

CF ≥ 12 years F/MF

110 sites 13 countries: Australia, Austria, Belgium, Canada, Czech Republic, France, Germany, Greece, Italy, Netherlands, Sweden, UK, US

VX17-445-103

(8/3/18 to 12/28/18)

03525548 R, DB, AC, PG

• ELX 200 mg/TEZ 100 mg/IVA 150 mg qAM + IVA 150 qPM • PBO/TEZ 100 mg/IVA

150 mg qAM + IVA 150 qPM

-Absolute Δ ppFEV1 at Wk 4 - Absolute Δ SwCl at Wk 4 - Absolute Δ CFQ-R RD at Wk 4

4 wk Run-In (TEZ/IVA) 4 wk DBP (ELX/TEZ/IVA or TEZ/IVA) Follow-up: 4 wks or open-label extension

R: 108 Tx: 107 C: 107

CF ≥ 12 years F/F

44 sites 4 countries: Belgium, Netherlands, UK, US

Uncontrolled Studies to Support Safety VX17-445-105

(10/9/18 – ongoing)

03525574 Open-label extension

• ELX 200 mg/TEZ 100 mg/IVA 150 mg qAM + IVA 150 qPM

Safety 96 wks E: 507 Tx: 505

Subjects who completed trials 102 or 103

ongoing (Sites from 102 and 103)



76




Up No.

enrolled Study


Phase 2 Studies VX16-445-001

Part D,E

(01/17 to 03/18)

03227471

R, DB, PG, PC, MC

Part D (dose-ranging) • ELX 50 mg/TEZ 100

mg/IVA 150 mg qAM + IVA 150 qPM • ELX 100 mg/TEZ 100

mg/IVA 150 mg qAM + IVA 150 mg qPM • ELX 200 mg/TEZ 100

mg/IVA 150 mg qAM + IVA 150 qPM • PBO BID

-Absolute Δ ppFEV1 through Day 29 - Absolute Δ SwCl through Day 29 -Relative Δ ppFEV1 through Day 29 - Absolute Δ CFQ-R RD at Day 29

4 wk DBP (ELX/TEZ/IVA or PBO) 1 wk DBPTEZ/IVA or PBO Follow-up: 28 days

65 CF ≥ 18 years F/MF

37 Sites 4 countries: US, Australia, Netherlands and Belgium 37 Sites 4 countries: US, Australia, Netherlands and Belgium

Part E • ELX 200 mg/TEZ 100

mg/IVA 150 mg qAM + IVA 150 mg qPM • PBO/TEZ 100 mg/IVA

150 mg qAM + IVA 150 mg qPM

-Absolute Δ ppFEV1 Through Day 29 - Absolute Δ SwCl through Day 29 -Relative Δ ppFEV1 Through Day 29 - Absolute Δ CFQ-R RD at Day 29

4 wks Run-In (TEZ/IVA) 4 wk DBP: (ELX/TEZ/IVA or TEZ/IVA) 4 wks: (TEZ/IVA) Follow-up: 28 days

28 CF ≥ 18 years F/F

Relevant Phase 1 Studies in Healthy Volunteers to Support Safety VX16-445-001

Part C

(01/17 to 03/18)

03227471

R, DB, PC, MAD

ELX 100, 200, or 280 mg /TEZ 100 mg/IVA 150 mg qAM + IVA 150 mg qPM or PBO

S, T, and PK 14 days 23 HV 1 Site Countries: US

VX17-445-002

(1/18 to 4/18)

OL, PK, DDI

LN /EE with or without ELX/TEZ/IVA

ELX/TEZ/IVA: • ELX 200 mg/TEZ 100

mg/IVA 150 mg qAM + IVA 150 mg qPM

LN/EE: • LN 150-μg/EE 30-μg qd

PK and S 31 days total • 21 days LN/EE • 10 days LN/EE + ELX/TEZ/IVA

16 (1 received LN/EE only)

Female HV 18 to 35 years

2 Sites Countries: US

VX18-445-009

(6/18 to 8/18)

R, DB, PC and AC, TQT/QTc

Group 1 ELX 200 mg QD followed by ELX 400 mg QD, and

QTcF, S, and T 16 days total Group 1

Group 1: 32

HV 1 Site Countries: US



77




Up No.

enrolled Study


moxifloxacin-matched PBO Group 2A Moxifloxacin (400 mg) followed by ELX-matched PBO Group 2B ELX-matched PBO followed by moxifloxacin (400 mg)

7 days ELX 200 mg 7 days ELX 400 mg Groups 2A and 2B Single dose moxifloxacin

Group 2A: 16 Group 2B: 16

AC: active controlled, BMI: body mass index, C: completed, CF: cystic fibrosis, CFQ-R: cystic fibrosis questionnaire-revised (respiratory domain), DB: double-blind, DBP: double-blind period, E: enrolled, EE: ethinyl estradiol, ELX: elexacaftor, F/F: homozygous F508 del-CFTR mutation, F/MF: heterozygous F508 del-CFTR mutation and 2nd minimal function CFTR mutation, HV: healthy volunteers, LN: levonorgestrel, mg: milligrams, QTcF: QT interval corrected by Fridericia’s formula, PBO: placebo, PC: placebo-controlled, PEx: pulmonary exacerbations, PG: parallel-group, PK: pharmacokinetic, ppFEV1: percent predicted forced expiratory volume in 1 second, qAM: every morning, QD: daily, qPM: every evening, R: randomized , S: safety, T: tolerability, TEZ: tezacaftor, TQT: Thorough QT, Tx: treated, UK: United Kingdom, US: United States, wk: week, Δ: change



78 Version date: October 12, 2018

7.2 Review Strategy

Support for the efficacy and safety of ELX/TEZ/IVA in the proposed indication is primarily based on two trials in different mutation subgroup populations: Trial VX17-445-102 in CF patients with a single F508del mutation and a second MF mutation (F/MF genotype; MF defined below in Section 8.1.1) and Trial VX17-445-103 in CF patients homozygous for the F508del mutation (F/F genotype). For the evaluation of efficacy, results from these two individual trials are presented in Sections 8.1.1 and 8.1.3, while a discussion of the overall efficacy for the proposed indication is provided in Section 8.1.6. The statistical reviewer, Dr. Mingyu Xi conducted efficacy analyses using methods pre-specified in the statistical analysis plan (SAP) and generated tables and figures for the efficacy review. Section 8.3 presents the statistical issues and considerations. Section 8.2 presents the safety data. The analysis of safety data from the two phase 3 trials was conducted individually using JMP 12.0, JMP clinical, and MAED. Given differences in study design including the control arm, trial population and treatment duration, the safety analysis did not pool Trials VX17-445-102 and VX17-445-103. The safety review also considered safety data from the phase 1 and 2 studies as well as the interim analysis (IA) of the ongoing phase 3 open-label extension (OLE), Study VX16-445-105. Section 8.2.8 discusses Study VX16-445-105 to evaluate the safety of chronic ELX/TEZ/IVA use. Finally, Section 8.4 provides overall conclusions and recommendations, including a discussion of the Combination Rule. For brevity, trials will be referred to in this review by the last 3 digits of the trial name.




8 Statistical and Clinical and Evaluation

8.1 Review of Individual Trials Used to Support Efficacy

8.1.1 VX17-445-102 (Trial 102) Study Design

Overview and Objectives Trial 102 was a multinational pivotal trial to provide evidence of efficacy and safety of ELX in combination with TEZ/IVA in patients with CF who are heterozygous for F508del mutation on the CFTR gene and a second minimal function mutation. The study was conducted from June 15, 2018 to April 14, 2019. Study Title: A Phase 3, Randomized, Double-blind, Placebo-controlled Study Evaluating the Efficacy and Safety of ELX Combination Therapy in Subjects With Cystic Fibrosis Who Are Heterozygous for the F508del Mutation and a Minimal Function Mutation (F/MF) Primary Objective:

• To evaluate the efficacy of ELX in triple combination (TC) with TEZ and IVA in subjects with CF who are heterozygous for F/MF

Secondary Objectives: • To evaluate the safety of ELX in TC with TEZ and IVA • To evaluate the PD of ELX in TC with TEZ and IVA • To evaluate the PK of ELX, TEZ, and IVA when administered in TC

Trial Design Trial 102 was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study. The trial included a 28-day screening period, 24-week treatment period, and 28-day follow-up period. After screening, eligible subjects were randomized with a 1:1 allocation ratio to either ELX/TEZ/IVA or placebo. Randomization was stratified by screening ppFEV1 (<70 versus ≥70), age at screening visit (<18 versus ≥18 years of age), and sex (male versus female). At the Week 24 visit, subjects completing the treatment period could enroll in the OLE study (105). Subjects declining participation in the OLE should complete safety follow-up approximately 28 days after the last dose of study drug. Subjects who discontinued treatment prematurely should also have an early treatment termination visit as soon as possible after the decision to discontinue study drug treatment. The trial prespecified an IA after at least 140 subjects completed the Week 4 visit and 100 subjects completed the Week 12 visit. The trial schematic appears in Figure 5 and a detailed schedule of study assessments appears in the Clinical Appendix 15.4.1 (Table 105).




Figure 5. Design of Trial 102

VX-445 = ELX Source: Clinical Trial Protocol VX17-445-102, page 5.

Reviewer comment: Overall, the study design is typical of other trials with CFTR modulators. The 24-week treatment duration allows for assessment of less frequent events such as exacerbations and other parameters that may respond more slowly to treatment such as BMI. A placebo control is the appropriate comparator given the lack of an approved CFTR modulator therapy in the F/MF population; the Division previously concluded lack of efficacy for IVA monotherapy (NDA 203188) and TEZ/IVA (NDA 210491) in the F/MF population, obviating the need for these arms. However, despite the Agency’s recommendation, the Applicant did not include an ELX/IVA treatment arm.

Entry Criteria The study enrolled adults and adolescents (12 years and older) with stable CF who were heterozygous for F/MF genotype per the following enrollment criteria. Key inclusion criteria:

1. Male or female, age 12 years or older with confirmed diagnosis of CF as determined by the investigator

2. ppFEV1 ≥40% and ≤90% predicted mean for age, sex, and height (per ATS standards) 3. Stable CF disease as judged by the investigator 4. Willing to remain on stable CF treatment regimen 5. Heterozygous for F508del and a MF mutation, with genotype confirmed at screening

Eligible MF CFTR Mutations: The Applicant defined MF mutations as mutations that are non-responsive to TEZ, IVA, or TEZ/IVA. A MF mutation was required to meet at least 1 of the following 2 criteria:




(1) Biological plausibility of no translated protein (genetic sequence predicts the complete absence of CFTR protein)

(2) In vitro testing that supports lack of responsiveness to TEZ, IVA, or TEZ/IVA, and evidence of clinical severity on a population basis (per large patient registry), where

Supportive in vitro testing for the mutation met the following two criteria: • Baseline chloride transport that was <10% of wildtype CFTR • An increase in chloride transport of <10% over baseline following the addition of

TEZ, IVA, or TEZ/IVA in the assay

Clinical severity on a population basis was defined by the following two criteria (per the CFTR2 patient registry accessed on February 15, 2016) :

o Average SwCl >86 mmol/L, and o Prevalence of pancreatic insufficiency >50%

*These clinical severity criteria did not apply to the individual subjects to be enrolled in the study, but were used to categorize each mutation on a population level. A list of acceptable mutations as provided in the protocol appears in Table 106. Although there is no standard definition or consensus for “minimal function” mutations, the Applicant’s proposed criteria and approach were reasonable to identify the study population. Key exclusion criteria:

1. Significant illness or clinical condition that may confound results of the study or pose additional risk (e.g. cirrhosis with or without portal hypertension, solid organ / hematological transplantation, cancer, alcohol or drug abuse within the past year)

2. Abnormal laboratory values at Screening a. Hemoglobin < 10 g/dL b. Aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl

transferase (GGT), or alkaline phosphatase (ALP) ≥ 3x ULN c. Total bilirubin ≥ 2x ULN d. Abnormal renal function defined as glomerular filtration rate (GFR)≤ 50

mL/min/1.73 m2 for adults and ≤ 45 mL/min/1.73 m2 for adolescents 3. Acute upper or lower respiratory tract infection, pulmonary exacerbation (PEx) or

change in therapy (including antibiotics) for sinopulmonary disease within 28 days before Day 1 (first dose of study drug)

4. Lung infection with organisms associated with more rapid decline in pulmonary status (e.g., Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus)

5. Use of prohibited medications (see Table 21) 6. Pregnant or nursing females 7. Acute illness within 14 days of Day 1 (not related to CF)

Reviewer comment: Given that weight, cytochrome P450 enzyme maturity, lung maturity, and overall disease status in adolescent patients approaches that of adults, it was reasonable to include adolescent subjects in this study, and this has been the common practice in other CF




programs. Conceptually, it is reasonable for the Applicant to group the studied mutations based on the “minimal function” criteria. However, as discussed in Section 2.1, there is no widely accepted granular criteria for what defines minimal CFTR function and certain aspects of the criteria are based on responsiveness to the Applicant’s drugs. However, overall the inclusion and exclusion criteria were generally reasonable to define the study population and support the proposed indication.

Study Drug Interruption Rules Rash The protocol stated that study drug should be interrupted if a subject develops a generalized rash of Grade 3 or higher, or a rash that is considered a serious adverse event (SAE). The investigator would notify the medical monitor of any rash that results in interruption of study drug, is Grade 3 or higher or is a serious adverse event (SAE). Investigators should consider additional evaluation including laboratory testing (e.g., complete blood count with differential, LFTs), photographs of the rash, and dermatology consultation. The investigator could consider resumption of study drug if considered clinically appropriate. Liver Function Tests The protocol stated that study drug administration must be interrupted immediately (prior to confirmatory testing) if any of the following criteria are met: • ALT or AST >8 × upper limit of normal (ULN) • ALT or AST >5 × ULN for more than 2 weeks • ALT or AST >3 × ULN, in association with total bilirubin >2 × ULN and/or clinical jaundice

A thorough investigation of potential causes should be conducted, and the subject should be followed closely for clinical progression. Study drug administration must be discontinued if the following criterion is met: • Subsequent ALT or AST values confirm the initial elevation that satisfied the interruption

rule (above), and no convincing alternative etiology (e.g., acetaminophen use, viral hepatitis, alcohol ingestion) is identified, regardless of whether transaminase levels have improved

Subject Removal Criteria Subjects were withdrawn from the study for any of the following: • Anytime at the discretion of the investigator or the Applicant for safety, behavior,

noncompliance with study procedures, or administrative reasons. • Pregnancy • Screening CFTR genotype that does not confirm study eligibility • Meets any study discontinuation criteria (see above) Subjects withdrawn from the study were to be followed, provided that the subject did not withdraw consent (or assent where applicable).




Dose and Duration of Treatment

Table 20. Dose and Duration of Treatment Study arm ELX TEZ IVA ELX/TEZ/IVA 200 mg qd 100 mg qd 150 mg q12h Placebo 0 0 0 ELX/TEZ/IVA; IVA: ivacaftor; q12hr: every 12 hours; qd: once daily; TEZ: tezacaftor

Patients remained on their stable standard-of-care CF regimen with the exception of CFTR modulators. The study prohibited moderate or strong CYP3A inducers or inhibitors (including herbal and fruit sources), moderate and strong CYP2C9 inducers, and sensitive OATP1B1 substrates.

Reviewer comment: Similar to the TEZ/IVA studies, hypertonic saline was not a prohibited medication. The dose selected for the ELX/TEZ/IVA combination was explored in Study 001 Part D as described in Section 6. The TEZ/IVA dosage is the approved dose under NDA 210491.

Concomitant medications The trial allowed administration of study drug on a background of standard-of-care therapy. Stable medication and supplement regimens for CF were allowed if there were no changes from 28 days before Day 1 through completion of study participation. New chronic therapies could not be initiated from 28 days before Day 1 visit through completion of study participation. Subjects taking chronically inhaled antibiotics remained on the regimen throughout the study; subjects who cycle on and off an antibiotic or who alternate between two different inhaled antibiotics were to continue the prior schedule. Subjects could receive doses of prednisone or prednisolone up to 10 mg/day chronically, or up to 60 mg daily for up to 5 days. Bronchodilators were allowed, but were to be withheld prior to spirometry assessments. Prohibited medications and foods appear in Table 21.

Table 21. Prohibited Medications Medication Start Restriction End Restriction Moderate and strong CYP3A inducers None allowed within 14 days before the

first dose of the study drug on Day 1 None allowed through completion of study participation Moderate and strong CYP3A inhibitors

(except ciprofloxacin) Sensitive OATP1B1 substrates CFTR modulators (investigational or approved), except for study drugs

None allowed within 28 days before the first dose of the study drug on Day 1

None allowed until after the last dose of study drug

CYP: cytochrome P450; IVA: ivacaftor; OATP1B1: organic anion transporting polypeptide 1B1 Source. Adapted from Table 9.2 Protocol VX17-445-102, Version 3.0

Reviewer comment: Overall, the handling of concomitant and prohibited medications is reasonable.

Blinding An interactive web response system was used to assign subjects to treatment. All subjects (and their parents/caregivers/companions), site personnel (including investigators, site monitor, and




study team), and members of the Vertex study team were blinded to treatment codes. Individual SwCl (with exception of screening values) were not disclosed to the study sites. Study-related spirometry was not revealed to subjects and parents/caregivers/companions until after the study was completed as determined by finalization of the Clinical Study Report. Before any planned efficacy analysis, the spirometry and SwCl data were reviewed by a biostatistician for data cleaning purposes; this biostatistician did not have access to treatment codes. A limited Vertex team was unblinded to the IA after the independent data monitoring committee declared the study had crossed the efficacy boundary. The Applicant states that the limited unblinded Vertex team was not involved and did not influence the conduct of the remaining part of the study. An external independent biostatistician performed the IA and the analyses were reviewed by the independent data monitoring committee . After the independent data monitoring committee declared the study crossed the pre-specified efficacy boundary, a limited Vertex unblinded team, not involved in the study, was to prepare a regulatory submission. The study continued through Week 24 and subjects, site personnel and members of the Vertex team remained blinded until final database lock. Unblinding of individual subject’s treatment by the Investigator was limited to medical emergencies or urgent clinical situations. Unblinding of individual subject’s treatment by Vertex Global Patient Safety or designee was permitted for any SAE report in compliance with regulatory reporting requirements and for matters related to safety concerns.

Reviewer comment: The study blinding was acceptable.

Study Endpoints Primary Endpoint: • Absolute change in ppFEV1 from baseline at Week 4

Key Secondary Endpoints: • Absolute change in ppFEV1 from baseline through Week 24 • Number of PEx through Week 24 • Absolute change in SwCl from baseline through Week 24 • Absolute change in CFQ-R RD score from baseline through Week 24 • Absolute change in BMI from baseline at Week 24 • Absolute change in SwCl from baseline at Week 4 • Absolute change in CFQ-R RD score from baseline at Week 4

Other Secondary endpoints (not reviewed in detail): • Time-to-first PEx through Week 24 • Absolute change in BMI z-score from baseline at Week 24 • Absolute change in body weight from baseline at Week 24




Other efficacy endpoints (not reviewed in detail): • Absolute change in Treatment Satisfaction Questionnaire for Medication) domains from

baseline at Week 24 (only for subjects aged ≥12 years to <18 years at the date of informed consent)

Reviewer comment: Overall, the primary and secondary endpoints evaluate a number of factors considered to be clinically meaningful to patients with CF (ppFEV1, CFQ-R RD, BMI, SwCl, weight, and PExs). The Applicant initially proposed to use the Week 4 IA as the basis of the initial NDA in the F/MF population and justified the 4-week endpoint noting the demonstration of a treatment effect (ppFEV1) by Week 4 in the phase 2 clinical program; however, key secondary endpoints are evaluated at 24 weeks in order to assess for durability of the treatment effect.

Efficacy Assessments Spirometry The investigators performed spirometry according to the American Thoracic Society Guidelines/European Respiratory Society Guidelines. After screening, spirometry was to be performed pre-bronchodilator. The trial defined pre-bronchodilator spirometry per the following three criteria: • Withheld their short-acting bronchodilators (e.g., albuterol) or anticholinergic (e.g.,

ipratropium bromide) for more than 4 hours before the spirometry assessment • Withheld their long-acting bronchodilator (e.g., salmeterol) for more than 12 hours before

the spirometry assessment; and • Withheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide) for more

than 24 hours before the spirometry assessment During the screening period, spirometry could be performed pre- or post-bronchodilator. At all other visits, spirometry was to be performed pre-bronchodilator. During the Treatment Period, spirometry was to be performed before study drug dosing and at approximately the same time at each visit. Spirometry was transmitted to a centralized spirometry service for quality review. Measured spirometric values (FEV1 (L), forced vital capacity (FVC) (L), FEV1/FVC (ratio), forced expiratory flow , mid expiratory phase (FEF25%-75%) (L/s)) were converted to percent predicted values using the standard equations of Global Lung Function Initiative (GLI).6 Pulmonary exacerbations The study considered new or changed antibiotic therapy (intravenous (IV), inhaled, or oral) for the following sinopulmonary signs/symptoms:

6 Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic reference values for spirometry for the 3–95-yr age range: the global lung function 2012 equations. Eur Respir J. 2012;40(6):1324-43.




• Change in sputum • New or increased hemoptysis • Increased cough • Increased dyspnea • Malaise, fatigue, or lethargy • Temperature above 38°C (equivalent to approximately 100.4°F) • Anorexia or weight loss • Sinus pain or tenderness • Change in sinus discharge • Change in physical examination (PE) of the chest • Decrease in pulmonary function by 10% • Radiographic changes indicative of pulmonary infection The trial defined PEx as a new or change in antibiotic therapy (IV, inhaled, or oral) for any 4 or more of the listed signs/symptoms.

Reviewer comment: The PEx definition is consistent with that used in pivotal trials in the IVA monotherapy, LUM/IVA combination and TEZ/IVA combination development programs.

Weight and Height Weight and height were measured with shoes off. Following screening, height was collected only for subjects ≤21 years of age on the date of informed consent. Cystic Fibrosis Questionnaire-Revised Respiratory Domain (CFQ-R RD) Score The CFQ-R is a disease-specific health-related quality of life measure for CF that consists of generic and CF-specific scales grouped into 3 modules and 9 domains. The scales measure quality of life, health perception, and symptoms over a 2-week recall period. It is available in age appropriate versions: child age 6-11 years (interview format), child age 12-13 years (self-reported format), adolescent/adult ages ≥14 years (self-reported), and a parent/caregiver proxy format. The RD of the CFQ-R has also been utilized independently to evaluate for respiratory symptoms relevant to patients with CF. In patients with stable respiratory symptoms and chronic Pseudomonas aeruginosa infection, a difference of at least 4 points in the CFQ-R RD score is generally considered the minimum clinically important difference.7 Subjects were asked to complete the CFQ-R in their native language, if validated translations were available. If no validated translation was available in the subject’s native language, the subject did not complete the questionnaire. Subjects 12 and 13 years of age at the date of informed consent were asked to complete the CFQ-R Child version themselves, and their parents/caregivers completed the CFQ-R Parent version, at all visits, regardless of whether the subject subsequently turned 14 years of age during the study. Subjects 14 years of age and

7 Quittner AL, Modi AC, Wainwright C, Otto K, Kirihara J, Montgomery AB. Determination of the minimal clinically important difference scores for the Cystic Fibrosis Questionnaire-Revised Respiratory Symptom Scale in two populations of patients with cystic fibrosis and chronic Pseudomonas aeruginosa airway infection. Chest. 2009;135(6):1610-18.




older at the date of informed consent completed the Adolescent/Adult version of the questionnaire themselves at all visits. Sweat Chloride SwCl is an in vivo pharmacodynamic measure of CFTR function. A SwCl concentration ≥60 mmol/L is diagnostic of CF. The studies completed the SwCl test (quantitative pilocarpine iontophoresis) using an approved collection device. The protocol required collection before study drug dosing. At each time point, 2 samples will be collected, 1 from each arm (left and right). Samples were sent to a central laboratory for testing and interpretation. Safety assessments Safety evaluations included AEs, clinical laboratory assessments, pregnancy testing, VS, ECGs, pulse oximetry, spirometry, physical exams, and ophthalmologic exams, monitored as per the schedule in Table 105.

Statistical Analysis Plan Analysis Sets Five analysis sets were defined in this study: All Subjects Set, Full Analysis Set, Safety Set and Analysis Sets for IA. Furthermore, there were two analysis sets defined under Analysis Sets for IA: interim Full Analysis Set (iFAS) and interim Safety Set (IA Safety Set). The All Subjects Set was defined as all subjects who are randomized or receive at least 1 dose of study drug. The FAS was defined as all randomized subjects who carry the intended CFTR allele mutation and receive at least 1 dose of study drug. The Safety Set was defined as all subjects who receive at least 1 dose of study drug. The iFAS set was defined as all subjects in the FAS whose scheduled week 4 visit is on or before the IA data cutoff date. The IA data cutoff date was defined as the latter of at least 140 subjects complete week 4 visit and at least 100 subjects complete week 12 visit. The IA Safety Set was defined as all subjects in the Safety Set who complete the week 4 visit or receive their first dose of study drug at least 28 days before the IA data cutoff date. All efficacy analyses were based on the iFAS or FAS. Statistical Analysis Methods

1. Primary Endpoint The primary endpoint of absolute change in ppFEV1 from baseline at Week 4 was analyzed




using a mixed-effects model for repeated measures (MMRM) with change from baseline at Day 15 and Week 4 as the dependent variables. The model included treatment group, visit, and treatment by visit interaction as fixed effects, with continuous baseline ppFEV1, age at screening (<18 versus ≥18 years of age) and sex (male versus female) as covariates. The treatment comparison was ELX/TEZ/IVA group versus placebo group. The treatment difference at Week 4 was estimated from the model. The adjusted means with 2-sided 95% confidence intervals and 2-sided P values were reported.

2. Secondary Endpoints The seven secondary endpoints are listed in the order of testing hierarchy:

1. Change from baseline in ppFEV1 through Week 24 2. Number of PEx through Week 24 3. Change from baseline in SwCl through Week 24 4. Change from baseline in CFQ-R RD score through Week 24 5. Change from baseline in BMI at Week 24 6. Change from baseline in SwCl at Week 4 7. Change from baseline in CFQ-R RD score at Week 4

Analysis of number of PEx was performed using a negative binomial regression model with a fixed effect for treatment, as well as continuous baseline ppFEV1, age at screening (<18 versus ≥18 years of age), and sex (male versus female) as covariates. The logarithm of the subject-specific PEx analysis period duration (in years) was treated as the offset in the model. Analysis of change from baseline in ppFEV1 through Week 24 was based on same MMRM as the analysis of primary endpoint, but Day 15 Visit was not included in the estimation of the average treatment effect through Week 24 as the treatment effect was not expected to reach the steady state at Day 15. Analysis of change from baseline in SwCl through Week 24 was based on same MMRM as the analysis of primary endpoint. Data obtained from Week 4, Week 8, Week 12, and Week 24 Visits were included in the model, and all of these visits were included in the estimation of the average treatment effect through Week 24. Analysis of change from baseline in CFQ-R RD score through Week 24 was based on the same MMRM as the analysis of primary endpoint. Data obtained from Week 4, Week 8, Week 12, Week 16, and Week 24 Visits was included in the model and all of these visits were included in the estimation of the average treatment effect through Week 24. Analysis of change from baseline in BMI at Week 24 was based on the same MMRM as the analysis of primary endpoint; data obtained from Day 15, Week 4, Week 8, Week 12, Week 16, and Week 24 Visits was included in the model.




Analysis of change from baseline in SwCl at Week 4 was based on same MMRM as the analysis of primary endpoint; data obtained from Week 4, Week 8, Week 12, and Week 24 Visits was included in the model to estimate the treatment effect at Week 4. Analysis of change from baseline in CFQ-R RD score at Week 4 was based on same MMRM as the analysis of primary endpoint; data obtained from Week 4, Week 8, Week 12, Week 16, and Week 24 Visits was included in the model to estimate the treatment effect at Week 4. Missing Data Handling and Sensitivity Analysis Missing measurements were assumed to be missing at random in the MMRM model. For the primary endpoint, the Applicant conducted a sensitivity analysis using multiple imputation (MI) approach. Under MI approach, first, assuming that the imputation distribution for the missing change from baseline in ppFEV1 at visit “t” was a normal distribution, subjects were classified into one of the three categories according to pre-specified rules; second, the missing data in a category were imputed using a category specific normal distribution estimated using non-missing changed from baseline at visit “t” ; third, the 20 imputed datasets were analyzed using MMRM and the estimates were combined using SAS MIANALYZE to derive the MI estimator. Additional details may be found in the Applicant’s SAP. Multiplicity The overall type I error probability was controlled using a hierarchical testing procedure for key secondary endpoints if test of the primary endpoint is statistically significant. Within the key secondary endpoints, the test was conducted sequentially. Refer to Secondary Endpoints on page 111 for the testing order. Subgroup Analysis and Bayesian Shrinkage Subgroup Analysis To examine whether the treatment effects vary among the levels of a baseline factor, we conducted subgroup analyses on the primary endpoint, in the following categories using traditional subgroup analysis and the Bayesian shrinkage subgroup analysis:

• Age (>=12 to <18 years, or >=18 years) • Sex (Female, or Male) • ppFEV1 at baseline (<70, or >=70) • Region (Europe, or North America) • Prior use of inhaled antibiotic (No, or Yes) • Prior use of dornase alfa (No, or Yes) • Prior use of inhaled bronchodilator (No, or Yes) • Prior use of inhaled hypertonic saline (No, or Yes) • Prior use of inhaled corticosteroids (No, or Yes)




• Prior use of azithromycin (No, or Yes) • Pseudomonas aeruginosa status within 2 years prior to screening (Negative, or Positive)

Because >90% subjects were white, subgroup analysis on race was not conducted.

Protocol Amendments The study protocol was amended twice; key protocol changes included additional PK assessments, guidance on study drug interruption for rash, edited categories of eligible mutations, removal of exclusion criteria for glucose-6-phosphate dehydrogenase (G6PD) deficiency and history of hemolysis. There were two amendments to the SAP:

1. On December 17, 2018, the Applicant amended the analysis of SwCl such that subjects with a pre-dose SwCl value (average of left and right arms, if available) <60.0 mmol/L would be excluded. At the time the amendment was finalized, a total of 3 subjects (102-

, 102- , 102- ) were identified as potentially meeting this exclusion criterion based on the blinded assessment. This addendum also defined a Modified Full Analysis Set; at that time, the Applicant stated that no subjects were identified as potentially meeting these criteria.

2. On March 21, 2019, the Applicant amended the statistical analysis to add additional

statistical analysis for number of PEx through Week 24. The amendment stated that the analysis pre-specified in the protocol based on the negative binomial regression model would be performed first, and if the negative binomial regression did not converge, the analysis would be performed using the Poisson regression with the same covariates and offset. If the number of events were less than 5 in either treatment group, the analysis of event counts would be based on a Fisher’s Exact test.

8.1.2 Trial 102 Results

Compliance with Good Clinical Practices The Applicant states that the study was conducted in accordance with Good Clinical Practices as described in the International Conference for Harmonization (ICH) guidelines. The study protocol, amendments, informed consent, and other necessary documents were reviewed and approved by an independent ethics committee or institutional review board for each study site before initiation of the study at that site. Written informed consent was obtained from each subject before study participation. This study was conducted under IND 132,547.

Financial Disclosure The Applicant has adequately disclosed financial interests and arrangements with clinical investigators as recommended in the guidance for industry Financial Disclosure by Clinical Investigators (Appendix Section 15.1).


(b) (6) (b) (6) (b) (6)



Patient Disposition Trial 102 had high completion rates. Although three patients prematurely discontinued from the ELX/TEZ/IVA arm, the percentages of subjects completing the trial were balanced across treatment arms.

Table 22. Subject Disposition, Trial 102 Disposition

Reason Placebo

n (%) ELX/TEZ/IVA

n (%) Total n (%)

All Subjects Set 204 201 405 Randomized 204 201 405 Randomized but not dosed 1 1 2 FAS 1 203 200 403 iFAS 2 203 200 403 Safety Set 3 201 202 403 Completed treatment 203 (100) 197 (98) 400 (99)

Prematurely discontinued treatment 0 3 (2) 3 (<1) Adverse event 0 2 (1) 2 (<1) Pregnancy (self or partner) 0 1 (<1) 1 (<1)

Completed study 4 203 (100) 197 (98) 400 (99)

Prematurely discontinued study 0 3 (2) 3 (<1)

Adverse event 0 1 (<1) 1 (<1)

Withdrawal of consent (not due to AE) 0 1 (<1) 1 (<1)

Other 0 1 (<1) 1 (<1)

ELX: elexacaftor, TEZ: tezacaftor, IVA: ivacaftor, n: size of subsample; FAS: Full Analysis Set; iFAS: interim Full Analysis Set; AE: adverse event 1 FAS includes all randomized subjects with intended CFTR allele mutation and received at least 1 dose of study drug. 2 iFAS was defined as all subjects in the FAS who completed the Week 4 Visit or were randomized at least 28 days before the IA data cutoff date.

3 Safety Set includes all subjects who received at least 1 dose of study drug. 2 subjects were randomized to the placebo group, yet received at least 1 dose of active study drug. These subjects were counted in the placebo group for the FAS and in the ELX/TEZ/IVA group for the Safety Set. Subject IDs: 102- and 102- . 4 Completed study defined as completed Week 24 Visit, with Safety Follow-up, or rolled over to open-label study within 28 days. Source: Clinical Study Report, Trial VX17-445-102, Table 10-1, page 58 and verified with ADSL.xpt in JMP 12.0.

Protocol Violations/Deviations The Applicant defined an important protocol deviation (IPD) as a deviation with potential to significantly impact the completeness, accuracy, and/or reliability of the study data or to significantly affect the subject’s rights, safety, or well-being. In general, the number of IPDs was low, and occurred more frequently in the placebo arm. The number and type of IPDs are unlikely to impact the outcome of the trial.


(b) (6) (b) (6)



Table 23. Important Protocol Deviations, Trial 102, FAS Protocol Deviation Placebo

N=203 n (%)

ELX/TEZ/IVA N=200 n (%)

Total N=403 n (%)

Exclusion criteria 3 (1) 0 3 (<1) Use of prohibited medication 1 2 (1) 0 2 (<1) Acute illness within 28 days of study start 1 (<1) 0 1 (<1)

Safety assessment 2 5 (2) 1 (<1) 6 (1) Study drug 3 2 (1) 0 2 (<1)

Other 4 0 2 (1) 2 (<1) ELX: elexacaftor, TEZ: tezacaftor, IVA: ivacaftor, n: size of subsample; FAS: Full Analysis Set 1 Use of itraconazole or clarithromycin when enrolled. 2 Subjects < 14 years of age incorrectly considered of non-childbearing potential and 1 or more pregnancy test was not performed. 3 Placebo subjects dispensed ELX/TEZ/IVA or IVA. Subjects assigned to placebo in FAS and ELX/TEZ/IVA in SAS. See discussion in Section 8.2.3. 4 Two subjects used rifampicin or clarithromycin during study Source. Table 13.1.2.3, Listing 16.2.2. Reviewer verified using DV.xpt dataset in JMP 12.0.

Demographic Characteristics Subjects in Trial 102 were predominately young (mean/median age, 24 to 26 years), white (92%) and non-Hispanic (90%) adults, which reflects the demographics of the CF patient population. There were no major differences in demographic characteristics between the study arms.




Table 24. Demographic Characteristics of the Primary Efficacy Analysis, FAS

Characteristic Placebo (N=203)

n (%)

ELX/TEZ/IVA (N=200)

n (%)

Total (N=403)

n (%) Sex

Male 105 (52) 104 (52) 209 (52) Female 98 (48) 96 (48) 194 (48)

Age Mean years (SD) 26.8 (11.3) 25.6 (9.7) 26.2 (10.5) Median (years) 25.0 24.4 24.4 Min, max (years) 12.3, 64.0 12.1, 59.9 12.1, 64.0

Age Group 12 to <18 years 60 (30) 56 (28) 116 (29) ≥18 years to <65 years 143 (70) 144 (72) 287 (71)

Race White 184 (91) 186 (93) 370 (92) Black or African American 2 (1) 4 (2) 6 (1) Asian 1 (<1) 0 1 (<1) American Indian or Alaska Native 1 (<1) 0 1 (<1) Other 1 (<1) 2 (1) 3 (<1) Not collected per local regulations 1 16 (8) 9 (5) 25 (6)

Ethnicity Hispanic or Latino 12 (6) 4 (2) 16 (4) Not Hispanic or Latino 175 (86) 187 (94) 362 (90) Not collected per local regulations 1 16 (8) 9 (4) 25 (6)

Region North America 120 (59) 118 (59) 238 (59) Europe (including Australia) 83 (41) 82 (41) 165 (41)

ELX: elexacaftor, TEZ: tezacaftor, IVA: ivacaftor, n: size of subsample; FAS: Full Analysis Set; SD: standard deviation

1 Data on race and/or ethnicity were not collected because of local regulations. Source. CSR Study VX17-445-102, Table 10-2. Confirmed with ADSL.xpt in JMP 12.0 selecting FASFL(Y) and variables AAGE, SEX, RACE, RACE1, RACE2, RACE3, RACE4, AETHNIC, REGION1, STRAT2 by TRT01P.

Other Baseline Characteristics (e.g., disease characteristics, important concomitant drugs) Overall, the baseline disease characteristics and background therapy were balanced across the two treatment arms (Table 25). The majority of enrolled patients were colonized by pseudomonas (71%). The trial population had a mean baseline ppFEV1 of 61.4% and a CFQ-R RD score of 69.1.

Table 25. Baseline Characteristics of the Primary Efficacy Analysis, FAS: Trial 102 Parameter Placebo

(N=203) ELX/TEZ/IVA

(N=200) Total

(N=403) ppFEV1

Mean (SD) 61.3 (15.5) 61.6 (15.0) 61.4 (15.2) Median 60.9 61.6 61.2 Min, max 32.3, 93.7 33.8, 97.1 32.3, 97.1




Parameter Placebo (N=203)

ELX/TEZ/IVA (N=200)

Total (N=403)

ppFEV1 by severity group, n (%) <40% 16 (8) 18 (9) 34 (8) ≥40 to <70% 120 (59) 114 (57) 234 (58) ≥70 to <90% 62 (30) 66 (33) 128 (32) >90% 5 (2) 2 (1) 7 (2)

SwCl (mmol/L) Mean (SD) 102.9 (9.8) 102.3 (11.9) 102.6 (10.9) Median 104.0 103.0 103.5 Min, max 68.5, 137.0 22.5 1, 156.0 22.5, 156.0

Weight (kg) Mean (SD) 58.3 (12.7) 59.8 (12.9) 59.1 (12.8) Median 58.0 58.0 58.0 Min, max 31.3, 105.2 29.0, 108.0 29.0, 108.0

BMI (kg/m2) Mean (SD) 21.31 (3.14) 21.49 (3.07) 21.40 (3.10) Median 20.80 21.36 21.00 Min, max 14.42, 33.80 15.01, 30.86 14.42, 33.80

CFQ-R respiratory domain score (points) Mean (SD) 70.0 (17.8) 68.3 (16.9) 69.1 (17.3) Median 72.2 72.2 72.2 Min, max 16.7, 100.0 16.7, 100.0 16.7, 100.0

Background therapy, 2 n (%) Dornase alfa 164 (81) 162 (81) 326 (81) Azithromycin 114 (56) 110 (55) 224 (56) Inhaled antibiotic 132 (65) 118 (59) 250 (62) Inhaled Bronchodilator 191 (94) 187 (94) 378 (94) Inhaled hypertonic saline 127 (63) 147 (74) 274 (68) Inhaled corticosteroids 119 (59) 120 (60) 239 (59)

Pseudomonas colonization within 2 years Positive 142 (70) 150 (75) 292 (72)

BMI: body mass index; CFQ-R: Cystic Fibrosis Questionnaire-Revised; FAS: Full Analysis Set; IVA: ivacaftor; n: size of subsample; N: total sample size; ppFEV1: percent predicted forced expiratory volume in 1 second; SwCl: sweat chloride; TEZ: tezacaftor; kg: kilograms, m: meter 1 Reflects subjects 102- and 102- enrolled before the protocol amendment restricting enrollment for SwCl < 60 mmol/L. 2 Medications administered within 56 days before first dose study drug. Source. CSR Study VX17-445-102, Table 10-3. Confirmed with ADSL.xpt in JMP 12.0 selecting FASFL(Y) and variables PPFEV1BL, PPFEVG1, SWBL, CFQRRBL, BMIBL, WTBL, PSEUGR1 by TRT01P. The enrolled population included 79 different MF mutations. Most subjects had a Class I mutation (314, 78%) and the remainder had missense or in-frame deletions (89, 22%). Specific mutations reported in at least 6 trial subjects appear in Table 26.


(b) (6) (b) (6)



Table 26. Genotype Distribution for Mutations Occurring in at Least 6 Subjects, Trial 102, FAS

Genotype Placebo (N=203)

n (%)

ELX/TEZ/IVA (N=200)

n (%)

Total (N=403)

n (%) F508del/G542X 40 (20) 25 (13) 65 (16)

F508del/N1303K 21 (10) 19 (10) 40 (10)

F508del/621+1G>T 13 (6) 14 (7) 27 (7)

F508del/1717-1G>A 12 (6) 12 (6) 24 (6)

F508del/R553X 11 (5) 8 (4) 19 (5)

F508del/W1282X 9 (4) 9 (5) 18 (4)

F508del/R1162X 7 (3) 7 (3) 14 (3)

F508del/CFTR dele2, 3 4 (2) 7 (3) 11 (3)

F508del/3659delC 3 (1) 7 (3) 10 (2)

F508del/R347P 3 (1) 7 (3) 10 (2)

F508del/I507del 5 (2) 4 (2) 9 (2)

F508del/2184insA 7 (3) 1 (<1) 8 (2)

F508del/G85E 3 (1) 5 (2) 8 (2)

F508del/1898+1G>A 4 (2) 4 (2) 8 (2)

F508del/1154insTC 3 (1) 4 (2) 7 (2)

F508del/E60X 5 (2) 1 (<1) 6 (1)

ELX: elexacaftor, TEZ: tezacaftor, IVA: ivacaftor, n: size of subsample; FAS: Full Analysis Set Source. Reviewer calculated in JMP 12.0 with ADLB FASFL(Y) by TRT01P and CFGENOTP. Review of medical history noted a 5% or greater difference between the placebo and ELX/TEZ/IVA subjects reporting chronic sinusitis (26% vs 38%), bronchiectasis (21% vs 28%), bronchopulmonary aspergillosis allergic (11% vs 16%), drug hypersensitivity (18% vs 23%), and depression (11% vs 17%). However, overall the subject medical history and prior medication use were consistent with a CF subject population, and sufficiently balanced across the two arms.

Treatment Compliance, Concomitant Medications, and Rescue Medication Use Site personnel reviewed compliance at each study visit and reminded subjects of requirements. Investigators formally assessed compliance by ongoing study drug count. The Applicant calculated the compliance rate using the following formula:

𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 = 100 𝑥𝑥 [1 −𝑡𝑡𝑐𝑐𝑡𝑡𝑐𝑐𝑐𝑐 𝑑𝑑𝑐𝑐𝑑𝑑𝑑𝑑 𝑑𝑑𝑡𝑡𝑢𝑢𝑑𝑑𝑑𝑑 𝑑𝑑𝑑𝑑𝑢𝑢𝑑𝑑 𝑐𝑐𝑐𝑐𝑡𝑡𝑐𝑐𝑑𝑑𝑑𝑑𝑢𝑢𝑐𝑐𝑡𝑡𝑐𝑐𝑐𝑐𝑐𝑐

𝑑𝑑𝑢𝑢𝑑𝑑𝑐𝑐𝑡𝑡𝑐𝑐𝑐𝑐𝑐𝑐 𝑐𝑐𝑜𝑜 𝑑𝑑𝑡𝑡𝑢𝑢𝑑𝑑𝑑𝑑 𝑑𝑑𝑑𝑑𝑢𝑢𝑑𝑑 𝑐𝑐𝑥𝑥𝑐𝑐𝑐𝑐𝑑𝑑𝑢𝑢𝑑𝑑𝑐𝑐 𝑑𝑑𝑐𝑐𝑑𝑑𝑑𝑑

The mean compliance rate was approximately 99% for both the placebo and ELX/TEZ/IVA arms. About 2.0% in each arm reported <80% of tablets taken. Concomitant medication use, defined as medication that was continued or newly received during the Treatment Emergent Period (TE Period), reflected a CF population and was generally balanced across the arms. Comparison of concomitant medications use by Anatomical Therapeutic Chemical categories was notable for small differences in the use of systemic




antibacterial medications (98% vs 92%) for placebo and ELX/TEZ/IVA arms, respectively. Individual medications with greater than a 5% difference between trial arms appear in Table 27.

Table 27. Concomitant Medications With Rate Difference of ≥5% Between the ELX/TEZ/IVA and Placebo Arms, Trial 102, FAS

Medication (Preferred name) Placebo (N=203)

ELX/TEZ/IVA (N=200)

Total (N=403)

Sodium chloride 152 (75) 163 (82) 315 (78) Tobramycin 113 (56) 78 (39) 191 (47) Ursodeoxycholic acid 43 (21) 56 (28) 99 (25) Sulfamethoxazole ; trimethoprim 53 (26) 34 (17) 87 (22) Ciprofloxacin 71 (35) 32 (16) 103 (26) Colistimethate sodium 45 (22) 28 (14) 73 (18) Tocopherol 34 (17) 21 (10) 55 (14) Levofloxacin 43 (21) 13 (6) 56 (14) Prednisone 31 (15) 11 (6) 42 (10) Doxycycline 25 (12) 9 (4) 34 (8) Ondansetron 18 (9) 7 (4) 40 (10) Ceftazidime 34 (17) 6 (3) 25 (6) Linezolid 14 (7) 3 (2) 17 (4)

Subjects counted once for each medication. Concomitant medication was defined as medication that was continued or newly received during the Treatment Emergent Period. ELX: elexacaftor, TEZ: tezacaftor, IVA: ivacaftor, n: size of subsample; FAS: Full Analysis Set Source. CSR VX17-445-102, Table 14.1.6.2. Reviewer confirmed using ADAM dataset in JMP 12.0 selecting for FASFL(Y) ONTRTFL(Y) by CMDECOD and TRT01P.

Efficacy Results – Primary Endpoint For Trial 102 the primary endpoint was change from baseline in ppFEV1 at Week 4. Treatment with ELX/TEZ/IVA resulted in statistically significant improvements in ppFEV1 at Week 4 compared to placebo. The LS mean treatment difference for the ELX/TEZ/IVA group versus placebo for the change from baseline in ppFEV1 at Week 4 was 13.8% (95% CI: 12.1, 15.4; p<0.0001). These data are summarized in Table 28.

Table 28. MMRM Analysis of Absolute Change from Baseline in ppFEV1 (%) at Week 4 (iFAS, Trial 102)

Parameter Placebo N = 203

ELX/TEZ/IVA N = 200

Mean (SD) of ppFEV1 at baseline 61.3 (15.5) 61.6 (15.0) N at week 4 188 185 LS mean change from baseline in ppFEV1 at week 4

-0.2 13.6

LS mean difference, 95% CI 13.8 (12.1, 15.4)

P value versus placebo <0.0001 Source: Statistical Reviewer




For the primary endpoint, the overall missing rate is low at each visit. Please refer to “Discussion of Estimands, Missing Data Handling, and Sensitivity Analyses”, in Section 8.1.4 where missing data in both trials (102 and 103) will be discussed together.

Data Quality and Integrity This review did not reveal any inconsistencies in the data or issues with trial design or conduct which might influence the efficacy results.

Efficacy Results – Secondary and other relevant endpoints Testing treatment differences in each of the key secondary endpoints achieved statistical significance in Trial 102. Treatment with ELX/TEZ/IVA resulted in statistically significant improvements in ppFEV1 through Week 24 compared to placebo, demonstrating that the improvements observed at Week 4 were sustained through Week 24. The LS mean treatment difference for the ELX/TEZ/IVA group versus placebo for the change from baseline in ppFEV1 through Week 24 was 14.3% (95% CI: 12.7, 15.8; p<0.0001). These data are summarized in Table 29 and Figure 6.

Table 29. MMRM Analysis of Absolute Change from Baseline in ppFEV1 (%) Through Week 24 (FAS, Trial 102)


ELX/TEZ/IVA N = 200

Mean (SD) of ppFEV1 at baseline: % 61.3 (15.5) 61.6 (15.0) N at week 24 203 196 LS mean change from baseline in ppFEV1 at week 24

-0.4 13.9






Figure 6. MMRM Analysis of Absolute Change from Baseline in ppFEV1 (%) by Visit (FAS, Trial 102)

Source: Statistical Reviewer Treatment with ELX/TEZ/IVA resulted in statistically significant reduction in PEx through Week 24, with a PEx rate ratio of 0.37 compared to placebo group (95% CI: 0.25, 0.55; p<0.0001). These data are summarized in Table 30.

Table 30. Negative Binomial Analysis of the Number of Pulmonary Exacerbations During the Pulmonary Exacerbation Analysis Period (FAS, Trial 102)


ELX/TEZ/IVA N = 200

Number of subjects with events, n (%)

76 (37.4) 31 (15.5)

Number of events 113 41 Estimated event rate per year 0.98 0.37 Rate ratio, 95% CI 0.37 (0.25,0.55) P value versus placebo <0.0001

Source: Statistical Reviewer




Treatment with ELX/TEZ/IVA resulted in statistically significant improvements (i.e., reduction) in SwCl through Week 24 compared to placebo. The LS mean treatment difference for the ELX/TEZ/IVA group versus placebo group for the change from baseline in SwCl through Week 24 was -41.8 mmol/L (95%CI: -44.4, -39.3; p<0.0001). These data are summarized in Table 31.

Table 31. MMRM Analysis of Absolute Change from Baseline in Sweat Chloride (mmol/L) Through Week 24 (FAS, Trial 102)


ELX/TEZ/IVA N = 200

Mean (SD) of SwCl at baseline 102.9 (9.8) 102.3 (11.9) N at week 24 201 199 LS mean change from baseline in SwCl through week 24

-0.4 -42.2

LS mean difference, 95% CI -41.8 (-44.4, -39.3)


Treatment with ELX/TEZ/IVA resulted in statistically significant improvements in CFQ-R RD score through Week 24 compared to placebo. The LS mean treatment difference for the ELX/TEZ/IVA group versus placebo group for the change from baseline in CFQ-R RD score through Week 24 was 20.2 points (95%CI: 17.5, 23.0; p<0.0001). These data are summarized in Table 32.

Table 32. MMRM Analysis of Absolute Change from Baseline in Cystic Fibrosis Questionnaire-Revised Respiratory Domain Score (Points) Through Week 24 (FAS, Trial 102)


ELX/TEZ/IVA N = 200

Mean (SD) of CFQ-R RD score at baseline

70.0 (17.8) 68.3 (16.9)

N at week 24 203 200 LS mean change from baseline in CFQ-R RD score through week 24

-2.7 17.5



Treatment with ELX/TEZ/IVA resulted in statistically significant improvements in BMI at Week 24 compared to placebo. The LS mean treatment difference for the ELX/TEZ/IVA group versus placebo group for the change from baseline in BMI at Week 24 was 1.04 kg/m2 (95%CI: 0.85, 1.23; p<0.0001). These data are summarized in Table 33.

Table 33. MMRM Analysis of Absolute Change from Baseline in BMI (kg/m2) at Week 24 (FAS, Trial 102)


ELX/TEZ/IVA N = 200

Mean (SD) of BMI at baseline 21.31 (3.14) 21.49 (3.07) N at week 24 202 198





ELX/TEZ/IVA N = 200

LS mean change from baseline in BMI at week 24

0.09 1.13



Treatment with ELX/TEZ/IVA resulted in statistically significant improvements (i.e., reduction) in SwCl at Week 4 compared to placebo. The LS mean treatment difference for the ELX/TEZ/IVA group versus placebo group for the change from baseline in SwCl at Week 4 was -41.2 mmol/L (95%CI: -44.0, -38.5; p<0.0001). These data are summarized in Table 34.

Table 34. MMRM Analysis of Absolute Change from Baseline in Sweat Chloride (mmol/L) at Week 4 (FAS, Trial 102)


ELX/TEZ/IVA N = 200

Mean (SD) of SwCl at baseline 102.9 (9.8) 102.3 (11.9) N at week 4 196 193 LS mean change from baseline in SwCl at week 4

0.1 -41.2



Treatment with ELX/TEZ/IVA resulted in statistically significant improvements in CFQ-R RD score at Week 4 compared to placebo. The LS mean treatment difference for the ELX/TEZ/IVA group versus placebo group for the change from baseline in CFQ-R RD score at Week 4 was 20.1 points (95%CI: 16.9, 23.2; p<0.0001). These data are summarized in Table 35.

Table 35. MMRM Analysis of Absolute Change from Baseline in CFQ-R RD Score (Points) at Week 4 (FAS, Trial 102)


ELX/TEZ/IVA N = 200

Mean (SD) of CFQ-R RD score at baseline

70.0 (17.8) 68.3 (16.9)


-1.9 18.1



Dose/Dose Response Trial 102 included a single dosage level. Section 8.1.5 discusses dose response.




Durability of Effect Treatment with ELX/TEZ/IVA resulted in sustained improvements in ppFEV1 over the entire 24-week treatment period (Figure 6). With respect to additional key secondary endpoints, there were sustained effects for absolute changes in SwCl (Figure 7), CFQ-R RD (Figure 8), and BMI (Figure 9) over the entire 24 week treatment period.

Figure 7. Absolute Change from Baseline in SwCl by Visit, Trial 102 (FAS)





Figure 8. Absolute Change from Baseline in CFQ-R RD Score by Visit, Trial 102 (FAS)





Figure 9. Absolute Change from Baseline in BMI by Visit, Trial 102 (FAS)


Efficacy Results – Secondary or exploratory COA (PRO) endpoints The Applicant’s exploratory analysis of additional secondary endpoints was notable for a nominal decrease in time to first PEx through 24 weeks for ELX/TEZ/IVA vs placebo (HR 0.34; 95% CI: 0.22, 0.52). Improvements were observed for absolute change from baseline in BMI z-score and body weight at Week 24, with a treatment difference in BMI z-score of 0.30 (95% CI: 0.17, 0.43), and a treatment difference in body weight of 2.9 kg (95% CI: 2.3, 3.4) for ELX/TEZ/IVA versus placebo.

Additional Analyses Conducted on the Individual Trial The review team conducted an exploratory analysis of change from baseline in FEV1 (liters) using an MMRM model and adjusting for the same covariates as the analysis of primary endpoint. The LS mean difference in FEV1 between ELX/TEZ/IVA and placebo at Week 24 was 0.51 liters (95% CI: 0.392, 0.631; p<0.0001). These data are summarized in Table 36 and Figure 10.




Table 36. MMRM Analysis of Absolute Change from Baseline in FEV1 (L) at Week 24 (FAS, Trial 102)


ELX/TEZ/IVA N = 200

Mean (SD) of ppFEV1 at baseline: % N at week 24 203 196 LS mean change from baseline in ppFEV1 at week 24

-0.042 0.470



Figure 10. MMRM Analysis of Absolute Change from Baseline in FEV1 by Visit (FAS, Trial 102)

Source: Statistical Reviewer (post hoc analysis)

Traditional Subgroup Analysis

Traditional subgroup analysis of the primary endpoint used the same MMRM model used in the primary analysis, but for a subset of the data for each group.




Figure 11 presents the traditional subgroup analysis results of primary endpoint change from baseline in ppFEV1 at Week 4 for Trial 102. Tests of treatment difference in all subgroups evaluated reached statistical significance as all the 95% CIs were greater than zero. These results are consistent with the overall result.

Figure 11. Least Squares Mean Difference Between Treatments With 95% CI for Change From Baseline in ppFEV1 at Week 4 by Subgroup (iFAS, Trial 102)

Abbreviations: ppFEV1BL – Baseline ppFEV1, PUHA – Prior use of inhaled antibiotic, PUDA – Prior use of dornase alfa, PUIB – Prior use of inhaled bronchodilator, PUHS – Prior use of inhaled hypertonic saline, PUIC – Prior use of inhaled corticosteroids, PUAZ – Prior use of azithromycin, PSAS – Pseudomonas aeruginosa status within 2 years prior to screening , N – No, Y – Yes, TC – ELX/TEZ/IVA, PBO – Placebo, LCL – lower confident limit, UCL – upper confident limit, CFB – change from baseline, diff – difference Source: Statistical Reviewer

Bayesian Shrinkage Subgroup Analysis

We also determined shrinkage estimates of subgroup treatment effects using a Bayesian hierarchical model. Shrinkage estimates use more information and are more precise and closer to the true subgroup treatment effects than the sample estimates. In traditional subgroup analyses, sample estimates are susceptible to random highs and random lows due to small sample size or large variability for some subgroups. The total variability in the sample estimates is the sum of the within subgroup variability of the sample estimator and the




cross-subgroup variability in underlying true parameter values. A shrinkage estimate of the subgroup treatment effect, which borrows information from the other subgroups while estimating the treatment effect for a specific subgroup, is a “weighted” average of the sample estimate and overall estimate. With a shrinkage method, the sample estimate is “shrunk” towards the overall estimate. The weights are based on the ratio of the between subgroup variability to the within subgroup variability. The greater that ratio the smaller the weight on the overall estimate (the less the shrinkage). The Bayesian hierarchical model was used in this review as a shrinkage method with sample estimates from the traditional subgroup analysis with the same flat prior (i.e., non-informative prior) to derive shrinkage estimates for all subgroups and assumptions as followings: Yi: the observed sample estimate of treatment effect in a subgroup level i (i=1,2, …, total number of subgroups), assume Yi ~ N (µi, σi2) where

• σi2 are the observed variance for sample estimates • µi ~ N (µ, τ2) with µ ~ N (0, 0.0001), 1/τ2 ~ Gamma (0.001, 0.001)

Shrunken estimates and 95% credible interval (equivalent to the confidence interval of the sample estimate) are calculated and depicted in the forest plot. Figure 12 presents the Bayesian shrinkage subgroup analysis results of the primary endpoint change from baseline in ppFEV1 at Week 4 for Trial 102.




Figure 12. Least Squares Mean Difference Between Treatments With 95% CI for Change From Baseline in ppFEV1 at Week 4 by Subgroup Using Bayesian Shrinkage Subgroup Analysis (iFAS, Trial 102)

Abbreviations: ppFEV1BL – Baseline ppFEV1, PUHA – Prior use of inhaled antibiotic, PUDA – Prior use of dornase alfa, PUIB – Prior use of inhaled bronchodilator, PUHS – Prior use of inhaled hypertonic saline, PUIC – Prior use of inhaled corticosteroids, PUAZ – Prior use of azithromycin, PSAS – Pseudomonas aeruginosa status within 2 years prior to screening , N – No, Y – Yes, w/o – without, w/ – with, F – Female, M – Male Source: Statistical Reviewer

Examining Figure 12 , we found that:

• All the subgroup means from the Bayesian shrinkage subgroup analysis shrunk towards the overall mean

• All the 95% credible intervals of subgroup mean from Bayesian shrinkage subgroup analyses were narrower than the sample estimates’ 95% confidence interval

SubgroupAge >=12 to <18 >=18Sex F MppFEV1BL <70 >=70Region Europe N. AmericaPUHA N YPUDA N YPUIB N Y PUHS N YPUIC N YPUAZ N Y PSAS positive negative

Summary

diff w/oShrink 13.7713.6413.7713.6414.1613.0215.2912.6212.8614.0911.0914.3810.7814.021413.4913.3514.1113.2814.3113.913.74

13.8

diff w/Shrink13.6913.6613.6313.913.8113.514.2613.2213.4213.7512.7313.9813.0313.8713.7513.6213.6513.8113.7213.9913.8113.78

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18diff of TC vs Placebo in CFB ppFEV

w/o shrinkw/ shrink




• Although the Bayesian shrinkage subgroup analysis produced more accurate subgroup means and their credible intervals, the difference compared to the traditional subgroup analysis results were not large.

In Trial 102, the Applicant completed an exploratory ad-hoc analysis of the primary endpoint for the subpopulation of subjects with a “Class I MF allele.” The Applicant selected this subpopulation because the mutant allele does not generate a protein. The efficacy analysis in this population resulted in an absolute change from baseline in ppFEV1 through Week 24 increase of 14.8 percentage points compared to placebo (95% CI: 13.0, 16.6). This provides additional support for the proposed indication as it appears that only a single F508del allele is necessary to receive a treatment benefit.

8.1.3 VX17-445-103 (Trial 103) Study Design

Overview and Objective Trial 103 was a multinational pivotal trial to provide evidence of efficacy and safety of ELX in combination with TEZ/IVA in subjects with CF who are homozygous for the F508del mutation on the CFTR gene (F/F). The study was conducted from August 3, 2018 to December 28, 2018. Study Title: A Phase 3, Randomized, Double-blind, Controlled Study Evaluating the Efficacy and Safety of ELX Combination Therapy in Subjects With Cystic Fibrosis Who Are Homozygous for the F508del Mutation (F/F). Primary Objective:

• To evaluate the efficacy of ELX in triple combination with TEZ and IVA in subjects with CF who are homozygous for F508del.

Secondary Objectives • To evaluate the safety, PD and PK of ELX in triple combination with TEZ and IVA.

Trial Design This was a Phase 3, randomized, double-blind, active-controlled, parallel-group, multicenter study in subjects with CF with F/F genotype. After screening and a 4-week open label TEZ/IVA run-in, the study randomized eligible subjects (1:1) to ELX/TEZ/IVA or TEZ/IVA for a 4 week treatment period. The study stratified subjects by age at screening (<18 versus ≥18 years of age) and ppFEV1 (<70% versus ≥70% predicted measured on day -14). The trial schematic appears in Figure 13.




Figure 13. Design of Trial 103

VX-445 = ELX Source. Protocol VX17-445-103, page 4

Reviewer comment: TEZ/IVA is approved for treatment of CF in the F/F population and is an appropriate active control for the study; Study 661-106 of the TEZ/IVA development program demonstrated a statistically significant improvement in ppFEV1 of approximately 4.0 percentage points versus placebo through Week 24. A 4-week TEZ/IVA run-in is reasonable; previous studies with CFTR modulators demonstrated efficacy at Week 4. Inclusion of the TEZ/IVA comparator allows evaluation of the contribution of ELX to efficacy.

Trial Population The eligibility criteria for Trial 103 was like Trial 102 except the trial required subjects to have a F/F genotype. Study Drug Interruption Rules and Subject Removal Criteria The study drug interruption rules and subject removal criteria were similar to Trial 102. Dose and Duration of Treatment

Table 37. Dose and Duration of Treatment Study arm ELX TEZ IVA ELX/TEZ/IVA 200 mg qd 100 mg qd 150 mg q12h

TEZ/IVA 0 100 mg qd 150 mg q12h ELX: elexacaftor; IVA: ivacaftor; q12hr: every 12 hours; qd: once daily; TEZ: tezacaftor

Concomitant medications were similar to Trial 102.

Efficacy Endpoints

Primary Endpoint: • Absolute change in ppFEV1 from baseline at Week 4




Key Secondary Endpoints: • Absolute change in SwCl from baseline at Week 4 • Absolute change in CFQ-R RD score from baseline at Week 4

Additional Exploratory Endpoints (not reviewed in detail):

• Absolute change in Treatment Satisfaction Questionnaire for Medication domains from baseline at Week 4 (only for subjects aged ≥12 years to <18 years at the date of informed consent)

Efficacy and safety assessments and their methods of collection were similar to those described for Trial 102. The timing of assessments is outlined in Supportive Tables, Trial 103 Table 110.

Reviewer comment: The proposed efficacy endpoints are acceptable endpoints for a CF development program, and acceptable for a 4 week trial.

Statistical Analysis Plan Analysis Sets Four analysis sets were defined in this study: All Subjects set, Full Analysis Set, Safety Set for the Run-in Period, and Safety Set for the Treatment Period.

The All Subjects Set was defined as all subjects who were randomized or received at least 1 dose of study drug.

The Full Analysis Set (FAS) was defined as all randomized subjects who carry the intended CFTR allele mutation and received at least 1 dose of study drug in the treatment period.

The Safety Set for the Run-in Period was defined as all subjects who receive at least 1 dose of TEZ/IVA in the Run-in Period.

The Safety Set for the Treatment Period was defined as all subjects who receive at least 1 dose of study drug in the treatment period.

All the efficacy analyses were based on FAS.

Statistical Analysis Methods

1. Primary Endpoint The primary analysis of the primary endpoint of change from baseline in ppFEV1 at Week 4 used a MMRM with at Day 15 and Week 4 data as the dependent variable. The model included treatment group, visit, and treatment-by-visit interaction as fixed effects, with continuous baseline ppFEV1, and age at screening (<18 versus ≥18 years of age) as covariates.




The treatment comparison was ELX/TEZ/IVA group versus TEZ/IVA group. The treatment difference at Week 4 was estimated from the model. The adjusted means with 2-sided 95% confidence intervals and 2-sided P values were reported.

2. Key Secondary Endpoints There were two key secondary endpoints. They are listed in the following order of testing hierarchy:

• Change from baseline in SwCl at Week 4 • Change from baseline in CFQ-R RD score at Week 4

Analysis of change from baseline in SwCl and change from baseline in CFQ-R RD score used an MMRM similar to the analysis of the primary endpoint. The model included treatment, visit, and treatment-by-visit interaction as fixed effects with continuous baseline ppFEV1, and age at screening (<18 versus ≥18 years of age) as covariates. Missing Data Handling and Sensitivity Analysis Missing data handling and sensitivity analysis used same approach as in Trial 102. Multiplicity The overall type I error probability was controlled using the same hierarchical testing procedure as in Trial 102. Traditional Subgroup Analysis and Bayesian Shrinkage Subgroup Analysis Same as in Trial 102, subgroup analyses of the primary endpoint were conducted using both traditional subgroup analysis and Bayesian shrinkage subgroup analysis. Because all patients were White, a subgroup analysis by race was not conducted. The approach and parameters used in both traditional and Bayesian shrinkage analysis were the same as used in Trial 102. Please refer to Section 8.1.1 for details.

Protocol Amendments The global trial protocol was amended twice from the original version (February 1, 2018). The first amendment (April 13, 2018) added specific guidance for study drug interruption for rash, updated the Statistical Analysis section for clarity and updated the study drug regimen to ivacaftor (in place of deuterated ivacaftor). The second amendment (July 19, 2018) removed exclusion criteria for G6PD and history of hemolysis, clarified rules for subjects with CF not stable at the end of the Run-in period, updated the study drug interruption/stopping rules, and defining of the TE Period for the Run-in Period.




There were no changes to the SAP.

8.1.4 Trial 103 Results

Compliance with Good Clinical Practices The Applicant states that the study was conducted in accordance with Good Clinical Practices as described in ICH guidelines. The study protocol, amendments, informed consent, and other necessary documents were reviewed and approved by an independent ethics committee or institutional review board for each study site before initiation of the study at that site. Written informed consent was obtained from each subject before study participation. This study was conducted under IND 132,547.

Financial Disclosure The Applicant has adequately disclosed financial interests and arrangements with clinical investigators as recommended in the guidance for industry Financial Disclosure by Clinical Investigators (Section 15.1).

Patient Disposition Table 38 summarizes the disposition of patients in Trial 103. The study had high (100%) completion rates in both arms.

Table 38. Subject Disposition, Trial 103

Disposition TEZ/IVA

n (%) ELX/TEZ/IVA

n (%) Total n (%)

All Subjects Set 52 55 107 FASa 52 55 107 Safety Setb 52 55 107 Randomized 52 56 108 Randomized but not dosed in Treatment periodc 0 1 1 Completed treatment 52 (100) 55 (100) 107 (100) Prematurely discontinued treatment 0 0 0 Completed studyd 52 (100) 55 (100) 107 (100) Prematurely discontinued the study 0 0 0

ELX: elexacaftor, TEZ: tezacaftor, IVA: ivacaftor, n: size of subsample; FAS: Full Analysis Set a FAS includes all randomized subjects with intended CFTR allele mutation and received at least 1 dose of study drug. b Includes all subjects who received at least 1 dose of study drug. c Subject randomized prior to Day 1, not dosed in Treatment Period due to an AE. d Completed study defined as completed Week 4 Visit and either Safety Follow-up or rolled over to open-label study within 28 days.

Source: Clinical Study Report, Trial VX17-445-103, Table 10-2, p51 and verified with ADSL.xpt in JMP 12.0.

Protocol Violations/Deviations The Applicant reported two IPDs that included one subject in the ELX/TEZ/IVA arm for exclusion criteria (amoxicillin prophylaxis in run-in) and a second subject in the TEZ/IVA arm for safety assessment (no pregnancy test).




Table of Demographic Characteristics Table 39 summarizes patient demographic data. Patients were predominately young (mean/median age, 27 to 28 years), white (99%) and non-Hispanic (94%) adults. There were no major differences in demographic characteristics between the study arms.

Table 39. Demographic Characteristics of the Primary Efficacy Analysis, Trial 103, FAS

Characteristic

TEZ/IVA (N=52) n (%)

ELX/TEZ/IVA (N=55) n (%)

Total (N=107)

n (%) Sex

Male 24 (46) 24 (44) 48 (45) Female 28 (54) 31 (56) 59 (55)

Age Mean years (SD) 27.9 (10.8) 28.8 (11.5) 28.4 (11.1) Median (years) 27.6 27.4 27.4 Min, max (years) 12.4, 60.5 12.7, 54.1 12.4, 60.5

Age Group 12 to <18 years 14 (27) 16 (29) 30 (28) ≥18 years to <65 years 38 (73) 39 (71) 77 (72)

Race White 52 (100) 54 (98) 106 (99) Black or African American 0 0 0 Asian 0 0 0 American Indian or Alaska Native 0 0 0 Other 0 0 0 Not collected per local regulations 0 1 (2) 1 (<1)

Ethnicity Hispanic or Latino 3 (6) 2 (4) 5 (5) Not Hispanic or Latino 49 (94) 52 (94) 101 (94) Not collected per local regulations 0 1 (2) 1 (<1)

Region North America 33 (63) 34 (62) 67 (63) Europe (including Australia) 19 (37) 21 (38) 40 (37)

ELX: elexacaftor, TEZ: tezacaftor, IVA: ivacaftor, n: size of subsample; FAS: Full Analysis Set, SD: standard deviation Source. Reviewer calculated with ADSL.xpt in JMP 12.0 selecting FASFL(Y) and variables AAGE, SEX, RACE, AETHNIC, REGION1, STRAT2 by TRT01P.

Other Baseline Characteristics (e.g., disease characteristics, important concomitant drugs) The trial population had mean baseline ppFEV1 of 60.9% and CFQ-R RD score of 71.5. The majority of enrolled patients were colonized by Pseudomonas (65%); however, numerically more ELX/TEZ/IVA subjects (71%) were colonized with Pseudomonas than TEZ/IVA subjects (60%). There were also small imbalances between the ELX/TEZ/IVA and TEZ/IVA arms with the use of hypertonic saline (69% vs 79%), inhaled corticosteroids (65% vs 54%) and azithromycin (60% vs 48%) between the two trial arms, respectively. Table 40 summarizes the baseline characteristics for Trial 103.




Table 40. Baseline Characteristics of the Primary Efficacy Analysis, FAS: Trial 103

Characteristic TEZ/IVA (N=52)

ELX/TEZ/IVA (N=55)

Total (N=107)

ppFEV1 Mean (SD) 60.2 (14.4) 61.6 (15.4) 60.9 (14.9) Median 58.4 61.0 59.2 Min, max 35.0, 89.0 35.0, 87.4 35.0, 89.0

ppFEV1 by severity group, n (%) <40% 4 (8) 6 (11) 10 (9) ≥40 to <70% 34 (65) 31 (56) 65 (61) ≥70 to ≤90% 14 (27) 18 (33) 32 (30) >90% 0 0 0

SwCl (mmol/L) Mean (SD) 90.0 (12.3) 91.4 (11.0) 90.7 (11.6) Median 90.8 92.8 92.3 Min, max 60.6, 112.0 67.0, 114.0 60.5, 114.0

Weight (kg) Mean (SD) 59.8 (14.8) 59.9 (12.7) 59.9 (13.7) Median 55.0 59.0 57.0 Min, max 36.0, 100.0 36.0, 91.2 36.0, 100.0

BMI (kg/m2) Mean (SD) 21.9 (4.1) 21.7 (3.2) 21.8 (3.7) Median 20.7 21.3 21.2 Min, max 15.6, 34.6 16.0, 28.4 15.6, 34.6

CFQ-R RD score (points) Mean (SD) 72.6 (17.9) 70.6 (16.2) 71.5 (17.0) Median 72.2 72.2 72.2 Min, max 27.8, 100.0 22.2, 94.4 22.2, 100.0

Background therapy, n (%) Dornase alfa 48 (92) 51 (93) 99 (92) Azithromycin 25 (48) 33 (60) 58 (54) Inhaled antibiotic 28 (54) 35 (64) 63 (59) Inhaled Bronchodilator 47 (90) 54 (98) 101 (94) Inhaled hypertonic saline 41 (79) 38 (69) 79 (74) Inhaled corticosteroids 28 (54) 36 (65) 64 (60)

Prior CFTR modulator use, n (%) Tezacaftor / ivacaftor 20 (38) 17 (31) 37 (35) Lumacaftor / ivacaftor 14 (27) 14 (25) 28 (26)

Pseudomonas colonization within 2 years Positive 31 (60) 39 (71) 70 (65)

BMI: body mass index; CFQ-R: Cystic Fibrosis Questionnaire-Revised; FAS: Full Analysis Set; IVA: ivacaftor; n: size of subsample; N: total sample size; ppFEV1: percent predicted forced expiratory volume in 1 second; SwCl: sweat chloride; TEZ: tezacaftor. Baseline was defined as the most recent non-missing measurement before the first dose of study drug in the Treatment Period. Source. CSR VX17-445-103 Table 14.1.6.1. Reviewer calculated with ADSL.xpt in JMP 12.0 selecting FASFL(Y) and variables PPFEV1BL, PPFEVG1, SWBL, CFQRRBL, BMIBL, WTBL, PSEUGR1 by TRT01P.




Medical history was generally balanced with the exception of the following preferred terms (PTs): sinus disorder (13% vs 25%), constipation (27% vs 19%), bronchiectasis (13% vs 23%), gastroesophageal reflux disease (45% vs 60%) and bronchopulmonary aspergillosis allergic (20% vs 12%) for ELX/TEZ/IVA compared to TEZ/IVA, respectively.

Reviewer comment: Overall, the baseline disease characteristics and background therapy were sufficiently similar.

Treatment Compliance, Concomitant Medications, and Rescue Medication Use Investigators evaluated compliance on an ongoing basis by review of missed doses. There were no study drug interruptions or major compliance issues identified. The Applicant identified no subjects reporting <80% tablets taken during the trial.

Efficacy Results – Primary Endpoint

For Trial 103 the primary endpoint was change from baseline in ppFEV1 at Week 4.

Treatment with ELX/TEZ/IVA resulted in statistically significant improvements in ppFEV1 at Week 4 compared to TEZ/IVA. The LS mean treatment difference for the ELX/TEZ/IVA group versus TEZ/IVA group for the change from baseline in ppFEV1 at Week 4 was 10.0% (95% CI: 7.4, 12.6; p<0.0001). These data are summarized in Table 41.

Table 41. MMRM Analysis of Absolute Change from Baseline in ppFEV1 (%) at Week 4 (FAS, Trial 103)

Parameter TEZ/IVA

N=52 ELX/TEZ/IVA

N=55 Mean (SD) of ppFEV1 at baseline 60.2 (14.4) 61.6 (15.4) N at week 4 49 53 LS mean change from baseline in ppFEV1 at week 4

0.4 10.4


P value versus TEZ/IVA <0.0001 Source: Statistical Reviewer

Discussion of Estimands, Missing Data Handling, and Sensitivity Analyses The Applicant did not specify the target estimand in the SAP for Trial 102 or 103. The number of subjects who prematurely discontinued study treatment in both trials was very low. In Trial 102, only 3 subjects (all in ELX/TEZ/IVA group) and 0 subjects in placebo group discontinued the study treatment prematurely. InTrial 103, no subjects discontinued the study treatment. After treatment discontinuation, lung function data were not collected for these subjects. Thus, the study did not target the treatment policy estimand. There were some missing measurements at different visits for some subjects. Table 42 lists numbers of missing measurements at different visits by treatment group for for the primary endpoint in Trials 102 and 103. Overall, the percentage in each arm is low. In the primary




analysis, the MMRM treats these missing measurements as missing at random. The Applicant conducted sensitivity analyses using multiple imputation with assumptions of missing not at random, and the results were consistent with the primary analysis results. Therefore, the sensitivity analyses support the robustness of analysis results regarding missing data.

Table 42. Number and Percentage of Missing Measurements in Primary Endpoint ppFEV1 by Visits (FAS, Trial 102 & Trial 103)

Visit

Trial 102 Trial 103 PBO

N=203 ELX/TEZ/IVA

N=200 TEZ/IVA

N=52 ELX/TEZ/IVA

N=55 Day 15 16 (8%) 15 (8%) 1 (2%) 3 (5%) Week 4 15 (7%) 15 (8%) 3 (6%) 2 (4%) Week 8 9 (4%) 14 (7%) n/a Week 12 9 (4%) 17 (9%) Week 16 12 (6%) 13 (7%) Week 24 12 (6%) 17 (9%)


Data Quality and Integrity This review did not reveal any inconsistencies in the data or issues with trial design or conduct which might influence the efficacy results.

Efficacy Results – Secondary and other relevant endpoints Testing of treatment difference in each of the key secondary endpoints achieved statistical significance in Trial 103. Treatment with ELX/TEZ/IVA resulted in a statistically significant decrease in SwCl at Week 4 compared to TEZ/IVA, with an LS mean treatment difference of -45.1 mmol/L (95% CI: -50.1, -40.1; p<0.0001). These data are summarized in Table 43.

Table 43. MMRM Analysis of Absolute Change from Baseline in SwCl (mmol/L) at Week 4 (FAS, Trial 103)

Parameter TEZ/IVA

N=52 ELX/TEZ/IVA

N=55 Mean (SD) of SwCl at baseline 90.0 (12.3) 91.4 (11.0) N at week 4 48 54 LS mean change from baseline in SwCl at week 4

1.7 -43.4



Treatment with ELX/TEZ/IVA resulted in a statistically significant increase in CFQ-R RD scores at Week 4 compared to TEZ/IVA, with an LS mean treatment difference of 17.4 points (95% CI: 11.8, 23.0; p<0.0001). These data are summarized in Table 44.




Table 44. MMRM Analysis of Absolute Change from Baseline in CFQ-R RD Score (points) at Week 4 (FAS, Trial 103)

Parameter TEZ/IVA

N=52 ELX/TEZ/IVA

N=55 Mean (SD) of CFQ-R RD score at baseline

72.6 (17.9) 70.6 (16.2)


-1.4 16.0



Dose/Dose Response Not applicable.

Efficacy Results – Secondary or exploratory COA (PRO) endpoints The Applicant provided the following additional secondary analyses. As the statistical analysis did not control for multiplicity, this review considers these endpoints to be exploratory.

• Increase in absolute change from baseline in BMI at Week 4 for ELX/TEZ/IVA compared to TEZ/IVA with LS mean treatment difference of 0.60 kg/m2 (95% CI 0.41, 0.79).

• Increase from baseline in weight at Week 4 for ELX/TEZ/IVA compared to TEZ/IVA with LS mean treatment difference of 1.6 kg (95% CI 1.0, 2.1)

• Improvements in Treatment Satisfaction Questionnaire for Medication global satisfaction score in adolescent subjects for ELX/TEZ/IVA compared to TEZ/IVA.

Additional Analyses Conducted on the Individual Trial

Traditional Subgroup Analysis Figure 14 presents the traditional subgroup analysis results on the primary endpoint of change from baseline in ppFEV1 at Week 4 for Trial 103. Tests of treatment differences in all subgroups evaluated reached statistical significance as all the 95% CIs are greater than zero. These results are consistent with the overall result.




Figure 14. Least Squares Mean Difference Between Treatments With 95% CI for Change From Baseline in ppFEV1 at Week 4 by Subgroup (FAS, Trial 103)

Abbreviations: ppFEV1BL – Baseline ppFEV1, PUHA – Prior use of inhaled antibiotic, PUDA – Prior use of dornase alfa, PUIB – Prior use of inhaled bronchodilator, PUHS – Prior use of inhaled hypertonic saline, PUIC – Prior use of inhaled corticosteroids, PUAZ – Prior use of azithromycin, PSAS – Pseudomonas aeruginosa status within 2 years prior to screening , N – No, Y – Yes, TC – ELX/TEZ/IVA, PBO – Placebo, LCL – lower confident limit, UCL – upper confident limit, CFB – change from baseline, diff – difference Source: Statistical Reviewer




Figure 15. Least Squares Mean Difference Between Treatments With 95% CI for Change From Baseline in ppFEV1 at Week 4 by Subgroup Using Bayesian Shrinkage Subgroup Analysis (FAS, Trial 103)

Abbreviations: ppFEV1BL – Baseline ppFEV1, PUHA – Prior use of inhaled antibiotic, PUDA – Prior use of dornase alfa, PUIB – Prior use of inhaled bronchodilator, PUHS – Prior use of inhaled hypertonic saline, PUIC – Prior use of inhaled corticosteroids, PUAZ – Prior use of azithromycin, PSAS – Pseudomonas aeruginosa status within 2 years prior to screening , N – No, Y – Yes, w/o – without, w/ – with, F – Female, M – Male Source: Statistical Reviewer From Figure 15 we found that:

• All the subgroup means from the Bayesian shrinkage subgroup analysis shrunk to the overall mean

• All the 95% credible intervals of subgroup mean from Bayesian shrinkage subgroup analyses were narrower than the sample estimates’ 95% confidence intervals

SubgroupAge >=12 to <18 >=18Sex F MppFEV1BL <70 >=70Region Europe N. AmericaPUHA N YPUDA N YPUIB N Y PUHS N YPUIC N YPUAZ N Y PSAS positive negative

Summary

diff w/oShrink 14.678.3711.977.5111.196.348.7110.769.4710.6317.059.6730.049.7910.529.1510.769.5510.439.798.1610.66

10.0

diff w/Shrink12.089.0110.518.6810.17.939.6410.1510.0110.2812.2710.0129.499.879.729.4210.159.8810.089.949.4310.08

0 2 5 5 7 5 10 12.515 17.520 22 525 27 530 32 535 37 540 42 545diff of TC vs TEZ/IVA in CFB ppFEV

w/o shrinkw/ shrink




• Although the Bayesian shrinkage subgroup analysis produced more accurate subgroup means and credible intervals, the difference compared to the traditional subgroup analysis results were not large.

8.1.5 Assessment of Efficacy Across Trials

Primary Endpoints For the proposed population of CF patients with at least one F508del allele, treatment with ELX/TEZ/IVA demonstrated clinically and statistically significant improvements in ppFEV1 over placebo (Trial 102) and TEZ/IVA (Trial 103).

Secondary and Other Endpoints Improvements with ELX/TEZ/IVA treatment demonstrated in other clinically meaningful secondary endpoints such as number of PEx, SwCl, BMI, and CFQ-R RD score in Trials 102 and 103 also provided additional support for efficacy in the proposed population.

Additional Efficacy Considerations

Dose/Dose Response Both pivotal trials included evaluation of a single ELX/TEZ/IVA dosage and therefore, could not be used to evaluate a dose response. However, Study 001 Part D supported the selection of ELX 200 mg qd as the ELX dose component of the triple combination. A numerically greater improvement in ppFEV1 and SwCl were identified at the higher dose (see Section 6.2.2).

Reviewer comment: While the statistical analysis for Study 001 Part D for the ppFEV1 endpoint considered the within group change, the numerical trend supported the selection of the high dose. As discussed in Section 8.2.8.3 there was no clear dose response identified on safety review of Part D.

Considerations on Benefit in the Postmarketing Setting While clinical data is not available for all CFTR mutations encompassed in the proposed indication, given the magnitude and consistency of the treatment effect on numerous clinically meaningful outcomes, patients with other alleles such as gating and residual function mutations are expected to derive benefit from ELX/TEZ/IVA as well. However, the review team recommends a PMC for a clinical study in CF patients heterozygous for F508del and a second gating or residual function mutation.

8.1.6 Integrated Assessment of Effectiveness

The Applicant demonstrated substantial evidence of effectiveness of ELX/TEZ/IVA (elexacaftor 200 mg QD/tezacaftor 100 mg QD/ivacaftor 150 mg q12) in CF patients ≥ 12 years of age with at least one F508del mutation with respect to clinically and statistically significant improvements in ppFEV1 in both Trial 102 and 103. Results from all key secondary endpoints from Trial 102 and 103 support effectiveness of ELX/TEZ/IVA in the lung function change: number of PEx, BMI, CFQ-R RD, and SwCl. Furthermore, efficacy findings were generally consistent in both study




populations, inclusive of CF subjects with one or two F508del alleles. Exploratory analyses in the subgroup of subjects with Class I mutations (i.e., those predicted to make no CFTR protein and therefore representing a single F508del), were consistent with the overall population of Trial 102. As the second allele is not expected to interfere with the efficacy of ELX/TEZ/IVA, taken together, the totality of the efficacy data supports an indication for CF patients with at least one F508del mutation.

8.2 Review of Safety

8.2.1 Safety Review Approach

All clinical studies conducted as part of the ELX/TEZ/IVA development program were evaluated for safety; however, given the short exposure periods and small study size in the phase 1 and 2 studies, the focus of the safety review is on the two well-controlled phase 3 trials evaluating ELX/TEZ/IVA in CF: Trials 102 and 103. Due to differences in the study design of these trials, including both the study population, treatment duration and comparator arm, the trials were not pooled, and safety data will be presented individually from Trials 102 and 103. This review used MAED, JMP and JMP clinical to independently analyze safety data from both trials. Section 8.2.4 discusses the safety data from Trial 102 and 103, including but not limited to AEs, laboratory parameters, VS, and ECGs. Section 8.2.5 discusses Submission-Specific Safety issues from Trials 102 and 103 that were either pre-specified adverse events of special interest (AESI), potential safety issues identified in the pre-NDA review of ELX/TEZ/IVA or known safety issues with related CFTR modulator products. Specifically, the Applicant identified liver enzyme elevation and rash as AESI in the development program, and blood creatine phosphokinase elevation emerged as a safety signal during the pre-NDA review. Cataracts, respiratory-related AEs and menstrual abnormalities are known safety signals with IVA monotherapy, TEZ/IVA (Symdeko®) dual therapy and the related CFTR modulator product lumacaftor/ivacaftor (Orkambi®). Section 8.2.8 explores additional safety data from early development and interim data from the ongoing open-label extension (Study 105). This review analyzed Study 105 to evaluate for potential long-term safety signals and Submission Specific Safety Concerns. The review explored Study 001 Part D, the single dose-ranging study, for potential dose response with respect to safety events. Finally, this section also discusses Submission Specific Safety Concerns from Phase 1 and 2 to highlight the presence of safety signals throughout the development program. For a detailed summary of the protocols, refer to Section 8.1.1 (Trial 102) and Section 8.1.3 (Trial 103).




8.2.2 Review of the Safety Database

Overall Exposure The safety database includes 619 CF subjects receiving ELX combination therapy and 46 HV receiving ELX/TEZ/IVA combination therapy. An additional 145 HV received either ELX monotherapy (101 subjects) or ELX as part of another investigational triple combination (ELX/TEZ/deuterated-IVA, 44 subjects). As discussed in Section 8.2.1, the focus of the safety review will be on the Phase 3 program (Trials 102 and 103), which included a combined 257 subjects exposed to ELX/TEZ/IVA. Table 45 summarizes the entire population of subjects exposed to ELX/TEZ/IVA in the development program for CF.

Table 45. Safety Database for ELX/TEZ/IVA (N=665)

Clinical Trial Group ELX/TEZ/IVA (n= 810)

Active Control (n=59)

Placebo (n= 274)

Healthy volunteers 46 -- 54

Controlled trials conducted for this indication

Phase 2 Trials

001 95 7 20

Phase 3 Trials

102 202 -- 201

103 55 52 --

Uncontrolled trials conducted for this indication

105 2512 -- --

106 16 -- -- ELX: elexacaftor, TEZ: tezacaftor, IVA: ivacaftor, n: number of subjects 1 Study drug means the drug being considered for approval (i.e. ELX/TEZ/IVA). Table does not include additional 145 HV exposed to at least one dose of ELX monotherapy or ELX/TEZ/deuterated-IVA. 2Number of placebo and active control arm patients who switch to study drug in open label extension; rollover subjects who received active treatment in parent study are not double counted. Source. Table 2.3.1.4

In Trial 102, most subjects in the ELX/TEZ/IVA arm (97.5%) were exposed to ELX/TEZ/IVA for at least 20 weeks; the mean ELX/TEZ/IVA exposure was 23.6 weeks (SD 2.62). By study design, all patients in Trial 103 had ELX/TEZ/IVA exposures less than 8 weeks (mean ELX/TEZ/IVA exposure: 3.9 weeks). The duration of exposure to ELX/TEZ/IVA in the Trials 102 and 103 appears in Table 46.

Table 46. Number of Subjects Exposed to ELX/TEZ/IVA, by Duration of Exposure, Trials 102 and 103

Trial <8 weeks >8 to ≤16

weeks >16 to ≤20

weeks >20 to ≤24

weeks >24 weeks

102 3 0 2 138 59 103 55 0 0 0 0

Total 58 0 2 138 59 ELX: elexacaftor, TEZ: tezacaftor, IVA: ivacaftor




Total exposure was defined as the sum total of the study drug exposure across all subjects. Duration of study drug exposure (weeks) = (last dose date – first dose date + 1)/7, regardless of study drug interruption. Duration of study drug exposure (years) = duration of study drug exposure (weeks)/48; 1 year = 48 weeks. Source: Trial 102 CSR/Table 14.1.7 and Trial 103 CSR/Table 14.1.7. Reviewer verified in JMP 12.0 using ADSL datasets for Trial 102 and Trial 103.

The Applicant provided an IA for Study 105 inclusive of data through July 10, 2019. ELX/TEZ/IVA exposure included 280 subjects less than 24 weeks and 225 subjects greater than or equal to 24 weeks. When considering cumulative individual subject exposure from both controlled trials and the ongoing OLE, 364 subjects were exposed to ELX/TEZ/IVA for at least 24 weeks and 58 subjects for at least 48 weeks (Table 47).

Table 47. Number of Subjects Exposed to ELX/TEZ/IVA, by Duration of Exposure, Controlled Trials and Open Label Extension

Trial(s) <24 weeks ≥24 and <36

wks ≥36 and <48

wks ≥48 and <60

wks ≥60 wks

Exposure during individual trials1 102 2 78 124 0 0 0 103 55 0 0 0 0 105 280 196 29 0 0

Total exposure (parent trial + OLE)3 102 + 105 143 69 132 58 0 103 + 105 2 65 40 0 0

ELX: elexacaftor, TEZ: tezacaftor, IVA: ivacaftor, OLE: open label extension, wks: weeks 1 Duration of study drug exposure (weeks) = (last dose date of ELX/TEZ/IVA regimen - first dose date of ELX/TEZ/IVA regimen + 1)/7, regardless of study drug interruption. If a subject was still on study drug on the interim analysis data cutoff date (July 10, 2019), the cutoff date was used as the last dose. 2 In Trial 102, the Week 24 visit was scheduled to occur on week 24 (± 5 days). Therefore, the calculated exposure can be greater than or less than 24 weeks. 3 Duration of ELX/TEZ/IVA exposure during the parent studies (controlled Trials 102 or 103) and the open-label study (Study 105, if applicable) through 10 July 2019. This category includes unique subjects enrolled in Study 105, and subjects who received ELX/TEZ/IVA in the parent study. Source: Ad hoc Table 1, VX17-445-105 IA1, Response to FDA Information Request dated 28 August 2019, NDA 212273

Adequacy of the safety database Overall, the safety database is of sufficient size and duration for a rare disease such as CF to assess the safety of the proposed dose of ELX/TEZ/IVA when taken chronically. The proposed indication of a single F508del mutation includes CF genotypes for which there is an unmet medical need, as there are no FDA-approved disease-modifying treatments (i.e. minimal function). However, as Study 105 is ongoing, as later discussed in Section 13, this reviewer recommends a postmarketing commitment for Study 105.

8.2.3 Adequacy of Applicant’s Clinical Safety Assessments

Issues Regarding Data Integrity and Submission Quality No data quality issues were identified in the review of this NDA. Due to the Agency’s experience with the Applicant, including the recent approval of TEZ/IVA (Symdeko®) and quality of the datasets as judged by the clinical and statistical review teams, and the unmet medical need for the rare, life-threatening disease, Office of Scientific Investigations audits were deemed unnecessary for this submission. The small number of patients at each site made it unlikely that




issues at any one site would substantially impact the efficacy or safety findings. In Trial 102, the Applicant assigned two placebo subjects that received active study drug in error to the ELX/TEZ/IVA arm. One subject received IVA instead of placebo on Day 172, the last day of study drug exposure. The second subject received ELX/TEZ/IVA from Day 112 to Day 165 (the last day of study drug exposure). Both subjects reported multiple non-serious AEs during the study. None of the AEs reported were severe or led to interruption or discontinuation of treatment. This review considered the impact of these subjects’ AEs and treatment arm classification on the safety evaluations, and determined that the assignment of both subjects to the ELX/TEZ/IVA arm did not have a meaningful impact on safety conclusions. Therefore, for purposes of this review, the safety evaluation assigned both subjects to the ELX/TEZ/IVA arm.

Categorization of Adverse Events The Applicant provided accurate definitions of AEs and SAEs consistent with 21 CFR 312.32. Investigators captured AEs from the time the informed consent form (ICF) was signed and through the TE Period for each study (i.e., premature discontinuation or 28 days after last study drug exposure). TEAEs were defined as any AE that worsened (either in severity or seriousness) or that was newly developed at or after the first dose date of study drug through the end of the TE Period. For purposes of this review, summary tables present TEAEs. The Applicant coded AEs using the MedDRA dictionary versions 22.0 (Trials 102 and 105) and 21.1 (Trial 103). The Applicant graded AE severity using the Common Terminology Criteria for Adverse Events version 4.0 toxicity scale or as mild/moderate/severe/life-threatening. The Applicant assessed AEs assessed frequency, rather than rate, a method appropriate for trials of this duration. The Applicant analyzed AEs by System Organ Class (SOC) and PT for the following subgroups: • Age at screening (<18, ≥18 years) • ppFEV1 at baseline (<70, ≥70) • Sex (male, female) • Geographic region (North America, Europe [including Australia])

Reviewer comment: The Applicant’s coding of verbatim terms to PTs was acceptable. The Common Terminology Criteria for Adverse Events severity scale is consistent with other CF development programs and appropriate for the enrolled subject population.

Routine Clinical Tests Routine clinical tests included laboratory tests, ECGs, PEs, VS, pulse oximetry, and ophthalmologic examinations. The Applicant defined baseline as the most recent non-missing measurement collected before the first dose of study drug in Trial 102 and before the first dose of study drug in the Treatment Period of Trial 103. Investigators documented abnormal values as an AE if considered clinically significant as determined by one or more of the following:




(1) Concomitant signs or symptoms related to abnormal study assessment, (2) Further diagnostic testing or medical/surgical intervention, or (3) A change in the dose of study drug or discontinuation from the study.

In addition, for treatment-emergent VS, ECGs and laboratory measurements, the Applicant summarized observed values, changes from baseline and number/percentage of subjects meeting a prespecified threshold analyses. The pre-specified threshold analysis criteria were reviewed and deemed reasonable. However, this reviewer completed an independent analysis of laboratory, VS and ECG parameters using both the Applicant’s pre-specified threshold criteria and where indicated, additional analyses for potentially clinically significant changes using alternative threshold criteria.

8.2.4 Safety Results

8.2.4.1 Deaths

There were no deaths reported in the clinical development program.

8.2.4.2 Serious Adverse Events

In Trial 102, 42 (21%) placebo subjects and 28 (14%) ELX/TEZ/IVA subject reported at least one SAE. Most SAEs occurred in the Infections and Infestations SOC, including 36 (18%) subjects in the placebo arm and 13 (6%) in the ELX/TEZ/IVA arm, of which the most common SAE was infective PEx of CF. More ELX/TEZ/IVA subjects (3, 1%) reported SAEs in the Gastrointestinal Disorders SOC and Hepatobiliary Disorders SOC than placebo subjects (1, <1%); however, the SAEs were single occurrences and distributed across PTs. Review of additional SAEs that occurred as single occurrences in the ELX/TEZ/IVA arm and could be potentially drug-related included rhabdomyolysis and upper abdominal pain. Table 48 summarizes the SAEs occurring in at least 2 subjects in any treatment arm.

Table 48. Serious Adverse Events Occurring in at Least 2 Subjects in Any Treatment Arm, by Preferred Term, Trial 102, Safety Set

Preferred Term Placebo N=201 n (%)


Any serious adverse event 42 (21) 28 (14) Infective pulmonary exacerbation of cystic fibrosis 33 (16) 11 (5) Influenza 0 3 (1) Rash 1 1 (<1) 3 (1) Hemoptysis 3 (1) 2 (1) Intestinal obstruction 2 1 (<1) 2 (1)

IVA: ivacaftor, TEZ: tezacaftor, ELX: elexacaftor, PT: preferred term n: number of subjects in subset, N: total subjects in trial arm Subjects counted once for each preferred term. 1 Includes PT: rash and rash pruritic adverse events 2 Includes PT: DIOS and small intestine obstruction Source. Reviewer calculated in JMP 12.0 using ADAE dataset selecting subjects by SAFFL(Y), TRTEMFL(Y), AESER(Y) by USUBJID, TRT1A, AEDECOD.




In Trial 103, there were three SAEs, including one subject in each study arm with infective PEx of CF, and one subject in the ELX/TEZ/IVA arm with rash in the setting of hormonal contraceptive use (ethinyl estradiol/norethisterone). Investigators considered the rash event to be medically important.

Reviewer comment: Hemoptysis, infective PEx of CF and small intestinal obstruction / DIOS are events seen in the CF population. Section 8.2.5 discusses rhabdomyolysis / CK-related, hepatobiliary and rash AEs in more detail.

8.2.4.3 Dropouts and/or Discontinuations Due to Adverse Effects

In Trial 102, 2 ELX/TEZ/IVA subjects discontinued study treatment for moderate AEs including one subject with a non-serious AE of rash and a second subject with a history of hepatic cirrhosis with an SAE of portal hypertension. Each case is discussed in more detail in Section 8.2.5. Treatment interruptions occurred more often in the ELX/TEZ/IVA arm (9%) than the placebo arm (5%). Five subjects interrupted treatment for hepatobiliary-related AEs in the ELX/TEZ/IVA arm compared with 4 placebo subjects. The most common reason for treatment interruption in the ELX/TEZ/IVA arm was rash. Table 49 summarizes the reason for treatment interruption that occurred in at least 2 subjects in any treatment arm.

Table 49. Treatment Interruptions Due to Adverse Events in at Least 2 Subjects in Any Treatment Arm, Trial 102, Safety Set

Preferred Term

Placebo N=201 n (%)


Subjects requiring drug interruption for at least 1 AE 10 (5) 19 (9) Rash 1 1 (<1) 4 (2) Alanine aminotransferase increased 2 (1) 2 (1) Infective pulmonary exacerbation of cystic fibrosis 1 (<1) 2 (1) Influenza 0 2 (1) Rhabdomyolysis 0 2 (1) Intestinal obstruction 2 0 2 (1)

IVA: ivacaftor, TEZ: tezacaftor, ELX: elexacaftor, PT: preferred term, AE: adverse event, n: number of subjects in subset, N: total subjects in trial arm Subjects counted once for each preferred term. 1 Includes PT: rash and rash pruritic. 2 Includes PT: DIOS or small intestine obstruction Source. Reviewer calculated in JMP 12.0 using ADAE dataset selecting subjects by SAFFL(Y), TRTEMFL(Y), AEACN (drug interrupted) by USUBJID, TRT1A, AEDECOD. Additional AEs leading to treatment interruption reported once in the ELX/TEZ/IVA arm and not in the placebo arm included the following: gastritis, cholangitis, gallbladder enlargement, herpes simplex (single patient with genital and oral infection), and hemoptysis.




In Trial 103, no subject had an AE that led to study drug discontinuation or interruption.

Reviewer comment: The AEs requiring interruption and discontinuation support labeling for liver-related events, CK elevation and rash. All three safety concerns are individually discussed in more detail in Section 8.2.5.

8.2.4.4 Significant Adverse Events

The following section discusses severe (Grade 3) and life threatening (Grade 4) AEs in Trial 102 and 103. In Trial 102, 14 (7%) placebo and 19 (9%) ELX/TEZ/IVA subjects reported at least 1 severe AE. One placebo subject developed a life-threatening AE of neuroglycopenia. No life-threatening Grade 4 AEs occurred in the ELX/TEZ/IVA arm. In the placebo arm, the most common severe AE was infective PEx of CF. In the ELX/TEZ/IVA arm, the most frequent severe AEs were elevated blood creatinine phosphokinase and increased ALT/AST. Severe AEs that occurred in at least 2 subjects in any treatment arm in Trial 102 appear in Table 50.

Table 50. Severe (Grade 3) Adverse Events Occurring in At Least 2 Subjects in Any Treatment Arm, Trial 102, Safety Set

Preferred Term

Placebo N=201 n (%)


Subjects reporting any grade 3 AE 14 (7) 1 19 (9) Infective exacerbation of cystic fibrosis 9 (4) 0 Blood creatinine phosphokinase increased 0 4 (2) Aspartate aminotransferase increased 0 2 (1) Alanine aminotransferase increased 0 2 (1) Abdominal pain2 0 2 (1)

AE: adverse event, IVA: ivacaftor, TEZ: tezacaftor, ELX: elexacaftor, n: number of subjects in subset, N: total subjects in trial arm, PT: preferred term Subjects counted once for each preferred term. 1 Count only includes severe (Grade 3) TEAEs. One additional placebo subject reported a life-threatening (Grade 4) TEAE. 2 Includes PT: abdominal pain and abdominal pain upper Source. Reviewer calculated in JMP 12.0 using ADAE dataset selecting subjects by SAFFL(Y), TRTEMFL(Y), AETOXGR(3) by USUBJID, TRT1A, AEDECOD. In Trial 103, 1 TEZ/IVA subject had a severe AE of musculoskeletal pain. There were no severe or life threatening AEs reported by subjects in the ELX/TEZ/IVA arm.

Reviewer comment: The severe AEs suggest the potential for clinically significant LFT and CK abnormalities with ELX/TEZ/IVA use.

8.2.4.5 Treatment Emergent Adverse Events and Adverse Reactions

In Trial 102, most AEs were mild and moderate in severity. Within the ELX/TEZ/IVA arm 50% subjects reported a moderate AE compared to 62% of placebo subjects. Mild AEs occurred in 33% of ELX/TEZ IVA and 26% of placebo. Considering any severity, the most common reported AEs in the ELX/TEZ/IVA arm were headache (17%), upper respiratory tract infection (16%), abdominal pain (14%), and diarrhea (13%). CF disease related AEs occurred more frequently in




the placebo arm than the ELX/TEZ/IVA arm including infective PEx of CF (47% vs 22%), constipation (6% vs 3%), fatigue/malaise (12% vs 7%), and decreased appetite (4% vs 1%). Common AEs occurring in greater than 5% of patients and ≥1% difference from placebo appear in Table 51.

Table 51. Common Adverse Events With ≥5% Frequency and ≥1% Difference From Placebo in Trial 102, Safety Set

Preferred Term

Placebo N=201 n (%)


Subjects with at least one adverse event 193 (96) 188 (93) Headache 30 (15) 35 (17) Upper respiratory tract infection 1 25 (12) 32 (16) Abdominal pain 2 18 (9) 29 (14) Diarrhea 14 (7) 26 (13) Rash 3 10 (5) 21 (10) Alanine aminotransferase increased 7 (3) 20 (10) Aspartate aminotransferase increased 4 (2) 19 (9) Blood creatinine phosphokinase increased 9 (4) 19 (9) Nasal congestion 15 (7) 19 (9) Rhinorrhea 6 (3) 17 (8) Rhinitis 11 (5) 15 (7) Influenza 3 (1) 14 (7) Sinusitis 8 (4) 11 (5) Blood bilirubin increased 2 (1) 10 (5)

IVA: ivacaftor, TEZ: tezacaftor, ELX: elexacaftor, PT: preferred term, n: number of subjects in subset, N: total subjects in trial arm. Subjects counted once for each preferred term. 1 Includes PT: upper respiratory tract infection, viral upper respiratory tract infection 2 Includes PT: abdominal pain, abdominal pain upper, abdominal pain lower 3 Includes PT: rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, rash generalized Source. Reviewer calculated in JMP 12.0 using ADAE dataset selecting subjects by SAFFL(Y), TRTEMFL(Y) by USUBJID, TRT1A, AEDECOD. Additional AEs that occurred >1% and <5% in the ELX/TEZ/IVA arm and ≥1% more than placebo included the following:

Lymphatic disorders: lymphadenopathy Cardiac disorders: palpitations Gastrointestinal disorders: abdominal distention, toothache, flatulence Infections: conjunctivitis, pharyngitis, respiratory tract

infection, tonsillitis, urinary tract infection Investigations: blood bilirubin unconjugated increased, c-reactive

protein increased Metabolic: hypoglycemia Musculoskeletal: arthralgia Nervous system disorders: dizziness




Psychiatric disorders: anxiety, insomnia Reproductive system: dysmenorrhea Skin disorders: acne, eczema, pruritus

Reviewer comment: The study was conducted during the winter season; the clinical relevance of the imbalance observed with influenza is uncertain.

In Trial 103, the incidence of subjects reporting at least 1 AE was lower in the ELX/TEZ/IVA arm (58%) than the TEZ/IVA arm (63%). Cough, oropharyngeal pain, and fatigue occurred more frequently in the ELX/TEZ/IVA arm than the TEZ/IVA arm. Similar to Trial 102, infective PEx of CF (12% vs 2%) and hemoptysis (10% vs 4%) occurred more often in the comparator arm than the ELX/TEZ/IVA arm. Table 52 summarizes the common AEs in Trial 103.

Table 52. Common Adverse Events with ≥5% Frequency and Greater Than TEZ/IVA in Trial 103, Safety Set

Preferred Term

TEZ/IVA N=52 n (%)


Patients with at least one Adverse Event 33 (63) 32 (58) Cough1 4 (8) 9 (16) Nasopharyngitis 2 (4) 4 (7) Oropharyngeal pain 0 4 (7) Upper respiratory infection 3 3 (6) 4 (7) Abdominal pain 4 2 (4) 4 (7) Fatigue 2 (4) 3 (5) Nasal congestion 1 (2) 3 (5) Respiration abnormal 0 3 (5)

IVA: ivacaftor, TEZ: tezacaftor, ELX: elexacaftor, PT: preferred term, n: number of subjects in subset, N: total subjects in trial arm Subjects counted once for each preferred term. 1 Includes the following PT: cough, productive cough 2 Includes PT: upper respiratory tract infection, viral upper respiratory tract infection 3 Includes PT: abdominal pain, abdominal pain upper, abdominal pain lower Source. Reviewer calculated in JMP 12.0 using ADAE dataset selecting subjects by SAFFL(Y), TRTEMFL(Y) by USUBJID, TRT1A, AEDECOD

Reviewer comment: The small sample size creates difficulty in drawing conclusions regarding the clinical relevance of the incidence of cough, oropharyngeal pain and fatigue observed in ELX/TEZ/IVA subjects in Trial 103.

8.2.4.6 Laboratory Findings

This reviewer analyzed chemistry (inclusive of LFT, non-LFT, and CK), hematology, coagulation, and urinalysis results in Trials 102 and 103, and where relevant, considered potential lab-related AEs. A discussion of LFT and CK-related laboratory changes for Trials 102 and 103 appears in Section 8.2.5.




Analysis of non-LFT and non-CK chemistry parameters, inclusive of mean changes and individual subject shift from baseline threshold analyses, did not identify any clinically significant trends. Analysis of coagulation factors identified small numerical differences in post-baseline elevations of partial thromboplastin time , prothrombin time, and international normalized ratio (INR) greater than 1.5x ULN for ELX/TEZ/IVA subjects compared to each comparator arm; however, most of the ELX/TEZ/IVA subjects had elevated baseline values (i.e. > ULN). No coagulation lab-related AEs were reported in Trial 102 or 103, or bleeding events in those subjects with elevation in coagulation factors. Comparison of mean changes in hematology parameters at Week 24 was notable for a trend towards mean decreases in the ELX/TEZ/IVA arm compared to the placebo arm for neutrophils (-13.7[3.03] vs 0.19[2.76), leukocytes (-1.44[3.23] vs 0.26[2.87), and platelets (-30.4[70.0] vs 4.5 [53.9]). No other mean trends were identified. Analysis of trends in individual subject hematology laboratory changes identified a small trend in hemoglobin and platelets. More ELX/TEZ/IVA subjects developed potentially clinically significant relative changes in post-baseline hemoglobin (defined as ≥ 20 g/L decrease from baseline). However, when looking at changes in both absolute post-baseline value and relative change from baseline the difference diminished. Further, the only subject developing a decrease from baseline ≥40 g/L was in the placebo arm, and the only two study subjects developing post-baseline values less than 100 g/L were in the placebo arm. With respect to platelets, 6 ELX/TEZ/IVA subjects developed post-baseline platelet values between 50 and 100 (109/L) compared with no placebo subjects; however, none of these ELX/TEZ/IVA subjects developed bleeding AEs and most of these resolved without treatment interruption. In addition, thrombocytopenia AEs were balanced across the two trial arms, and no ELX/TEZ/IVA subjects with a shift in platelets below 100 (109/L) developed bleeding AEs. Additional query of AEs related to hematology (white blood cell decreased, anemia) identified 1 to 3 subjects for each category. No subjects discontinued or interrupted treatment for hematology lab related AEs. There were no other clinically meaningful trends in hematology parameters. In Trial 103, when comparing mean changes in hematology parameters for the ELX/TEZ/IVA and TEZ/IVA arms, there were similar trends at Week 4 with respect to platelets (mean[SD]: -39.3 (58.9) vs 4.9[43.7]), leukocytes (mean[SD]: -1.67[2.91] vs 0.25[2.19]), and neutrophils (mean[SD]: -1.65[2.77] vs 0.34[2.08]). There was no clinically significant trend for these parameters with respect to threshold analysis, hematology lab-related AEs or additional trends in other hematology parameters.

Reviewer comment: Given that the majority of the platelet changes resolved without treatment interruption and not associated bleeding AEs, this reviewer recommends no additional labeling for platelets.




8.2.4.7 Vital Signs

In Trial 102, there were no clinically significant mean changes in VS parameters for either treatment arm. Examination of individual subject shift from baseline in pulse rate was notable for changes with respect to pulse rate and systolic blood pressure (SBP). Specifically, three ELX/TEZ/IVA subjects developed a pulse rate that was both <50 beats per minute (bpm) and a decrease of ≥10 beats/min from baseline. However, no subject met the threshold criterion on more than one occasion, and there were no concurrent AEs of low heart rate or bradycardia. The single subject with a pulse <50 bpm and decrease from baseline of 48 bpm reported a mild AE of palpitations during the treatment period; however, because the AE start date was not recorded, a correlation with heart rate could not be determined. With respect to blood pressure, more ELX/TEZ/IVA subjects reported SBP elevations on 2 or more occurrences compared to placebo for each threshold. A similar trend was not observed for diastolic blood pressure when considering post-threshold values that met the absolute (>90 mmHg) and relative (>10 mmHg from baseline) change criteria. Three AEs related to increased blood pressure occurred in the Trial 102, including 2 placebo (1%) and 1 (<1%) ELX/TEZ/IVA subject (PTs: increased blood pressure and hypertension). Table 53 summarizes SBP changes in Trial 102.

Table 53. Systolic Blood Pressure, Trial 102, Safety Set

Parameter Post-baseline threshold analysis criteria

Placebo N=201 n (%)


Subjects with ≥ 1 occurrences >140 mmHg and >10 mmHg increase from baseline 10 (5) 16 (8) >140 mmHg and >20 mmHg increase from baseline 5 (2) 9 (4) >160 mmHg and >10 mmHg increase from baseline 3 (1) 1 (<1) >160 mmHg and >20 mmHg increase from baseline 2 (1) 1 (<1)

Subjects with ≥2 occurrences >140 mmHg and >10 mmHg increase from baseline 3 (1) 8 (4) >140 mmHg and >20 mmHg increase from baseline 1 (<1) 2 (<1) >160 mmHg and >10 mmHg increase from baseline 0 0

IVA: ivacaftor, TEZ: tezacaftor, ELX: elexacaftor, n: number of subjects in subset, N: total subjects in trial arm, mmHG: millimeter of mercury Within each parameter, a subject is counted in all applicable post-baseline categories based on the worst assessment during the treatment-emergent period; percentage is n/N. Source. Adapted from Table 14.3.5.2, CSR Study VX17-445-102. Reviewer verified with ADVS in JMP 12.0 selecting for SAFFL(Y), ONTRTFL (Y) by BASE, AVAL, CHG. With respect to weight change, ≥5%, ≥10%, and ≥20% post-baseline increases in weight were observed by 63%, 26%, and <1% of ELX/TEZ/IVA subjects compared to 23%, 5%, and <1% of placebo subjects. Consistent with this trend, ≥5% decrease in weight occurred in more placebo than ELX/TEZ/IVA subjects (9% versus 2%). In Trial 103, there were no clinically significant meaningful trends in vital signs.




Reviewer comment: The Trial 102 suggest a trend towards increased SBP with ELX/TEZ/IVA. Given the imbalance in subjects reporting 2 or more occurrences of elevated SBP, the Applicant’s proposal to label for increased blood pressure is reasonable.

8.2.4.8 Electrocardiograms (ECGs)

In Trial 102, examination of post-baseline ECGs identified no clinically significant mean trends in RR interval, PR interval, QRS duration, and heart rate (HR). Evaluation of individual post-baseline values and individual subject relative changes from baseline identified 5 ELX/TEZ/IVA subjects with both HR < 50 beats/min and a decrease from baseline of ≥20 beats/min compared with no placebo subjects. Consistent with this finding, more ELX/TEZ/IVA than placebo subjects had post-baseline RR intervals greater than 1.2 seconds, with 3 ELX/TEZ/IVA and 1 placebo reporting maximum values exceeding 1.3 seconds. In Trial 103, one subject in the ELX/TEZ/IVA arm developed both HR < 50 beats/min and a decrease from baseline of ≥20 beats/min compared with no TEZ/IVA subjects. No other clinically significant trends were identified.

8.2.4.9 QT

This reviewer examined post-baseline QTcF changes by relative change from baseline (>30, >40, and >60 msec) and absolute post-baseline value (>450 to <500 msec (male) or >470 to <500 msec (female) and >500 msec). In Trial 102, a similar number of subjects reported a maximum change in the QTcF interval of > 30 msec in each study arm. Among the ELX/TEZ/IVA subjects meeting this criterion, 2 subjects had AEs of palpitations during the study; however, there was insufficient information to evaluate the concurrent QTc at the time of the AE reported. One ELX/TEZ/IVA subject developed relative increase from baseline in the QTcF interval of >60 msec. With respect to absolute post-baseline values, one subject in each arm with normal baseline QTc met the criterion for prolonged QTc; increase from baseline was 34 and 31 msec for the placebo and ELX/TEZ/IVA subjects, respectively. Table 54 summarizes the absolute and relative QTc interval changes in Trial 102.

Table 54. QTc, Trial 102, Safety Set

Post-baseline threshold analysis criteria

Placebo N=201 n (%)


Absolute QTc interval prolongation: >450 to <500 msec (male) or >470 to <500 msec (female) 1 (<1) 1 (<1) ≥500 msec 0 0

Change from baseline in QTc interval Increase from baseline >30 msec 20 (10) 21 (10) Increase from baseline >40 msec 8 (4) 4 (2) Increase from baseline >60 msec 0 1 (<1)1

IVA: ivacaftor, TEZ: tezacaftor, ELX: elexacaftor, n: number of subjects in subset, N: total subjects in trial arm, msec: millisecond 1 Single female subject with baseline value of 386 msec increased to 452 msec at Day 16. Source: Reviewer calculated in JMP 12.0 with ADEG dataset in JMP SAFFL(Y), ONTRTFL (Y), PARAMCD (QRSSB) by BASE, AVAL, CHG.




In Trial 103, there was one female ELX/TEZ/IVA subject with a relative increase from baseline in the QTcF interval of > 60 msec and QTC >470 to <500 msec on Day 15 (Subject 103- ). Evaluation of relative change identified one additional subject in each arm with >30 msec change post-baseline in QTcF. Query of the AE databases of Trial 102 and 103 for potential cardiac-related AEs in the ELX/TEZ/IVA subjects identified no cases of ventricular tachycardia, sudden death, ventricular fibrillation, ventricular flutter, or seizure. One subject in Trial 102 had mild and moderate syncopal events in the setting of nasopharyngitis. ECG on the same study day as the second episode was not clinically significant. In Study 105, there was one subject who developed an SAE of seizure.

• Subject 102- was a 38-year-old female subject with CF (F/MF) and a history of CF lung, systemic lupus erythematous, sleep paralysis and anxiety participated in Trial 102 in the ELX/TEZ/IVA arm. On Study 105 Day 53, the subject experienced a single seizure episode, witnessed by her family and friends, that ended spontaneously. Subsequent CT scan of the brain showed ethmoid sinus disease, but no acute intracranial abnormalities. ECG showed tachycardia (HR 107 beats per minute) with normal sinus rhythm and echocardiogram was normal. MRI with and without contrast showed bilateral sinus disease and no acute intracranial abnormality. A 24-hour video EEG were normal. The subject did not receive treatment for the event. Relevant concomitant medications at onset of the SAE of seizure included aztreonam lysine and tobramycin (inhaled). Study drug was not changed due to the event. Investigators considered the event to be unrelated to study drug.

The Applicant completed a TQT study. The Interdisciplinary Review Team for QT studies consult review (dated September 16, 2019) identified no significant QTc prolongation effect of elexacaftor in the QT assessment; at doses up to 2 times the maximum recommended dose of elexacaftor and 3 times the maximum recommended dose of tezacaftor and ivacaftor, the QT/QTc interval in healthy subjects was not prolonged to any clinically relevant extent. The reviewers identified no clinically relevant increases or decreases in heart rate for ELX.

8.2.5 Analysis of Submission-Specific Safety Issues

8.2.5.1 Hepatobiliary-Related Labs and Adverse Events

The Applicant prespecified LFT elevations as an AESI, as LFT abnormalities have been seen with IVA, TEZ/IVA, and LUM/IVA. This reviewer analyzed LFT laboratory changes (mean changes, maximum on-treatment elevations) as well as relevant AE PTs in the Investigations SOC and Hepatobiliary SOC in both Trials 102 and 103.


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Trial 102 Laboratory Data In Trial 102, examination of mean [SD] changes from baseline in LFT parameters noted a trend towards larger mean increases in the ELX/TEZ/IVA arm compared to placebo for AST, ALT, and total bilirubin throughout the TE Period. Mean increases at 24 weeks in the ELX/TEZ/IVA arm compared to the placebo arm included the following: AST (6.6 [31.6] vs 1.6 [15.6], respectively), ALT (8.2 [28.9] vs 1.2 [14.3], respectively), and total bilirubin (3.9 [5.3] vs 0.0 [3.1]). Examination of maximum post-baseline LFT elevations by threshold categories was notable for increased cases of clinically relevant post-baseline elevations in AST, ALT, GGT, total bilirubin, and indirect bilirubin in the ELX/TEZ/IVA arm compared to the placebo arm. There was no clear temporal trend for onset of AST and/or ALT elevation. Elevations in AST or ALT >8x ULN only occurred in ELX/TEZ/IVA subjects with normal baseline values (i.e. ≤ ULN). Most cases of elevated total bilirubin > 2x ULN in the ELX/TEZ/IVA arm occurred in subjects with baseline values between > 1x and ≤2x ULN (7/8, 88%). Comparison of subjects reporting both elevated (ALT or AST > 3x ULN) and bilirubin > 2x ULN identified 2 subjects in the ELX/TEZ/IVA arm and no placebo subjects; however, neither met Hy’s law as one subject developed elevations that were not concurrent, and the second subject had a history of Gilbert’s syndrome with elevated baseline total bilirubin. Table 55 summarizes the number of subjects meeting each category.

Table 55. Maximum Liver Function Test Elevations During Treatment Emergent Period: Trial 102, Safety Set

Lab parameter

Placebo N=201 n (%)


ALT (U/L), n (%) >3x to ≤5x ULN 7 (3) 8 (4) >5x to ≤8x ULN 1 (<1) 3 (1) >8x to ≤20x ULN 1 (<1) 1 (<1)

AST (U/L), n (%) >3x to ≤5x ULN 3 (1) 9 (4) >5x to ≤8x ULN 1 (<1) 0 >8x to ≤20x ULN 1 (<1) 3 (1)

AST or ALT (U/L), n (%) >3x ULN 11 (5) 16 (8) >5x ULN 3 (1) 5 (2) >8x ULN 2 (1) 3 (1) >20x ULN 0 0

Alkaline phosphatase (U/L), n (%) >1.5x ULN 16 (8) 15 (7) >2.5x to ≤5x ULN 1 (<1) 4 (2)

GGT (U/L), n (%) >2.5x ULN to ≤3x ULN 3 (1) 7 (3) >5x to ≤20x ULN 0 1 (<1)

Total Bilirubin (μmol/L), n (%)




Lab parameter

Placebo N=201 n (%)


>ULN to ≤1.5x ULN 13 (6) 26 (13) >1.5 ULN to ≤2x ULN 2 (1) 12 (6) >2x ULN to ≤3x ULN 1 (<1) 7 (3) >3x to ≤10x ULN 0 1 (<1)

Direct Bilirubin (μmol/L), n (%) >ULN to ≤1.5x ULN 13 (6) 33 (16) >1.5x ULN to ≤2x ULN 0 6 (3)

ALT or AST and total bilirubin, n (%) (ALT or AST >3x ULN) and bilirubin >1.5x ULN 0 0 (ALT or AST >3x ULN) and bilirubin >2x ULN 0 2 (1) 1

ALT: alanine aminotransferase, AST: aspartate aminotransferase, ULN: upper limit of normal, GGT: gamma-glutamyl transferase, IVA: ivacaftor, TEZ: tezacaftor, ELX: elexacaftor, n: number of subjects in subset, N: total subjects in trial arm, U: units 1 In 1 subject, the transaminase and bilirubin elevations were not concurrent. The other subject had a medical history of Gilbert’s syndrome and an elevated total bilirubin at screening >2 × ULN, which remained high throughout the study. See narratives below. Source: Table 14.3.4.2. Reviewer verified using ADLB dataset in JMP 12.0 selecting SAFFL(Y), ONTRTFL(Y), ANL02FL(Y) by PARAMCD, MCRIT1ML, TRT01A, AVALC. Narratives for the two subjects with ALT or AST >3x ULN and bilirubin >2x ULN appear below:

• Subject 102- . A 15-year-old female with F/MF mutation in the ELX/TEZ/IVA arm with a history of CF lung and pancreatic failure. Laboratory analysis at the Screening Visit included ALT and ALT < 2x ULN, ALP >2× ULN, and indirect bilirubin <2x ULN. On Study Day 13, the AST was >3 × ULN with ALP >2× ULN and total bilirubin <2x ULN. Concomitant medications included tobramycin and colistin. No study drug dosing changed due to ALT and AST increase. On Study Day 27, the AE of ALT increase and AST increase resolved. Subsequent AST and ALT values remained <3x ULN. On Study Day 169 (final day of study participation), the total bilirubin, indirect bilirubin, and ALP increased to >2× ULN, and direct bilirubin was > ULN. On the same day, ALT and AST levels were near baseline, and prothrombin time/INR were within normal range. GGT was within normal range. The subject entered the OLE. A summary of the LFT changes appears in the Clinical Appendix (Table 107).

• Subject 102- was a 19-year-old male with F/MF genotype in the ELX/TEZ/IVA arm. The subject had a history of CF lung, pancreatic failure, and Gilbert’s syndrome. Laboratory analysis at the Screening Visit included total bilirubin 45.4 μmol/L (>2× ULN), indirect bilirubin 40.2 μmol/L (>3x ULN), and normal AST/ALT/. On Study Day 18, the total bilirubin increased to 89.8 μmol/L (>2× ULN) in the setting of normal transaminases. The subject received no treatment, but study drug was interrupted on Day 21. The AE resolved on Day 153. The subject resumed study drugs on Day 154. On Study Day 167, the total bilirubin was 61.2 μmol/L (>2× ULN), AST >3× ULN, and CK 25× ULN. Prothrombin time/INR were within normal range. The investigator attributed the AST, ALT, and CK changes to intense physical activity the day prior to the visit. The


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subject entered the OLE. A summary of the LFT changes appears in the Clinical Appendix (Table 108).

Reviewer comment: While Subject 102- had concurrent elevations in AST and bilirubin, the subject had a baseline total bilirubin > 2x ULN in the setting of Gilbert’s Syndrome.

Adverse Events This reviewer queried the AE database for hepatobiliary-related AEs in the Investigations and Hepatobiliary Disorders SOCs. Considering the Investigations SOC, aminotransferase AEs (11% vs 4%), and blood bilirubin AEs (5% and 1%) occurred more frequently in ELX/TEZ/IVA than placebo subjects. Approximately 30 to 40% of the AEs in the ELX/TEZ/IVA arm were moderate severity. There were no discontinuations for transaminase or bilirubin AEs in Trial 102. Three subjects in each arm required drug interruption for increased transaminase or bilirubin AEs. No bilirubin AEs were serious or severe. With respect to the Hepatobiliary SOC, more AEs occurred in the ELX/TEZ/IVA arm (3%) compared to placebo (1%); however, AEs were generally spread across different PTs. One ELX/TEZ/IVA subject with a history of hepatic cirrhosis discontinued study drug due to a SAE of portal hypertension (moderate severity). Table 56 summarizes hepatobiliary-related TEAES for SOCs in Trial 102, and a narrative for the subject that discontinued treatment for portal hypertension appears below the table.

Table 56. Hepatobiliary-Related AEs Trial 102, Safety Set

Category Preferred Term

Placebo N=201 n (%)


Investigations SOC 9 (4) 30 (15) Alanine aminotransferase increased 7 (3) 20 (10) Aspartate aminotransferase increased 4 (2) 19 (9) Blood bilirubin increased 2 (1) 10 (5) Gamma-glutamyl transferase increased 3 (1) 3 (1) Blood bilirubin unconjugated increased 1 (<1) 3 (1) Bilirubin conjugated increased 1 (<1) 1 (<1)

Hepatobiliary disorders SOC 2 (1) 7 (3) Biliary colic 0 1 (<1) Cholangitis 0 1 (<1) Gallbladder enlargement 0 1 (<1) Hepatic cirrhosis 0 1 (<1) Hepatocellular injury 1 (<1) 1 (<1) Ocular icterus 0 1 (<1) Portal hypertension 0 1 (<1) Hypertransaminasemia 1 (<1) 0

Severe (Grade 3) 1 (<1) 3 (1) SAE 1 (<1) 3 (1) Treatment interruption1 4 (2) 5 (2)


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Category Preferred Term

Placebo N=201 n (%)


Treatment discontinuation1 0 1 (<1)

SOC: System Organ Class, ELX: elexacaftor, TEZ: tezacaftor, IVA: ivacaftor, SAE: serious adverse event, n: number of subjects in subset, N: total subjects in trial arm, U: units Subjects counted once for each preferred term. 1 Two placebo and 6 ELX/TEZ/IVA arms developed the AE at the final visit and outcome listed as “not applicable.” All subjects rolled over into the OLE (Subject IDs: 102- , 102- , 102- , 102- , 102- , 102- , 102-

, 102- ). Source. Reviewer calculated in JMP 12.0 with ADAE dataset per the following: AEHLGT (hepatobiliary investigations) SAFFL(Y), (TRTEMFL(Y), by USUBJID, TRT01A, AEDCODE, AESER, AEACN, AETOXGR AEHLGT (gallbladder disorders, hepatic and hepatobiliary disorders, bile duct disorders), SAFFL(Y), (TRTEMFL(Y), by USUBJID, TRT01A, AEDCODE, AESER, AEACN, AETOXGR

• Subject 102- . Subject 102- was a 12 year old male subject randomized to ELX/TEZ/IVA. The subject had a history of CF (F/MF), hepatic cirrhosis, splenomegaly, hepatic fibrosis, pancreatic failure, pancreatic fibrosis, decreased coagulation factor VII level, increased INR and APTT, increased LFTs (GGT, ALP, and AST), and thrombocytopenia. On Day 6, the subject had a nonserious AE of mild viral gastritis associated with abdominal pain and nausea. On Day 7, the subject was diagnosed with moderate portal hypertension (nonserious); abdominal ultrasound showed splenomegaly (15.1 cm increased from 11.5 cm) and stable liver findings of nodular restructured liver with in homogenous echo and increased echogenicity. Investigators considered bocavirus (positive throat culture) to be the viral etiology for gastritis. Study drug was discontinued on Day 7. On Day 9, abdominal MRI demonstrated splenomegaly (17 cm), liver cirrhosis, significant organ enlargement, hypertrophied left lobe of the liver, uneven liver surface, and inhomogeneous signaling. The periportal edema, portal vein, superior mesenteric vein, and splenic vein were visualized with regular contrast and significantly widened caliber — all without evidence of thrombosis. There were pronounced lymph nodes in the hepatic portal, and suspicion of development of esophageal varices was observed. There was no cholestasis or ascites. On Day 35, esophagoscopy identified slightly prominent Grade 1 veins in distal segment of the esophagus assessed to be initial esophageal varices due to liver cirrhosis and CF. The subject received no treatment for the AE and SAE of portal hypertension. At the ETT, there was persistent splenomegaly and intermittent thrombocytopenia. On the additional follow-up visit the event was assessed as resolved with sequelae. Throughout the course of the event, there were no substantial changes in ALT, AST, bilirubin, and albumin. INR and PT improved compared to predose values. Overall, there were no signs or symptoms suggestive of hepatic function decompensation. Immunologic workup was negative for ANA, ASMA, LKM1, and SLA). Virologic test results were negative for EBV, HAV, HCV, positive for cytomegalovirus IgGAb with negative IgM-Ab, positive for HHV6 IgG-AB with negative IgM, and positive for HBs antibodies with negative HBc antibodies


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and HBs antigen.

Reviewer comment: Subject 102- had a history of hepatic cirrhosis. The case suggests the potential for worsening of liver disease with ELX/TEZ/IVA use.

Trial 103 As seen in Trial 102, mean increases in AST, ALT, and total bilirubin were observed in the ELX/TEZ/IVA arm. Examination of maximum post-baseline changes identified more subjects reporting elevations in AST, ALT, and GGT for each threshold in the ELX/TEZ IVA arm compared to the TEZ/IVA arm. All study subjects developing post-baseline AST and ALT values >3x ULN had high baseline values (i.e. >ULN) for the respective laboratory parameter. No subjects reported increased total bilirubin >2x ULN. A summary of LFT laboratory changes appear in Table 57.

Table 57. Maximum Liver Function Test Elevations During Treatment Emergent Period: Trial 103, Safety Set

Lab parameter TEZ/IVA

N=52 n (%)


ALT (U/L), n (%) >3x to ≤5x ULN 0 2 (4) >5x to ≤8x ULN 0 2 (4)

AST (U/L), n (%) >3x to ≤5x ULN 0 1 (2)

GGT (U/L), n (%) >2.5x ULN to ≤3x ULN 1 (2) 1 (2) >5x to ≤20x ULN 0 1 (2)

Total bilirubin (μmol/L), n (%) >ULN to ≤1.5x ULN 4 (8) 3 (5) >2x ULN 0 0

Direct bilirubin (μmol/L), n (%) >ULN to ≤1.5x ULN 3 (6) 3 (5) >2x ULN 0 0

ALT: alanine aminotransferase, AST: aspartate aminotransferase, ULN: upper limit of normal, GGT: gamma-glutamyl transferase, ELX: elexacaftor, TEZ: tezacaftor, IVA: ivacaftor, U: units Source. CSR VX17-445-103, Table 14.3.4.2, Adhoc Table 14.3.4.10h, Adhoc table 14.3.4.10g. Reviewer verified using ADLB data set selecting SAFFL(Y), ONTRTFL(Y), ANL02FL(Y) by PARAMCD, MCRIT1ML, TRT01A, AVALC. With respect to AEs, 2 ELX/TEZ/IVA and 1 TEZ/IVA subject had at least 1 elevated transaminase AE. There were no treatment interruptions or discontinuations for hepatobiliary-related AEs in Trial 103.

Reviewer comment: Overall, the data suggest an imbalance in elevations of AST, ALT, and bilirubin in the ELX/TEZ/IVA arm compared to placebo and TEZ/IVA. This safety signal was identified throughout the clinical development program. With respect to bilirubin changes, the Applicant postulates that increased levels could be because blood bilirubin is a substrate of


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OATP1B1 and OATP1B3, and ELX is an OATP1B1 and OATP1B3 inhibitor (per in vitro data). However, given the presence of changes in AST, ALT, and bilirubin, this reviewer recommends specific labeling for all three laboratory changes.

8.2.5.2 Skin-Related Adverse Events

Following identification of rash as a potential safety issue early in the clinical development program, the Applicant defined rash as an AESI in both phase 3 trials. The following section discusses rash AEs from the pivotal trials. Review of the AE database for Trial 102 and 103 included exploration by Higher Level Term and PT to identify trends in related clinical events. In the discussion below, “rash AEs” pooled the following PTs: rash, rash generalized, rash pruritic, rash erythematous, rash macular.

Trial 102 More ELX/TEZ/IVA subjects reported any skin-related AE (22.8%) compared to placebo subjects (14.4%). The incidence of subjects reporting at least one rash AE was two-fold in the ELX/TEZ/IVA arm (21, 10.4%) compared to the placebo arm (10, 5.0%). Examination of additional Higher Level Terms also noted an imbalance in pruritus (3.4% vs <1%) and dermatitis/eczema (7% vs 0) AEs between the ELX/TEZ/IVA and placebo arms, respectively. Hypersensitivity vasculitis and photosensitivity reactions occurred more often in the placebo arm. Table 58 summarizes skin-related AEs reported in Trial 102.

Table 58. Incidence of Skin-Related Adverse Events, Trial 102, Safety Set

Higher Level Term Preferred term

Placebo N=201 n (%)


Subjects with at least 1 skin-related AE 29 (14) 46 (23) Rashes, eruptions, and exanthems 10 (5) 21 (10)

Rash 9 (4) 18 (9) Rash generalized 0 2 (1) Rash pruritic1 0 1 (<1) Rash erythematous 1 (<1) 0 Rash macular 0 1 (<1)

Pruritus NEC 1 (<1) 8 (4) Pruritus 0 6 Pruritus allergic 1 (<1) 0 Pruritus generalized 0 1 (<1) Rash pruritic1 0 1 (<1)

Acnes 4 (2) 8 (4) Acne 3 (1) 7 (3) Dermatitis acneiform 1 (<1) 1(<1)

Dermatitis and eczema 0 7 (4) Eczema 0 5 (2) Neurodermatitis 0 1 (<1) Dermatitis allergic 0 1 (<1)




Higher Level Term Preferred term

Placebo N=201 n (%)


Urticarias 4 (2) 1 (<1) Urticaria 3 (1) 1 Cold urticaria 1 (<1) 0

Photosensitivity and photodermatosis conditions 2 (1) 1(<1) Photosensitivity reaction 2 (1) 1(<1)

Skin vasculitides 2 (1) 0 Hypersensitivity vasculitis 2 (1) 0

AE: adverse event, IVA: ivacaftor, TEZ: tezacaftor, ELX: elexacaftor, n: number of subjects in subset, N: total subjects in trial arm, U: units Subjects counted once for each category. 1 Rash pruritic listed under both rash and pruritis AEHLT category Source. Reviewer calculated in JMP 12.0 using ADAE dataset selecting subjects by SAFFL(Y), TRTEMFL(Y), AESER(Y) by USUBJID, TRT1A, AEDECOD. To further investigate the clinical significance of the rash AEs, this review explored these AEs by time-to-onset, severity, outcome, and seriousness. The median time to onset of first rash AE was 12.0 days (mean[SD], 34.6[44.6] days) for ELX/TEZ/IVA subjects compared to 23.5 days for placebo (mean[SD], 39.6[47.5] days). Overall, most skin-related TEAEs in the ELX/TEZ/IVA arm were mild and moderate in severity. One ELX/TEZ/IVA subject reported severe TEAEs of rash and pruritus. Study drug interruptions for rash AEs occurred for 4 (2.0%) ELX/TEZ/IVA subjects and 1 (1.0%) placebo subject. A single ELX/TEZ/IVA subject with moderate AE of rash elected to discontinue from the study in order to continue hormonal contraception. There were no cases of Steven Johnson Syndrome reported or identified on query of the AE database. Narratives for the serious and severe AEs in the ELX/TEZ/IVA arm appear below: 1) Subject 102- was a 21 year old female with CF (F/MF) randomized to ELX/TEZ/IVA.

On Day 12, the subject received levofloxacin treatment for a moderate upper respiratory tract infection associated with weight loss, fatigue, and sore throat. The subject developed a rash on Day 15 a few hours after receiving levofloxacin (SAE due to eventual hospitalization). The rash was initially on the face and arms, but spread to the thorax on Day 16. The investigator consider the rash to be an allergic reaction to levofloxacin and discontinued the levofloxacin and began treatment with clemastine. The subject was hospitalized on Day 17 with worsening pruritic rash and dyspnea. Treatment for the SAE of rash included prednisolone, ranitidine, and levomenthol (prednisolone and ranitidine were also indicated for the levofloxacin allergy). The rash was markedly reduced within 4 to 5 days of treatment. On Day 21, the subject also had an SAE of infective PEx of CF, characterized by fever as well as increased fatigue, sputum, and cough, that was treated with IV piperacillin. Relevant concomitant medication at the time of onset of the rash included levonorgestrel (hormonal contraceptive administered via intrauterine device), azithromycin, and levofloxacin. Study drug dosing was not changed due to the SAE of rash. Use of hormonal therapy (levonorgestrel) was not changed during the course of the rash event.


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Reviewer comment: The Applicant’s assessment of association with levofloxacin appears reasonable.

2) Subject 102- was a 30 year old female with CF (F/MF) with a history of allergy to animal (hairs and dandruff), mite allergy (Dermatophagoides), seasonal allergy (grass, artemisia, birch, and ambrosia), and bronchospasm. The subject was randomized to ELX/TEZ/IVA on Day 1. On Day 12, the subject developed a moderate pruritic rash on the back. Evaluation by a dermatologist on Day 15 noted dermatitis irritation localized mainly on the chest. Laboratory results showed an elevated IgE of 405 kU/L (normal range: <200 kU/L), while hematology and other chemistry results were considered not clinically significant. On Day 18, the rash spread to the legs, and the subject received cetirizine and topical treatments: panthenol; glycerol/paraffin, liquid/white soft paraffin, and mometasone furoate. On Day 19, the investigator assessed the rash as an SAE (medically significant), given that it had become diffuse. The subject did not use concomitant hormonal therapy. The subject chose to self-interrupt study drug for 1 day (Day 19 to 20). The SAE resolved on Day 22. Subsequently, the subject had no recurrence of rash while on study drug. The subject experienced no systemic signs or symptoms associated with the rash.

3) Subject 102- was a 17 year old female with CF (F/MF) and a history of asthma, rhinitis and drug hypersensitivity (sulfa drugs). The subject was randomized to ELX/TEZ/IVA on Day 1. On Day 10, the subject developed a mild rash on her arms and back that slowly spread to the lower extremities. Relevant concomitant medication at the time of rash onset included EN/LN (oral hormonal contraceptive), colistin, and cetirizine hydrochloride. Physical examination 5 days later noted a diffuse erythematous maculopapular rash on arm and trunk with diffuse erythematous non-blanching pinpoint spots on the lower extremities. There was no rash noted on the face, palms, or soles. On Day 21, the subject had a slightly elevated eosinophil count at 3.2% (normal range: 1.0% to 3.0%) that normalized 2 days later. The investigator assessed the rash as an SAE (medically significant) on Day 23, given its persistent nature and appearance that was consistent with a drug rash. Study drug was interrupted on the same day, but the subject did not receive other treatment for the rash. VS and LFTs remained normal throughout the rash event. Investigators considered the SAE resolved on Day 34. On Study Day 58, the subject resumed dosing with study drug and stopped use of hormonal therapy without recurrence of rash.

4) Subject 102- was a 30 year old female with CF (F/MF) and a history of asthma, bronchopulmonary aspergillosis allergic, allergy to dogs, and mite allergy. The subject was randomized to ELX/TEZ/IVA on Day 1. On Day 10 the subject developed a nonserious severe rash and severe pruritus. The rash began as mild and quickly progressed to the back, shoulders, breast, arms, legs, and buttocks. Study drug was interrupted on the same day. The subject received oral prednisone (30 mg daily for 10 days), desloratadine, and topical emollients and protectives, as well as IV clemastine fumarate for rash prevention. Relevant concomitant medications at the time of onset of the rash included EE/LN (oral hormonal contraceptive), azithromycin, tacrolimus, cetirizine hydrochloride, and curcuma longa. Laboratory tests on Day 11 included leukocytosis (WBCs 14.7 × 109/L) and neutrophilia


(b) (6)

(b) (6)

(b) (6)



(neutrophils 11.66× 109/L), that were lightly increased from baseline. On Day 12, the subject stopped EE/LN, and the rash began to improve after 2 days. Pruritus resolved on Day 15.

The subject resumed study drug on Day 85. At that time, the rash was inactive but still slightly visible. The subject received additional treatment for the rash between Day 85 and 107 including prednisone (approximately 9 days at 30 mg, 5 days at 20 mg, and 3 days at 10 mg) and desloratadine. At the time of reporting, the AE of rash was considered not resolved.

As noted above, the majority of serious (75%) and severe (100%) rash events in female ELX/TEZ/IVA subjects occurred in those with concurrent hormonal therapy use. To investigate the potential association of rash AEs with sex and hormonal therapies, this review explored all rash AEs by sex and concomitant hormonal therapy. Approximately 16 (76%) of the ELX/TEZ/IVA subjects developing rash AEs were female. Among these female subjects, 7 (44%) reported concurrent hormonal therapy. The outcome of the 7 ELX/TEZ/IVA subjects with concurrent hormonal therapy included: • 4 subjects remained on study drug and hormonal therapy with resolution of rash • 2 subjects resumed study drug without further rash after both interruption of ELX/TEZ/IVA

treatment and discontinuation of hormonal therapy (see narratives above) • 1 subject discontinued ELX/TEZ/IVA, remained on hormonal therapy and rash resolved.

Trial 103 In Trial 103, 2 female subjects in each study arm reported rash AEs; the event for one of these subjects was considered serious (considered medically important by investigators) and was in the setting of concomitant use of hormonal therapy. The rash resolved after discontinuation of oral contraceptives and continued study drug treatment. In the TEZ/IVA arm, two subjects had nonserious rash events, of which 1 subject had concomitant use of hormonal therapy.

Reviewer comment: The rash-related AEs appear potentially drug-related and more common in female subjects. An association with hormonal therapy use cannot be excluded. This reviewer recommends additional labeling in Section 6 of the PI.

8.2.5.3 Creatinine Kinase Elevations

The following section discusses CK-related AEs from the pivotal trials. Review of the AE database for Trials 102 and 103 included exploration by PT to identify trends in related clinical events.




Trial 102 In Trial 102, comparison of changes from baseline at Week 24 identified a trend towards a greater mean and median increase in CK for ELX/TEZ/IVA compared to placebo. In addition, threshold analysis for elevations in CK identified more subjects with a maximum CK > 10x ULN in the ELX/TEZ/IVA arm (10, 5%) compared to the placebo arm (3, 1%). The majority of cases above >5x and >10x ULN occurred in subjects with baseline CK less than or equal to the ULN (Table 59).

Table 59. Creatine Kinase Laboratory Data, Trial 102, Safety Set

Analysis Placebo N=201 n (%)


Baseline (U/L) n 201 202 Mean (SD) 103.9 (140.3) 113.5 (209.0) Median 75.0 70.5 Min, max 19, 1336 18, 2347

Change from baseline at Week 24 (U/L) n 196 197 Mean (SD) 16.8 (301.3) 108.2 (650.2) Median 2.0 25.0 Min, max -1187, 3308 -2049, 6950

Post-baseline threshold category, n (%) Baseline

>2.5 to ≤5x ULN 9 (4) 13 (6) Low or normal baseline 6 (3) 11 (5) High baseline 3 (1) 2 (1)

>5x to ≤10x ULN 7 (3) 11 (5) Low or normal baseline 7 (3) 7 (3) High baseline 0 4 (2)

>10x ULN 3 (1) 10 (5) Low or normal baseline 3 (1) 8 (4) High baseline 0 2 (1)

ULN: upper limit of normal, ELX: elexacaftor, TEZ: tezacaftor, IVA: ivacaftor, n: number of subjects in subset, N: total subjects in trial arm, SD: standard deviation, U: units For threshold analysis, each subject counted once for worse assessment during TE period. Baseline defined as the most recent non-missing measurement before the first dose of study drug in the Treatment Period. n (%): n is the number of subjects in the post-baseline category who meet the baseline criterion; percentage is n/N. Post-baseline category determined based on the maximum post-baseline measurement relative to the upper limit of normal range. Source. Study VX17-445-102, CSR Table 14.3.4.4 and Ad hoc Table 14.3.4.111. Reviewer confirmed in JMP 12.0 using ADLB dataset selecting SAFFL (Y), ONTRTFL(Y) by USUBJID, BNRIND, MCRIT1ML, TRT01A. With respect to AEs, more subjects in the ELX/TEZ/IVA arm reported at least one CK-related or muscle-related TEAE than the placebo arm (13% vs 8%, respectively). Most AEs were attributed to the PT blood creatine phosphokinase increase, with other muscle-related TEAEs generally distributed across the study arms and PTs. In the ELX/TEZ/IVA arm, four subjects reported




severe AEs of increased blood creatinine phosphokinase, one of which required treatment interruption. There were no SAEs or study discontinuations for increased blood creatinine phosphokinase. In each study arm, more blood creatinine phosphokinase AEs occurred in adults than adolescents. Within the AE database, 1 placebo subject and 2 ELX/TEZ/IVA subjects had rhabdomyolysis AEs; both ELX/TEZ/IVA subjects required drug interruption, and one of the ELX/TEZ/IVA AE was classified as both serious and severe. Analysis of subgroups was notable for more male ELX/TEZ/IVA subjects (13%) reporting blood creatine phosphokinase AEs than female ELX/TEZ/IVA subjects (5%). Among the 5 ELX/TEZ/IVA subjects reporting severe AEs related to CK (PT blood creatine kinase increased and/or rhabdomyolysis), 4 were male and all were 18 years of age or older. The number of subjects requiring treatment interruption was too small to draw meaningful conclusions regarding subgroups. Table 60 summarizes muscle and CK-related AEs in Trial 102. Case narratives for the three subjects with rhabdomyolysis AEs appear below the table.

Table 60. Muscle-related AEs, Trial 102, Safety Set

Preferred Term Placebo N=201 n (%)


Muscle-related AE Blood creatine phosphokinase increased 9 (4) 19 (9) Myalgia 5 (2) 5 (2) Rhabdomyolysis 1 (<1) 2 (1) Muscle weakness 0 2 (1) Muscle spasms 1 (<1) 0 Muscle tightness 1 (<1) 0 Chromaturia 1 (<1) 1 (<1)

Muscle-related Grade 3 AE 0 5 (2) Muscle-related SAE 0 1 (<1) Muscle-related AE leading to treatment interruption 0 3 (1) Muscle-related AE leading to study discontinuation 0 0

AE: adverse event, SAE: serious adverse event, ELX: elexacaftor, TEZ: tezacaftor, IVA: ivacaftor, n: number of subjects in subset, N: total subjects in trial arm Subjects counted once per category. Source. Reviewer calculated in JMP 12.0 with ADAE in JMP selecting SAFFL(Y), ONTRTFL(Y) by USUBJID, TRT01A, AEDCODE, AESER, AEACN, AETOXGR 1) Subject 102- was a 20 year old white male with F/MF genotype and a history of CF

lung disease, hepatic steatosis, and hepatomegaly randomized to ELX/TEZ/IVA. The subject had a prior history of elevated CK with exercise (3071 units/liter [U/L], normal range: 30 to 200 U/L). Screening ALT was 58 U/L (ULN: 55 U/L) and liver parameters were within normal range. On Day 1, predose CK was 349 U/L (ULN 200 U/L). On Day 29 the subject developed an SAE of rhabdomyolysis; the subject had an elevated CK of >11,000 U/L (>10 × ULN), AST of 319 U/L (>8 × ULN; normal range: 5 to 34 U/L), an ALT of 115 U/L (>2 × ULN), and an ALP of 154 U/L; other LFT parameters and creatinine were


(b) (6)



within normal range. The investigator did not record a urinalysis. The subject was asymptomatic, but was referred to the emergency department by the investigator. The subject had been exercising more than usual in the week before the CK elevation, restarted power training, and increased his protein intake substantially. On Day 30 the subject was hospitalized, and study drugs were interrupted. Serum CK increased to 13,439 (U/L), with decreasing transaminases. The subject received IV fluids. Urinalysis was negative for blood, and serum CK decreased to 4222 U/L on Day 35. The subject resumed study drug on Day 36. CK remained < 2x ULN for the rest of the study.

2) Subject 102- was a 19 year old white male with F/MF genotype and a history of CF lung disease and hepatic enzyme increase randomized to ELX/TEZ/IVA. The subject had normal screening CK, AST, and ALT. On Day 15, the subject had a nonserious moderate AE of rhabdomyolysis marked by a CK elevation of 1187 U/L (>5 × ULN; normal range: 30 to 200 U/L), AST of 39 U/L (normal range: 5 to 34 U/L), and ALT within normal range. The subject had engaged in exercise, including CrossFit, before the study visit. The investigator did not record a physical exam or results of urinalysis. The subject did not receive treatment for the event. Study drug was interrupted on Day 23 and 24 for the AE. The AE resolved on Day 26, and study drug dosing resumed on Day 28. Repeat laboratory analysis on Day 29 showed CK and AST returned to normal and creatinine was in normal range.

On Day 63, the subject had a second nonserious moderate AE of rhabdomyolysis reported with a CK of 8677. The subject had engaged in exercise, including CrossFit and swimming, before the visit. The investigator did not record a physical examination or urinalysis at the onset of the event. Study drug was interrupted on Day 64 and 65, but no other treatment was provided. On Day 69, CK decreased to 334 mU/mL, kidney function was normal, and blood myoglobin was normal. On Day 113, the subject had a nonserious AE of mild blood creatine phosphokinase increased. The CK value was 396 U/L. The subject did not receive treatment and study drug dosing was not changed.

3) Subject 102- was a 17 year old white male with F/MF genotype randomized to placebo. Screening CK, AST, and ALT were within normal range. On Day 57, the subject had a nonserious moderate AE reported as rhabdomyolysis with CK of 4590 U/L (>10 × ULN; normal range: 2 to 238 U/L), an AST of 133 U/L (>3 × ULN; normal range: 0 to 38 U/L), and an ALT of 122 U/L (>3 × ULN). The investigator reported that the subject had engaged in strenuous cardiovascular and body-building exercises leading up to the day before the visit. The investigator did not record results of a physical examination or urinalysis at the time of the AE onset. The subject did not receive treatment for the event, and study drug dosing was not changed due to the event. On Day 59, CK was 2137 U/L (Normal < 171 U/L) and creatinine was 1.10 g/dL (normal 0.67 to 1.17 mg/dL). Serum myoglobin was 341 micro/L.


(b) (6)

(b) (6)



On Day 66, CK decreased to 298 U/L and serum myoglobin was within normal range.

Reviewer comment: The two ELX/TEZ/IVA subjects reporting rhabdomyolysis were accompanied by a recent history of strenuous exercise; serum CK elevation alone is not specific for rhabdomyolysis, and increased CK may be seen after strenuous exercise. The subjects were asymptomatic, without identified kidney involvement and/or myoglobinuria, and the CK elevation was first noted on scheduled CK study monitoring. While this reviewer agrees that it appears these cases did not likely meet criteria for clinical rhabdomyolysis, this conclusion is limited in part by the post-hoc nature of the analysis, and the absence of concurrent laboratory data on myoglobin at the onset of the AE. The Phase 3 program did not include prespecified criteria for the evaluation of CK elevations and rhabdomyolysis, including screening criteria for the presence of serum and/or urine myoglobin. During the conduct of the studies, these tests/clinical evaluation were at the discretion of the investigators.

To investigate for additional clinical cases of rhabdomyolysis, the Applicant also completed a post-hoc review of analysis of patients with CK elevations > 5x ULN. The Applicant considered clinical rhabdomyolysis to be characterized by renal involvement and/or increase serum/urine myoglobin levels. The Applicant concluded that none of the subjects receiving ELX/TEZ/IVA who had CK elevations had true features of clinical rhabdomyolysis. This reviewer completed an independent analysis of the laboratory (ADLB) and adverse event (ADAE) datasets from Trial 102, including a query of the AE database for muscle-related AEs in subjects developing a post-baseline CK value greater than 5x ULN. No subjects in this population reported potential muscle-related AEs (PT: myalgia, muscle weakness, muscle spasms, muscle tightness, myoglobinuria, hematuria, or chromaturia). One subject developed chromaturia on Day 22 (verbatim term: dark colored urine), but the chromaturia AE was not concurrent with the abnormal CK laboratory value reported on Day 183 (Subject 102- ). Additional query of this subject population for potential myoglobinuria (i.e. occult blood positive and negative urine microscopy for RBC) yielded no additional cases. However, as noted above, not all subjects with CK elevations received concurrent urine/myoglobin testing.

Trial 103 In Trial 103, 2 subjects reported muscle-related TEAEs, including myalgia (TEZ/IVA) and muscle spasms (ELX/TEZ/IVA). Fifteen ELX/TEZ/IVA subjects (27%) developed CK elevations between >ULN and ≤2.5xULN compared to 2 TEZ/IVA subjects (4%); post-baseline CK elevations >2.5x ULN occurred in 2 (4%) ELX/TEZ/IVA subjects and no TEZ/IVA subjects. No subjects reported CK-related AEs, CK elevations > 5x ULN or cases of rhabdomyolysis.

Reviewer comment: An imbalance in CK / muscle-related AEs was observed with overall AE incidence, study drug interruption, grade 3 severity, or SAEs for ELX/TEZ/IVA compared to controls. The persistence of the CK laboratory elevations and CK-related AEs throughout the clinical development program raise concern for causal role of study drug. A role of exercise in magnifying these CK changes cannot be ruled out. This reviewer recommends specific labeling for elevation in CK in Section 6 of the PI.


(b) (6)



8.2.5.4 Respiratory-Related Adverse Events

While not designated as an AESI in this development program, respiratory-related adverse events are listed as a Warning and Precaution on the LUM/IVA (Orkambi®) label. The safety review explored both Trials 102 and 103 for respiratory-related AEs overall and with study drug initiation. In Trial 102, most respiratory-related AEs occurred more frequently in the placebo arm than the ELX/TEZ/IVA arm; considering the entire treatment-emergent period, no respiratory-related AEs occurred at an incidence greater than 1% in the ELX/TEZ/IVA arm and more than placebo. AEs of pulmonary function decreased / FEV1 decrease occurred in no subjects in the ELX/TEZ/IVA arm and 6.5% of the placebo arm. In Trial 103, more ELX/TEZ/IVA subjects reported cough and dyspnea AEs compared to the TEZ/IVA subjects; however, the difference between the study arms was small (≤ 5 subjects). There were no AEs meeting the following criteria: serious, severe, treatment interruption, or treatment discontinuation. Analysis of time to onset of respiratory-related AE identified no clinically significant trends. Table 109 summarizes the respiratory-related AEs for Trials 102 and 103.

Reviewer comment: No additional labeling is recommended for respiratory-related AEs.

8.2.5.5 Cataracts

Cataracts have been observed in patients, particularly pediatric patients, treated with IVA monotherapy and in juvenile rat toxicology studies with ivacaftor. Trial 102 required ophthalmologic exams at screening/baseline, and at Week 24 for pediatric subjects <18 years of age. Two subjects developed treatment emergent cataracts:

1. Subject 102- . 16 year-old female (ELX/TEZ/IVA) with a mild cataract cortical (inferior, posterior) and lenticular opacity (focal, nuclear) in the right eye on Study Day 167. Concomitant medications for the subject included fluticasone propionate, insulin lispro, insulin glargine, and budesonide /formoterol fumarate.

2. Subject 102- . 20-year-old female (placebo) developed bilateral mild TEAE cataracts on Study Day 7.

In addition, three subjects had cataracts identified on baseline examination (1 ELX/TEZ/IVA and 2 placebo). On subsequent examination at Week 24, investigators did not observe a cataract in the ELX/TEZ/IVA subject. There were no treatment emergent cataracts in Trial 103.


(b) (6)

(b) (6)



Reviewer comment: Reports of cataract AEs were relatively rare and balanced across the treatment arms. This reviewer recommends labeling for cataracts that is consistent with the IVA and TEZ/IVA labels. No additional labeling is warranted.

8.2.5.6 Menstrual Abnormalities

While not designated as an AESI in this development program, menstrual abnormalities are listed as adverse drug reactions in the LUM/IVA (Orkambi®) label. This review explored Trials 102 and 103 for TEAEs potentially related to menstrual abnormalities. Similar to the LUM/IVA program, the Applicant completed a custom MedDRA Query in Trial 102 and 103.8 The terms included in the query were deemed reasonable. In Trial 102, 6 (6.1%) female ELX/TEZ/IVA subjects compared with 2 (2.1%) female placebo subjects reported at least one menstrual abnormality (PT: dysmenorrhea, menorrhagia, menstrual disorder, menstruation delayed, or menstruation irregular). The mean duration of menstrual-related events in ELX/TEZ/IVA subjects was 4 days (range 1 to 7 days) compared to 12.5 days (range 1 to 24 days) for placebo subjects. The median time-to-onset of first event was 79.0 days (range: 6, 166 days) and 89.0 days (range: 67 , 111 days) for the ELX/TEZ/IVA and placebo arms, respectively. Within the ELX/TEZ/IVA arm, the incidence of menstrual-related events was similar among those with and without concomitant hormonal therapy use. The majority of menstrual-related abnormalities occurred in subjects 18 years or older. There were no events meeting the following criteria: leading to discontinuation, leading to treatment interruption, serious, or Grade 3 severity. In Trial 103, no subjects reported a menstrual-related disorder.

Reviewer comment: There was a small imbalance in menstrual abnormalities; however, subjects were able to continue study treatment. In contrast to the LUM/IVA development program, there was no difference among those subjects on hormonal contraception. The less common adverse reactions listed in Section 6 of the PI capture the most frequent menstrual-related event, i.e. dysmenorrhea.

8.2.6 Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability

Review of trends in CFQ-R and TSMQ global satisfaction scores identified no additional safety concerns.

8 The following PTs included in the menstrual events CMQ were abnormal withdrawal bleeding, amenorrhoea, bleeding anovulatory, delayed menarche, dysfunctional uterine bleeding, dysmenorrhoea, hypomenorrhoea, menometrorrhagia, menorrhagia, menstrual discomfort, menstrual disorder, menstruation delayed, menstruation irregular, metrorrhagia, oligomenorrhoea, polymenorrhagia, polymenorrhoea, premature menarche, and premature menopause. The preferred terms uterine hemorrhage and vaginal hemorrhage were not included. Review of the AE database identified one case of uterine hemorrhage and one case of vaginal hemorrhage in the ELX/TEZ/IVA arm; the case of vaginal hemorrhage occurred in the setting of pregnancy.




8.2.7 Safety Analyses by Demographic Subgroups

This reviewer explored the safety database by sex, age, race, region, baseline ppFEV1, and study treatment arm. There were no clinically meaningful trends in safety analyses by baseline ppFEV1 or region. There were too few subjects of non-white racial groups to make meaningful comparisons across the subgroups. With respect to age, in contrast to the placebo arm, headaches occurred more often in adults (20%) than adolescents (9%) in the ELX/TEZ/IVA arm of Trial 102; however, the clinical significance is uncertain given the higher background prevalence of headaches in adults vs children/adolescents and the smaller proportion of adolescents in this study population. Comparison of AE distribution by sex was notable for numerical differences in the percentage of female and male ELX/TEZ/IVA subjects reporting headache (22% vs 13%) and rash (16% vs 5%). In contrast, among the ELX/TEZ/IVA subjects blood creatine phosphokinase elevation occurred more often in males (13%) than females (5%).

Reviewer comment: This reviewer recommends labeling for rash and increased incidence in females in the label. The clinical relevance of the remaining differences is uncertain.

8.2.8 Specific Safety Studies/Clinical Trials

8.2.8.1 OLE Study VX17-445-105

The following section presents safety data from the ongoing Study 105. The source of data for the review primarily considered the Applicant’s interim data analysis with a July 10, 2019 cutoff. Where specifically noted, this review included additional safety data from Safety Update (August 9, 2019 cutoff). Study Design

Study VX17-445-105 is the OLE study for subjects who completed Trials 102 and 103 and is currently ongoing. Uncontrolled safety data from this study provides support for the long-term use of ELX/TEZ/IVA. An overview of the study protocol and safety results thus far are provided below. Title: A Phase 3, Open-label Study Evaluating the Long-term Safety and Efficacy of ELX Combination Therapy in Subjects With Cystic Fibrosis Who Are Homozygous or Heterozygous for the F508del Mutation. Primary Objective: To evaluate the long-term safety and tolerability of ELX in TC with TEZ and IVA in subjects with CF who are homozygous or heterozygous for the F508del mutation Secondary Objectives: • To evaluate the long-term efficacy of ELX in TC with TEZ and IVA




• To evaluate the pharmacodynamics (PD) of ELX in TC with TEZ and IVA Design Study 105 is a phase 3, open-label, multicenter extension study in over 400 subjects with CF homozygous or heterozygous for F508del. Eligible subjects must complete study drug in the parent study or if there were study drug interruptions, complete study visits through the treatment period. After completion of the treatment period of the parent study (Trials 102 and 103), eligible subjects receive open-label ELX/TEZ/IVA (200 mg ELX/100 mg TEZ/150 mg IVA q12) for an additional 96 weeks. Safety assessments occur every 4 to 12 weeks. Monitored safety variables include clinical laboratory assessments (serum chemistry, hematology, urinalysis, and coagulation studies), pregnancy tests, ECGs, VS, pulse oximetry, and physical examinations. For subjects < 18 years of age, planned ophthalmologic examinations occur at Week 48 and at the completion of study participation if the cumulative drug exposure is at least 12 weeks since the last study ophthalmologic examination. Study Population Key Inclusion criteria: 1. Did not withdraw consent from parent study 2. Willing and able to comply with scheduled visits, treatment plan, study restrictions,

laboratory tests, contraceptive guidelines, and other study procedures. 3. At least 1 of the following criteria:

o Completed study drug treatment in a parent study, or o Had study drug interruption(s) in a parent study, but completed study visits up to

the last scheduled visit of the Treatment Period of a parent study. Key Exclusion criteria: 1. History of any comorbidity that might confound the results of the study or pose an

additional risk in administering study drug 2. Pregnancy and nursing 3. History of drug intolerance in parent study that would pose an additional risk to the subject

in the opinion of the investigator (e.g. subjects with a history of allergy or hypersensitivity to the study drug)

Figure 16. Study Design, Open Label Extension Study 105

VX-445: ELX, IVA: ivacaftor, TEZ: tezacaftor

Source. IND 132547, VX17-445-105, Protocol Version 3.0, Figure 9-1 Endpoints: ppFEV1, pulmonary exacerbations, spirometry, height/weight, CFQ-R, and SwCl.




Disposition and Exposure

Among the combined 507 subjects completing Trials 102 and 103, 505 entered the OLE (Study 105).9 Three subjects from Trial 102 required study drug interruption during the transition into Study 105, including two subjects with elevated LFTs (ELX/TEZ/IVA and placebo) and one placebo subject requiring use of a prohibited medication. As of July 10, 2019, eleven subjects (2.2%) discontinued treatment in Study 105; when grouping subjects by prior treatment in the parent study (i.e. placebo, TEZ/IVA, or ELX/TEZ/IVA), the number of subjects discontinuing from Study 105 was generally comparable. More subjects in the placebo ELX/TEZ/IVA group required at least 1 study drug interruption for an AE or elevated LFTs. Table 61 summarizes subject disposition in Study 105.

Table 61. Subject Disposition, Study 105 IA

Disposition Reason

Placebo

ELX/TEZ/IVA

N=200

TEZ/IVA

ELX/TEZ/IVA

N=52

ELX/TEZ/IVA

ELX/TEZ/IVA N=253

All Subjects

N=505

Number of enrolled subjects 1 203 52 252 507 Number of enrolled subjects receiving least 1 dose of study drug 202 52 251 505

Prematurely discontinued the treatment, n (%) 2 3 (1) 2 (4) 6 (2) 11 (2) Adverse event 2 (1) 1 (2) 3 (1) 6 (1) Subject refused further dosing (not due to AE) 0 0 1 (<1) 1 (<1) Lost to follow-up 1 (<1) 0 0 1 (<1) Pregnancy (self or partner) 0 1 (2) 2 (<1) 3 (<1)

At least 1 study drug interruption, n (%) 2, 3 15 (7) 4 (8) 11 (4) 30 (6) Adverse event 11 (5) 1 (2) 4 (2) 16 (3) Elevated liver function test results 5 (3) 1 (2) 4 (2) 10 (2) Prohibited medication 0 2 (4) 2 (<1) 4 (<1) Other 0 0 2 (<1) 2 (<1)

Number of subjects completed treatment 4 0 0 0 0 Data through July 10, 2019. ELX: elexacaftor, TEZ: tezacaftor, IVA: ivacaftor, N: total subject in group, n: subjects in subset, FAS: full analysis set OL Full Analysis Set is defined as all enrolled subjects who received at least 1 dose of study drug in the OLS. Treatment label is based on the treatment the subjects were randomized to in the parent study. 1 Subjects enrolled in 105 are defined as subject having data in the clinical database for the open label study (OLS). 2 Percentages are based on the number of subjects in the OL FAS 3 Study drug interruption includes all interruptions started on or after the first dose of study drug in the OLS for OL Full Analysis Set. A subject with multiple interruptions for the same reason is counted only once in that reason category. A subject with multiple interruptions for different reasons is counted in multiple reason categories.

4 Study is ongoing Source: Ad hoc Table 4, VX17-445-105 IA1, Response to FDA Information Request dated 28 August 2019, NDA 212273 In total, through July 10, 2019, 505 CF subjects received ELX/TEZ/IVA in Study 105 with a mean

9 3 subjects discontinued from parent studies. See Section 8.2.4.




exposure duration of approximately 21.5 weeks. By treatment group, the mean exposure was 18.7 weeks, 32.2 weeks, and 21.5 weeks for subjects originally in the placebo, TEZ/IVA, and ELX/TEZ/IVA arms of the parent studies, respectively. Table 62 summarizes subject exposure for Study 105.

Table 62. Duration of Exposure, Study 105 IA, OL Safety Set

Placebo

ELX/TEZ/IVA N=200

TEZ/IVA

ELX/TEZ/IVA N=52

ELX/TEZ/IVA

ELX/TEZ/IVA N=253

All Subjects N=505

Total exposure (patient-years) 1 78.0 34.9 113.4 226.4 Exposure duration (weeks)2

N 200 52 253 505 Mean (SD) 18.7 (6.24) 32.2 (4.96) 21.5 (8.08) 21.5 (8.09) Median 16.9 31.3 21.1 21.0 Min, max 1.4, 29.4 8.9, 39.3 2.0, 39.3 1.4, 39.3

Exposure duration interval, n (%) 0 to ≤8 weeks 3 (1) 0 5 (2) 8 (2) >8 to ≤16 weeks 92 (46) 1 (2) 93 (37) 186 (37) >16 to ≤24 weeks 45 (23) 0 46 (18) 91 (18) >24 to ≤36 weeks 60 (30) 36 (69) 97 (38) 193 (38) >36 to ≤48 weeks 0 15 (29) 12 (5) 27 (5) >48 to ≤60 weeks 0 0 0 0 >60 weeks 0 0 0 0

ELX: elexacaftor, TEZ: tezacaftor, IVA: ivacaftor, N: total subject in group, n: subjects in subset Exposure data only includes data from Study 105. For cumulative exposure, See Section 8.2.2. OL Safety Set is defined as all subjects who received at least 1 dose of study drug in the open label study (OLS). Subjects are assigned based on parent study actual treatment. If a subject was still on study drug on the interim analysis data cutoff date (July 10, 2019), the cutoff date was used as the last dose date to calculate the duration of study drug exposure. 1 Total exposure is defined as the sum of the study drug exposure across all subjects in the OLS. 2 Duration of study drug exposure (weeks) = (last dose date of study drug in the OLS - first dose date of study drug in the OLS + 1)/7, regardless of study drug interruption. Source: Ad hoc Table 2, VX17-445-105 IA1, Response to FDA Information Request dated 28 August 2019, NDA 212273

Deaths

There were no deaths. Serious Adverse Events

Data from the IA and safety update (i.e. August 9, 2019 cutoff), included 65 subjects reporting at least 1 SAE. SAEs reported in greater than 2 subjects included infective PEx of CF (37 subjects), DIOS (4 subjects), hemoptysis (4 subjects), influenza (3 subjects), and LFTs abnormal / transaminase increased (2 subjects). There were two additional serious AESI reported: rash (1) and CK elevation (1). The remaining SAE were single events distributed across PTs. The narratives for the serious AESI appear in the Submission Specific Safety Concerns Section below.




Adverse Events Leading to Discontinuation

Through the July 10, 2019 cutoff for the IA, six subjects developed AEs leading to study discontinuation, including the rash (1 subject) and increased LFTs (2 subjects) SAEs described above. One additional subject discontinued for a non-serious event of increased LFTs. Among the subjects with increased LFT, two subjects received ELX/TEZ/IVA in the parent study and 1 subject received placebo. The remaining AE PTs were single events: headache, tinnitus, contusion and depression. Common Treatment Emergent Adverse Events The most common AEs were infective PEx of CF (17.6%), cough (16.6%), sputum increased (9.5%), and oropharyngeal pain (9.3%). Comparison of AE incidence by parent study treatment group noted small numerical increases in the incidence of AEs in subjects previously receiving TEZ/IVA compared to the other groups; however, such comparisons are confounded by a longer mean duration for these subjects compared to the other arms (approximately 11 weeks). In general, AEs were consistent with those related to the underlying disease and identified in the pivotal trials.

Submission Specific Safety Concerns

The following section summarizes submission specific safety concerns inclusive of data through the July 10, 2019 IA. Hepatobiliary Events The Applicant provided a summary of the IA for laboratory changes and hepatobiliary-related AEs from Study 105. As seen in Trials 102 and 103, there were elevations in LFTs reported during the OLE. The incidence of increased total bilirubin >2x ULN was slightly higher for subjects that received ELX/TEZ/IVA in the parent study (8, 3%) than subjects that received placebo (2, 1%) or TEZ/IVA (1, 2%). Two subjects developed ALT or AST >3x ULN and bilirubin >2x ULN; one subject had nonconcurrent elevation in the parameters and the second subject had concurrent elevations in the setting of acute cholecystitis. The latter subject recovered following cholecystectomy and resumed study drug with return of AST, ALT, and bilirubin to baseline values. The following table summarizes the LFT elevations in Study 105.

Table 63. Maximum Liver Function Test Elevations During Treatment Emergent Period: Study 105 IA, OL Safety Set

Lab parameter ELX/TEZ/IVA

N=505 n (%)

ALT (U/L), n (%) >3x to ≤5x ULN 12 (2) >5x to ≤8x ULN 5 (1) >8x ULN 2 (<1)

AST (U/L), n (%) >3x to ≤5x ULN 5 (1)




Lab parameter ELX/TEZ/IVA

N=505 n (%)

>5x to ≤8x ULN 1 (<1) >8x to ≤10x ULN 0 >10x ULN 1 (<1)

Total Bilirubin (μmol/L), n (%) >2x ULN 11 (2)

ALT or AST and total bilirubin, n (%) 1 (ALT or AST >3x ULN) and bilirubin >2x ULN 2 (<1) 2

Data included through July 10, 2019. ALT: alanine aminotransferase, AST: aspartate aminotransferase, ULN: upper limit of normal, GGT: gamma-glutamyl transferase, IVA: ivacaftor, TEZ: tezacaftor, ELX: elexacaftor, n: number of subjects in subset, N: total subjects in trial arm, U: units 1 Subjects identified as meeting these criteria may have elevations in AST/ALT and total bilirubin at any visit during the OL Safety Period; the elevations in AST/ALT and total bilirubin might not necessarily be concurrent. 2 One subject had nonconcurrent elevation in transaminase and bilirubin. Second subject had concurrent elevations in the setting of acute cholecystitis. The subject recovered following cholecystectomy and resumed study drug with return of AST, ALT, and bilirubin to baseline. Source: VX17-445-105 IA1, Ad hoc Table 9.5 In Study 105, 7% and 1% of subjects reported AEs related to hepatobiliary investigations (labs) and hepatobiliary disorders, respectively. The incidence of hepatobiliary AEs in Study 105 was generally similar, regardless of treatment assignment in the parent study. Table 64 summarizes the hepatobiliary AEs.

Table 64. Hepatobiliary Adverse Events, Study 105 IA, OL Safety Set

SOC Preferred Term


Investigations SOC 36 (7) Alanine aminotransferase increased 15 (3) Aspartate aminotransferase increased 15 (3) Gamma-glutamyl transferase increased 8 (2) Transaminase increased 2 (<1) Liver function test increased 1 (<1) Blood bilirubin increased 15 (3) Blood bilirubin unconjugated increased 6 (1) Bilirubin conjugated increased 3 (<1) International normalized ratio increased 2 (<1) Activated partial thromboplastin time prolonged 1 (<1)

Hepatobiliary disorders SOC 5 (1) Cholecystitis 1 (<1) Cholecystitis acute 1 (<1) Cholelithiasis 1 (<1) Hepatic steatosis 1 (<1) Hepatomegaly 1 (<1)

SOC: System Organ Class, TEZ: tezacaftor, ELX: elexacaftor, n: number of subjects in subset, N: total subjects in trial arm, U: units




Data included through July 10, 2019. Subjects counted once for each category. Source. VX17-445-105 IA1, Ad hoc Table 9.1 The three subjects that discontinued study treatment for LFT abnormalities had a total duration of ELX/TEZ/IVA treatment of approximately 38, 93 and 202 days, respectively. Narratives for the three subjects appear below: 1. Subject 102- was a 35-year-old male with a medical history of intermittent bilirubin

elevations (total bilirubin was >1.5 × ULN at baseline) and increased hepatic enzymes who received ELX/TEZ/IVA in Trial 102. Baseline GGT, ALT, and AST were within normal range, and total bilirubin was 33 μmol/L (>1.5 × ULN). Results were generally similar throughout Trial 102. The subject had SAEs of infective PEx of CF and LFTs abnormal in Study 105.

On Day 1 of ELX/TEZ/IVA treatment in Study 105, the subject initiated oral antibiotic treatment for an ongoing infective PEx of CF (ciprofloxacin and flucloxacillin). On Day 5, the subject was hospitalized due to the infective PEx of CF and started treatment with IV antibiotics (colistimethate sodium and ceftazidime). On Day 10, laboratory values showed the following LFT elevations: GGT >8 × ULN, ALT >8 × ULN, and total bilirubin 1.95× ULN. LFTs improved after study drug interruption and completion of antibiotic treatment. On Day 15, abdominal ultrasound revealed a normal liver size with a collapsed gallbladder but no focal intrahepatic lesion. There was no intrahepatic or extrahepatic biliary duct dilation, and there was no ascites. Treatment with IV antibiotics was completed on that day. Repeat LFTs continued to trend down (see Table below), and study drug resumed on Day 29. However, on Day 32, AST, ALT, and bilirubin increased again, and study drug was discontinued on Day 33. No alternative etiology was identified for the laboratory elevations.

Table 65. Liver Function Test Values: Subject 102- , Study 105 Study Day or Visit/ Reference Point Date

ALT (NR: 0 to 55 U/L)

AST (NR: 5 to 34 U/L)

Total BILI (NR: 0 to

20.5 µmol/L)

GGT (NR: 12 to

64 U/L) TC safety baseline 50 27 33 (H) 18

Day 1 (first dose) 78 (H) 29 33 (H) 68 (H)

Day 5 218 (H)a -- 35 (H) --

Day 10 (event onset) 520 (H)a -- 41 (H)1 (NR<21) 946 (H) a

Day 11 412 (H)a -- 34 (H)1 (NR<21) 889 (H) a

Day 15 175 (H)a -- 22 (H)1 (NR<21) 563 (H) a

Day 23 60 (H) a -- 19 a (NR<21) --

Day 32; unscheduled 390 (H) 148 (H) 32.8 (H) 424 (H)

Day 36; unscheduled 102 (H) 32 18 234 (H)

ETT Visit 34 22 28.6 124

ALT: alanine transaminase; AST: aspartate transaminase; BILI: bilirubin; ETT: Early Termination of Treatment; GGT: gamma-glutamyl transferase; H: high; NR: normal range; TC: triple combination, U:units.

Text bold where ALT or AST > 3x ULN, T. Bili >2x ULN, GGT > 3xULN Shading: no study drug 1 Results from CIOMS Source. NDA 212273, 5.3.5.2, Study Report Body, VX1717-445-105- Narratives of Deaths, Other Serious and Other significant


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Adverse Events, and Pregnancies, Page 48. 2. Subject 103- was a 16-year-old male with CF (F/F). Pertinent medical history

included poorly controlled CF-related diabetes and increased ALT, AST, ALP, and GGT. In Trial 103, baseline laboratory analysis on TEZ/IVA included ALT >2× ULN, GGT >2× ULN, and ALP 330 U/L (normal range: 52 to 171 U/L). During treatment with ELX/TEZ/IVA in Trial 103, the subject received ursodeoxycholic acid for elevated ALT >5× ULN and AST >3× ULN. On Trial 103 Day 34 / Study 105 Day 1, the subject began OL treatment with ELX/TEZ/IVA. On Study 105 Day 10, the subject had nonserious AEs of ALT increased (>5× ULN), AST increased (>3x ULN), and GGT increased (>8x ULN). Total bilirubin remained in normal range. The subject did not receive additional treatment for these events. Study drug was discontinued on Study 105 Day 14. Relevant concomitant medications at onset of these AEs included mirtazapine and ursodeoxycholic acid. On Study 105 Day 58, the AE of GGT increased was considered resolved, but ALT increased and AST increased were ongoing.

3. Subject 102- was a 32-year-old female with CF (F/MF) and a medical history included nausea, pancreatic failure, hypovitaminosis, malnutrition, pain, and adjustment disorder with anxiety. The subject received placebo in Trial 102. All baseline liver function parameters were within normal range. The subject began open-label ELX/TEZ/IVA on Study 105 Day 1. From Day 24 to 28, the subject took a few doses of paracetamol and had 1 alcoholic drink. On Day 28, AST and ALT increased to 2x ULN, and the subject discontinued paracetamol, clonazepam, and zolpidem for the remainder of the study. The subject began having loose stools and nausea on Day 40. On Day 43, ALT was >8 × ULN and AST was >5 × ULN (classified as SAE). Relevant ongoing concomitant medications included azithromycin, tobramycin (inhaled), fluoxetine, ondansetron, and pancrelipase. Liver transaminases improved after dosing interruption and discontinuation of tobramycin. However, 8 days after resumption of study drug on Day 93, ALT increased to >3× ULN and AST to >2× ULN; study drug dosing was discontinued. At Safety Follow-up Visit, the AE resolved. The subject had negative or unremarkable workup for autoimmunity, viral serology, and toxicology laboratory tests were all negative or unremarkable; MRI of liver was normal morphology. Evaluation by a hepatologist assessed the subject’s liver synthetic function as intact and suspected the transaminase elevations may be secondary to drug-induced liver injury from the study drug. Other LFT values remained within normal range for the duration of the study.

Reviewer comment: The recurrence of LFT changes following resumption of study drug in two of these subjects is consistent with the safety signal observed in the controlled clinical trials that suggests the LFT abnormalities were likely related to the study drug.

Skin-Related Events Skin-related AEs occurred in 10% of the enrolled subjects. Overall, the pattern generally mirrored the pivotal trials. The incidence of rash was higher in subjects previously receiving


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placebo (19, 10%) in the parent study than either TEZ/IVA (3, 6%) or ELX/TEZ/IVA (10, 4%). Among the 5 total subjects requiring drug interruption for skin-related events (PT: rash, rash generalized, and pruritus generalized), all received either placebo (4) or TEZ/IVA (1) in the parent study. Table 66 summarizes the incidence of skin-related AEs in Study 105 IA.

Table 66. Skin-related Adverse Events, Study 105 IA, Safety Set

Preferred term ELX/TEZ/IVA

N=505 n (%)

Subjects with at least 1 skin-related AE 49 (10) Rash1 32 (6) Photosensitivity reaction2 9 (2) Dermatitis3 4 (<1) Pruritus generalized 1 (<1) Transient acantholytic dermatosis 1 (<1)

ELX: elexacaftor, TEZ: Tezacaftor, IVA: ivacaftor, IA: interim analysis, AE: adverse event, n: number of subjects in subset, N: number of subjects in study arm. Subjects counted only once in that category. 1 Includes PT: Rash, Rash erythematous, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic, Rash generalized 2 Includes PT: Photosensitivity reaction and Solar dermatitis 3 Includes PT: Dermatitis allergic, Dermatitis acneiform, Dermatitis contact, and Neurodermatitis Source. Ad hoc Table 9.3, VX17-445-105 IA1, Response to FDA Information Request dated 28 August 2019, NDA 212273 A single subject discontinued from the Study 105 for a rash AE: • Subject 102- was a 29-year-old male with F/MF mutation with a history of drug

hypersensitivities and chronic kidney disease. The subject received placebo in Trial 102. During the last 3 weeks of Trial 102, the subject had increasing cough and sputum. On Day 10 of ELX/TEZ/IVA treatment in Study 105, the subject developed a diffuse macular rash with mild peripheral eosinophilia (0.58 Giga particles per liter [Gpt/L]; NR: 0.03 to 0.44 Gpt/L), and study drug was discontinued. The subject received cetirizine and prednisolone for the rash. On Day 11, the subject was hospitalized for an SAE of rash. The subject had a fever and diffuse pruritic exanthema without involvement of the mucosal membranes. A consulting dermatologist diagnosed the subject with suspected drug-induced macular exanthema, accentuated on the torso, and a biopsy was deemed not necessary. On Day 11, the subject was also diagnosed with an SAE of infective PEx of CF. The subject had change in sputum, increased cough, malaise, dyspnea, and fever. Laboratory evaluation showed elevated inflammatory markers, elevated neutrophils (91.2%, NR: 42.0% to 77.0%) and a mildly elevated blood creatinine level (171 μmol/L; NR: 59 to 104 μmol/L). The patient received IV antibiotics for the infective PEx. The rash resolved on Day 15. On the same day, the subject had elevated transaminase levels (ALT >8x ULN and AST >2x ULN), which the investigator attributed to IV antibiotic treatment. The infective PEx of CF resolved on Day 24.


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Relevant concomitant medications at onset of the SAEs of rash and infective PEx of CF included salbutamol, Dornase alfa, colistin, sodium chloride, acetylcysteine, tiotropium, olodaterol, and azithromycin.

Creatine Kinase Elevation As seen in the controlled Trials 102 and 103, post-baseline laboratory analyses identified elevations in blood creatine phosphokinase in Study 105. There were no cases of rhabdomyolysis reported. More subjects with prior use of ELX/TEZ/IVA (20, 8%) in a parent study reported CK > 1000 U/L than those that received placebo (7, 4%) or TEZ/IVA (1, 2%) in Trial 102 or 103. However, the AE incidence of CK-related or muscle-related AEs was generally similar across the three groupings. A single subject in Study 105 developed an SAE of CK elevation: • Subject 102- was a 33 year old female with CF and a history of muscle pain, CF-

related liver disease, CF-related diabetes, diabetic retinopathy, diabetic nephropathy, microalbuminuria, nephrolithiasis, acute on chronic kidney failure, and chronic anemia. The subject participated in the ELX/TEZ/IVA arm in the parent study. CK was within normal range at baseline. The subject developed several occurrences of CK > ULN in Trial 102, but levels remained < 2x ULN. Beginning on Study 105 Day 14, the subject developed CK elevation that peaked at 12,408 U/L (>10x ULN) with AST and ALT elevations >3x ULN. The subject was hospitalized for IV fluids. There were no kidney abnormalities or myoglobinuria reported. The SAE resolved without study drug interruption. Of note, the subject reported a history of excessive exercise, endorsed not drinking enough water, and use of sauna in the week leading up to the SAE.

Menstrual Abnormalities Four female subjects (2%) reported at least 1 menstrual event. All events were nonserious and mild or moderate in severity (1 with missing severity). No menstrual events led to treatment discontinuation or interruption.

Reviewer comment: Overall, the safety data from the IA were generally consistent with the pivotal studies and support chronic use, with the exception that several discontinuations occurred for elevated transaminases after varying TC exposure durations. Because only limited interim data from Study 105 was available for this review, this reviewer recommends a PMC for the completion of Study 105.

8.2.8.2 Study VX16-445-001

Study Design

Study 001 was a Phase 1 / 2 study, 6 part study in health volunteers and subjects with CF. Parts A, B, and C evaluated safety and tolerability in healthy volunteers. Part D, E, and F was a randomized, double-blind, parallel-group, multi-part study in 123 CF subjects.


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Part D was a 2-cohort, placebo-controlled dose-ranging evaluation of ELX at multiple dose levels in TC with TEZ/IVA for 4 weeks in CF subjects with F/MF genotypes. The cohort evaluated ELX 50 mg, 100 mg, and 200 mg in combination with TEZ/IVA (hereafter, referred to as TCD-50, TCD-100, and TCD-200). Part E was a TEZ/IVA-controlled evaluation of ELX in TC with TEZ/IVA for 4 weeks in CF subjects with F/F genotypes, including a 4-week TEZ/IVA Run-in Period and a 4-week ELX washout period. The cohort evaluated ELX 200 mg in combination with TEZ/IVA (hereafter referred to as TCE-200). In Cohorts D and E, safety assessments included AEs, clinical laboratory assessments, clinical evaluation of VS, pulse oximetry, ECGs, PEs, and spirometry. This review examined the safety data from all cohorts, however, because Part F evaluated deuterated IVA in place of IVA, the safety data are not included below. The OCP Appendix (Section 15.3.1) discusses the study design in more detail. Safety Summary

In Study 001 Part D and E, 74 subjects received ELX in triple combination with TEZ/IVA. This reviewer queried the AE database for dose-related safety events. Apart from a small trend identified with bilirubin changes (see below), there were no other AEs occurring in more than 1 subject in a given arm that demonstrated a potential dose-related response. There were too few events in Cohort D to evaluate for a dose response with respect to SAEs. Submission Specific Safety Concerns

Hepatobiliary Events Similar to the pivotal trials, more subjects receiving any ELX/TEZ/IVA dosage developed elevations in AST and/or ALT than subjects in the comparator arm. A single TCE-200 subject developed ALT or AST elevations >5x ULN and required study drug interruption in the TEZ/IVA washout period. Three subjects developed asymptomatic elevations in total bilirubin > 2x ULN (TCD-100, TCD-200, and TEZ/IVA). Mild AEs related to bilirubin occurred in 4 subjects (TCD-100 [1], 2 TCD-200 [2], and 1 TEZ/IVA [1]). Blood bilirubin increased AEs led to study drug interruption for two subjects (TCD-200 and TCE-200) and study drug discontinuation for two subjects (TCD-100 and TEZ/IVA). No subject had an AST or ALT >3 × ULN and a total bilirubin >2 × ULN. This reviewer also queried the hepatobiliary AEs and LFT laboratory data from Part D for potential dose response across the study arms; there was a small trend towards increased subjects reporting bilirubin events with increasing triple combination dose: placebo (0), TCD-50 (0), TCD-100 (1), and TCD-200 (2). No other trends were noted. Skin-Related Events One CF subject and one healthy volunteer discontinued from Study 001 for rash AEs:




• Subject 001- was a 50-year-old White female with F/MF CF and a history of drug

hypersensitivity to penicillin randomized to the TCD-100. On Study Day 11 the subject had a nonserious AE of moderate rash papular with associated pruritus on the thighs, chest, arms, and buttocks; the subject received treatment with diphenhydramine hydrochloride and Sarna® for the event. Concomitant medications at the time of onset included estradiol and progesterone for hormonal replacement. There were no features suggestive of a severe skin reaction (e.g., fever or mucous membrane involvement). Study drug was discontinued on Day 14. The AE of rash resolved at the time of the follow-up visit on Day 36.

• Subject 001- was a 50-year-old white male with no relevant medical history randomized to receive the TC with ELX 200 mg in Study 001. The subject developed mild dermatitis, moderate pruritus, and mild fatigue on Day 11. The rash was diffuse and present on the subject’s thighs, arms, and left ankle. The subject was treated with diphenhydramine for 5 days. The study drug was discontinued on Day 11. The subject discontinued study drug on Day 11 due to the event of dermatitis. The event of dermatitis was last listed as ongoing and not resolved.

Reviewer comment: In contrast to Trial 102 and 103, Study 001 did not include prespecified discontinuation criteria for rash.

Creatine Kinase Elevations With respect to laboratory changes, four subjects developed elevated CK >5x ULN (1 TEZ/IVA and 3 TCE-200), of which two TCE-200 subjects developed CK > 10x ULN. AEs of blood CK increased occurred in 6 subjects from Parts D and E (1 placebo, 1 TCD-200, and 4 TCE-200). A single subject interrupted study drug for severe myopathy associated with moderate CK elevation in CK, AST, and ALT (TCE-200 mg). A narrative for this subject appears below:

• Subject 001- was a 23-year-old male subject with CF (F/F) and a history of

bronchiectasis, GERD, headache, pancreatic failure and sinusitis was randomized to TCE-200 mg. Baseline CK was normal. On Study Day 18 ( ) the subject had a severe AE of myopathy (muscle soreness) after lifting weights on . On the developed increased CK, ALT, and AST. The CK peaked at 11,000 (>10x ULN,), AST >8x ULN, and ALT >2x ULN on (Day 31). The subject had a normal urinalysis. From through study drug was interrupted due to protocol-defined study interruption criteria for AST levels. The subject did not receive treatment for the AE of myopathy. The subject completed study dosing on (Day 57). CK increased to 1940 U/L (>8x ULN) at the time of safety follow-up visit on .

Reviewer comment: Overall, the safety data from Study 001 were consistent with the safety profile identified in the phase 3 program.


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8.2.8.3 Study VX17-445-002

Study 002 was a phase 1, open-label, 2-period, fixed-sequence study to evaluate the effect of ELX triple combination on PK of oral contraceptives in healthy female subjects (see OCP Appendix, Section 15.3.1, for more details of the study design). The study enrolled 16 healthy female volunteers. This reviewer analyzed Study 002 for rash AEs to investigate for potential interaction with oral contraceptives. Subjects received levonorgestrel 150-μg / ethinyl estradiol 30-μg tablets (LN/EE) for 3 weeks followed by coadministration of LN/EE and ELX/TEZ/IVA for 10 days. Four subjects developed mild to moderate skin-related AEs, including three subjects with morbilliform rash (19%) and 1 subject with urticaria (6%). The AEs occurred on or after the last day of dosing.

8.2.8.4 Study VX18-445-009

Study 009 was a phase 1, randomized, double-blind, placebo- and active-controlled, multiple-dose, single-center ECG study with a parallel design with nested crossover groups for moxifloxacin and placebo (see OCP Appendix, Section 15.3.1, for more details of the study design). A single subject discontinued from the study for rash: • Subject 009- was a healthy 26-year-old white male with a history of contact

dermatitis randomized to Group 1 of Study 009. The subject received the first dose of placebo matched to moxifloxacin on Day 1, first ELX 200 mg starting on Day 2, and ELX 400-mg starting on Day 9. On Day 12, the subject had an AE of mild rash generalized on the trunk, arms, legs, feet, hands, and palms, with pruritus on both palms. The subject received oral diphenhydramine for 1 day at event onset. The subject discontinued study drug dosing on Day 12 due to the AE of rash generalized. At the Safety Follow-up Visit on Study Day 22), investigators considered the AE resolved. The subject’s eosinophil count was within the normal range throughout the study. The Applicant reports that there were no signs or symptoms suggesting a severe cutaneous adverse reaction.

8.2.8.5 Safety Update

Per the Agency’s request, the Applicant submitted the 120-day safety update on September 3, 2019. The submission included all new SAEs, AEs leading to treatment discontinuation, and pregnancies reported from May 21, 2019 through August 9, 2019 for ongoing studies in the ELX/TEZ/IVA program. The Applicant also included any significant new information for any SAEs, AEs leading to treatment discontinuation, and pregnancies submitted with the initial NDA. Table 67 summarizes the studies covered in the safety update.

Table 67. Studies Included in Safety Update

Study Population No. Enrolled Planned Duration Status

VX18-445-011 Phase 1, OL, R, CS, BA study of fixed-dose

HV 16 enrolled 18 days Completed dosing; data under review


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Study Population No. Enrolled Planned Duration Status

combination tablet of ELX/TEZ/IVA VX17-445-105 Phase 3, OL long-term safety study

CF, homozygous or heterozygous for F508del mutation 12 years of age and older

505 dosed 96 weeks Dosing ongoing

VX18-445-106 Phase 3, PK, S, and T study

CF, 6 to 11 years of age Part A (PK): 16 dosed Part B (safety): 56 planned 0 enrolled

15 days 24 weeks

Ongoing Part A: completed, data under review Part B: not started

VX18-445-113 Phase 3, OL long term safety of ELX combination therapy

CF, homozygous or heterozygous for F508del mutation 12 years of age and older Subjects enrolled from parent Study 659-105

>400 planned 1 enrolled

96 weeks Dosing ongoing

CF: cystic fibrosis, OL: open-label, PK: pharmacokinetic, S: safety, T: tolerability, ELX: elexacaftor, CS: cross over, BA: bioavailability, HV: healthy volunteer, R: randomized Data through August 9, 2019. Source: adapted from NDA 21773, Table 1, VX-445/Tezacaftor/Ivacaftor safety update While the Safety Update included the four clinical studies, all events identified during the reporting period occurred in the ongoing Study 105. Therefore, relevant data from the Safety Update are incorporated into Section 8.2.8.2 above (discussion of SAEs).

8.2.9 Additional Safety Explorations

Human Carcinogenicity or Tumor Development No human carcinogenicity studies have been performed for ELX/TEZ/IVA.

Human Reproduction and Pregnancy The use of ELX/TEZ/IVA during pregnancy or lactation has not been evaluated in well-controlled trials. A total of 7 subjects in the ELX/TEZ/IVA development program became pregnant during treatment. In Trial 102, three subjects became pregnant in the ELX/TEX/IVA arm including one chemical pregnancy, one elective termination, and ongoing pregnancy. There were no pregnancies in Trial 103. In the ongoing Study 105, five subjects reported pregnancies, of which two subjects had an elective termination. No additional findings were reported.

Pediatrics and Assessment of Effects on Growth CF is a rare, orphan disease and thus is not subject to pediatric study requirements as defined under the Pediatric Research Equity Act (PREA). However, both phase 3 trials included CF patients 12-17 years of age (inclusive). Efficacy and safety data in this adolescent age group was described in Section 8.1 and Section 8.2.7, respectively.

Overdose, Drug Abuse Potential, Withdrawal, and Rebound The Applicant did not complete studies on potential withdrawal, rebound effects, or systemic




examination of abuse potential of ELX/TEZ/IVA, nor were such studies required. However, the Applicant explored data during the washout and safety follow-up periods from applicable studies, and did not identify findings suggestive of potential withdrawal or rebound effect. Given the mechanism of action and intended use (chronic, life-long), ELX/TEZ/IVA is anticipated to have minimal to no abuse potential. This reviewer explored AEs by study period (treatment period, TEZ/IVA washout, and safety follow-up) for the ELX/TEZ/IVA arm in Parts D and E of Study 001. There was a small numerical trend towards increased infective PEx of CF events after the treatment period for ELX/TEZ/IVA subjects, but the incidence was generally comparable to that of the control subjects. Overall, the number of enrolled subjects was too small to make definitive conclusions.

8.2.10 Safety in the Postmarket Setting

Safety Concerns Identified Through Postmarket Experience There is no postmarketing experience with ELX/TEZ/IVA; however, both the IVA monocomponent and the TEZ/IVA fixed combination are approved. On August 27, 2018, a tracked safety issue (TSI 1943) was opened for potential ivacaftor withdrawal syndrome. After review of the available data, no regulatory action was recommended, and the TSI was closed on December 10, 2018.

There are no active TSIs for TEZ/IVA or IVA. Postmarketing experience with the mono- and dual- components, IVA (approved January 31, 2012, 16,127 person-years) and TEZ/IVA (approved February 12, 2018, 3,633 person-years), have not identified any additional safety concerns since their respective approval dates that alter the risk-benefit profile of the triple combination ELX/TEZ/IVA.

Expectations on Safety in the Postmarket Setting Since phase 3 trials excluded patients with certain co-morbidities and more severe disease, it is possible that sicker CF patients may experience side effects not observed in clinical trials. However, given the postmarketing experience with the IVA and TEZ/IVA components, and the demonstrated safety profile with ELX/TEZ/IVA, no substantial differences in the postmarketing setting are anticipated. The Agency recommends routine pharmacovigilance.


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8.2.11 Integrated Assessment of Safety

The safety data submitted with the NDA were sufficient to assess the safety of ELX/TEZ/IVA in the proposed CF patient population. The safety information for ELX/TEZ/IVA was primarily derived from two adequate and well-controlled phase 3 trials (102 and 103). In total, these trials included 510 adolescent and adult CF subjects, 257 of whom received at least one dose of the proposed ELX/TEZ/IVA dose. Given the varying treatment durations (24 and 4 weeks) and study designs (active vs placebo controlled), most safety data presented in this review are from Trial 102, the 24-week parallel group study, with safety findings or differences from the other phase 3 trial noted where applicable. Additional support for long-term safety comes from the ongoing 96-week OLE (Study 105), which provides support for long-term chronic use. While this reviewer evaluated all data from the clinical program, this review discussed relevant supportive data from the IA of Study 105, and completed phase 1/2 studies only where applicable. No deaths occurred in the clinical development program. Overall, SAEs occurred more frequently in the control subjects compared to ELX/TEZ/IVA subjects. In the pivotal trials, AEs requiring premature treatment discontinuation during the controlled treatment period were limited to two ELX/TEZ/IVA subjects for rash and portal hypertension, respectively. However, additional treatment discontinuations for rash and increased LFTs occurred in the OLE. In the controlled trials, treatment interruptions occurred in almost two fold more ELX/TEZ/IVA subjects than control subjects, but were generally distributed across PTs. The most common reason for treatment interruption in the ELX/TEZ/IVA arm was rash, followed by transaminase increased, infective PEx of CF, influenza, rhabdomyolysis, and intestinal obstructions. AESIs identified a priori were based upon existing knowledge of CFTR modulator safety profiles and safety data from early phase trials with ELX. To investigate submission specific safety issues, this review performed safety analyses for AESIs identified a priori, potential safety signals identified during the review, and those identified with related CFTR modulators. Liver-related toxicity, observed with IVA, TEZ/IVA, and LUM/IVA, was evaluated as an AESI. Hepatobiliary AEs as well as transaminase and total bilirubin elevations occurred more frequently in ELX/TEZ/IVA subjects than placebo subjects. In the overall phase 3 program, four subjects discontinued for hepatobiliary-related events including 1 subject in Trial 102 (portal hypertension) and 3 subjects in Study 105 (increased LFTs). Five subjects required treatment interruption for hepatobiliary-related AEs in Trial 102 (elevated LFTs and/or hepatobiliary disorders), and approximately 10 subjects in Study 105. Within the phase 3 program, the two subjects with concurrent elevations in total bilirubin > 2x ULN and AST or ALT >3x ULN had alternative explanations for the laboratory changes (Gilbert Syndrome and acute cholecystitis). The presence of hepatobiliary events across the clinical development program supports the finding of a drug-related side effect of ELX/TEZ/IVA and will be conveyed in product labeling. Furthermore, in the absence of a dedicated hepatic impairment study, the review team recommends against use in patients with moderate and severe hepatic impairment.




CK elevation emerged as a potential safety signal in the AE and laboratory data of the controlled trials and OLE. Evaluation of the laboratory data alongside CK and muscle-related AEs from the controlled phase 3 trials demonstrated an increased risk for CK elevation in ELX/TEZ/IVA subjects compared to placebo and TEZ/IVA subjects. In the phase 3 program, there were no discontinuations due to CK-related events among ELX/TEZ/IVA subjects, but multiple subjects required drug interruption. In Trial 102, two ELX/TEZ/IVA subjects with AE classified as rhabdomyolysis had asymptomatic elevations in CK without clear renal function changes or myoglobin elevation, and did not appear to meet clinical criteria for rhabdomyolysis. A role of exercise in magnifying these ELX/TEZ/IVA associated CK changes cannot be ruled out. Overall, the presence of CK laboratory elevations and CK-related AEs throughout the clinical development program raise concern for causal role of study drug and will be conveyed in product labeling. Rash-related AEs occurred more often in ELX/TEZ/IVA subjects than either comparator. The events appear potentially drug-related and more common in the female subjects and those on hormonal therapy. Events were identified throughout the program including in healthy volunteers. The risk of rash will be conveyed in product labeling. This review evaluated other adverse reactions associated with IVA, TEZ/IVA, and/or LUM/IVA. Cataracts are a potential risk associated with IVA monotherapy and TEZ/IVA. In Trial 102, a similar number of placebo and ELX/TEZ/IVA patients were found to have treatment emergent cataracts on ophthalmologic exam; no cataracts were reported in Study 105. However, given the established risk with the IVA component, cataracts remain a potential safety risk and will be conveyed in product labeling. Similar to LUM/IVA, more ELX/TEZ/IVA patients developed post-baseline elevations in SBP. This risk of hypertension will be conveyed in product labeling. Overall, the ELX/TEZ/IVA safety profile for the treatment of a rare, serious disease such as cystic fibrosis is favorable, and the observed drug-related safety concerns can be addressed by product labeling.

8.3 Statistical Issues

This section discusses two statistical issues: the combination rule and substantial evidence of effectiveness. Combination Rule For Trial 102, the study population were patients with F/MF mutation. In this trial, treatment comparison was made between the ELX/TEZ/IVA group versus placebo group; there were no comparisons between the ELX/TEZ/IVA versus TEZ/IVA or ELX/TEZ/IVA versus ELX/IVA. Thus, the contribution of ELX or TEZ to the ELX/TEZ/IVA combination was not directly assessed in this phase 3 trial. For Trial 103, the study population were patients with F/F mutation. Since TEZ/IVA was




approved for this patient population, it is appropriate that the study compared ELX/TEZ/IVA versus TEZ/IVA. However, due to lack of an ELX/IVA arm in this trial, contribution of TEZ to the ELX/TEZ/IVA combination was not assessed in this phase 3 trial. It is understandable that TEZ/IVA arm was not included in Trial 102, because TEZ/IVA is not approved for F/MF patients. At the early stage of the program, the Agency had advised the Applicant several times to include the ELX/IVA arm in their phase 3 trials, but the review team has concluded that the contribution of mono components to the ELX/TEZ/IVA can be assessed using in vitro data. Refer to the clinical pharmacology review and Section 8.4 for further discussion about the combination rule issue. This statistical reviewer thinks that a phase 3 trial is a more persuasive approach to demonstrate the satisfaction of combination rule for the study drug ELX/TEZ/IVA. Substantial Evidence of Effectiveness

Considering CF as a rare disease with unmet needs, this statistical reviewer thinks a single confirmatory study on patients with F/MF mutations with large treatment effect on the primary endpoint and all key secondary endpoints meets the statutory requirement, especially since a second Trial 103 demonstrated clinically and statistically significant treatment effects in subjects with F/F mutation. In this population, the study drug has demonstrated effectiveness in the following areas: lung function benefit, exacerbation benefit, SwCl benefit, CFQ-R RD score benefit, and BMI benefit. Overall, substantial evidence of effectiveness has been demonstrated.

8.4 Conclusions and Recommendations

The Applicant has demonstrated substantial evidence of safety and effectiveness for ELX/TEZ/IVA for the treatment of CF in patients ≥ 12 years of age with at least one F508del mutation in the CFTR gene. Therefore, the recommended regulatory action is Approval. The totality of the clinical efficacy data supports an indication for CF patients with at least one F508del mutation. Trials 102 and 103 demonstrated a robust lung function benefit (ppFEV1) as well as improvement in all clinically meaningful key secondary endpoints (i.e. number of PEx, BMI, SwCl, and CFQ-R RD for Trial 102; SwCl and CFQ-R RD for Trial 103). Efficacy findings were generally consistent in both study populations, inclusive of CF subjects with 1 or 2 F508del mutant alleles. The safety profile demonstrated in both Trial 102 and 103 identified several safety signals that will be conveyed in product labeling: elevated LFTs, elevated CK, rash, and hypertension. As a new combination product consisting of three active drug components, the regulatory evidentiary standard to support Approval must also consider the Combination Rule:




“Two or more drugs may be combined in a single dosage form when each component makes a contribution to the claimed effects and the dosage of each component (amount, frequency, duration) is such that the combination is safe and effective for a significant patient population requiring such concurrent therapy as defined in the labeling for the drug” (21CFR 300.50).

The Agency has often relied on factorial designed clinical trials to evaluate the contribution of each component in the combination. A full factorial design for a triple combination product ABC would require studies with the following comparisons: ABC vs. AB, vs. AC, vs CB. However, the Combination Rule does not specifically state that factorial studies must be conducted. Further, the Federal Register (FR) notice for the proposed revisions to the Combination Rule10 includes the following:

“The amount and type of data and information needed to demonstrate such a contribution may vary depending on a range of factors, including the types and number of active ingredients, the nature of the therapeutic intent of the product … and whether the individual active ingredients are already approved as single agents for the same indication(s) as are sought for the fixed-combination or co-packaged drug.” “In certain cases, a new factorial study may not be needed… it may be possible to use data from a previously approved fixed-combination drug to partially support an application for a new fixed-combination drug if the previously approved product is similar to the new product.”

In practice, the Agency has exercised flexibility in the interpretation of the combination rule with other combination products, and has not always relied on factorial trials to satisfy the Combination Rule, especially when the beneficial treatment effect of a particular drug class is well understood and established. Recent examples include the following combination products: Combivent Respimat (the fixed dose combination of albuterol and ipratropium) and Trelegy (fixed dose triple combination of fluticasone furoate/umeclidium/vilanterol). With the present product, during the End of Phase 2 meeting on February 20, 2018, the Agency indicated that in vitro data would not be sufficient to demonstrate the contribution of the individual components to the triple combination. At the time, the Agency conveyed an expectation that the Applicant show clinical data comparing the triple combination to the dual components (i.e. evaluation of an ELX/IVA arm). As noted in Section 8.3, the Applicant did not incorporate a ELX/IVA arm into either Trial 102 or 103. During the Pre-NDA meeting on June 26, 2019, following review of preliminary efficacy data from the completed program, the Agency re-evaluated the initial recommendation to include a full factorial design in the clinical program (i.e. ELX/IVA clinical data). The Agency asked the Applicant to provide justification to support the contribution of each component of the triple combination to the claimed effects, indicating the potential for flexibility in the interpretation of the type of data to fulfill combination rule.

10Proposed rule 12/23/2015, FDA-2015-N-1260




The Agency completed a multidisciplinary review of the clinical and in vitro data to evaluate the contribution of ELX, TEZ, and IVA to the triple combination. Both Trials 102 and 103 provide clinical evidence of the contribution of ELX to ELX/TEZ/IVA. In the F/F population, comparison of ELX/TEZ/IVA to TEZ/IVA provided a clinically and statistically significant improvement in ppFEV1, CFQ-R RD and SwCl. In the F/MF population, the Agency previously determined lack of efficacy for TEZ/IVA in the F/MF population. The addition of ELX to TEZ/IVA provided substantial effect on lung function compared to placebo. The Applicant provided in vitro data showing the drug effect on maturation and transport of mature CFTR to the cell surface of HBE cells by WB and chloride transport in HBE cells by Ussing chamber electrophysiology; both methods represent in vitro models that are biologically relevant to the clinical disease (i.e. CF). These data showed greater activity for the three drug combination versus the monocomponents and dual combinations (see Section 15.3.3). Based on the available clinical trial data with IVA, TEZ/IVA and ELX/TEZ/IVA, in vitro data and the robust treatment effect in Trials 102 and 103 observed with the triple combination in a serious and life-threatening disease, the Division concludes that there is adequate data from the development program to satisfy the Combination Rule (21CFR 300.50).

9 Advisory Committee Meeting and Other External Consultations

A pulmonary allergy drug Advisory Committee meeting was considered for this supplement. However, given the persuasiveness of the clinical trial results, the Division decided that the evidence supporting approval for the indicated populations were sufficiently robust that discussion by an Advisory Committee was not necessary.

10 Pediatrics

CF is a rare, orphan disease and thus is not subject to pediatric study requirements as defined under PREA. However, both phase 3 trials included CF patients 12-17 years of age (inclusive). Efficacy and safety data in this adolescent age group were consistent with the overall results.

11 Labeling Recommendations

The Applicant submitted proposed Prescribing Information, Patient Information, and carton and container labeling for the ELX/TEZ/IVA combination that included the tradename TRIKAFTA.




Labeling negotiations remain ongoing at the time of this review. The Division of Medication Error Prevention and Analysis reviewed the proposed PI, container labels, and carton labeling for areas of vulnerability that will be conveyed to the Applicant.

12 Risk Evaluation and Mitigation Strategies (REMS)

A REMS was not deemed necessary for this application.

13 Postmarketing Requirements and Commitment

PREA requirements do not apply to this orphan drug product; however, Vertex is voluntarily conducting clinical studies in CF patients less than 12 years of age. The Clinical Review team recommends the following PMCs:

1) A 4 week safety and efficacy study in CF patients 12 years and older with F508del mutation and a second gating or residual function mutation.

2) A 96 week open-label long term safety study in CF patients with one F508del mutation to characterize the long-term safety of ELX/TEZ/IVA.

The Nonclinical Review team recommends the following PMR:

1) Two-year oral carcinogenicity study of ELX in rats. The Clinical Pharmacology Review team recommends the following PMR:

1) A clinical trial to evaluate the PK, safety, and tolerability of elexacaftor in patients with hepatic impairment compared to healthy subjects.

The CMC Review team recommends the following PMCs for Quality CMC studies:

1) Implementation of three tier particle size specification (D10, D50, and D90) for VX-445 particle size distribution. Submission of the D10, D50 and D90 particle size distribution for at least five commercial batches along with complete dissolution profiles. These data along with similarity testing should be used to verify the design space for D50, revise D90 ranges and implement the ranges for D10.

2) Implementation of three tier particle size specification (i.e., D10, D50, and D90) for size. Submission of the D10, D50 and D90 size distribution for at least five

commercial batches along with complete dissolution profiles. These data along with


(b) (4)



similarity testing should be used to verify the design space and set the appropriate ranges for D10, D50 and D90.

14 Division Director (DPARP) Comments

This is a 505(b)(1) NDA for a triple combination therapy product containing elexacaftor (ELX), tezacaftor (TEZ), and ivacaftor (IVA) for the treatment of CF in patients 12 years of age and older who have at least one F508del mutation in the CFTR gene. The proposed dose and dosing regimen is ELX 200 mg/TEZ 100mg/IVA 150 mg qAM and IVA 150 mg qPM. ELX/TEZ/IVA has fast track, orphan drug, and breakthrough therapy designations. ELX is a new molecular entity. There are several CFTR modulator products currently available for patients with CF. The active pharmaceutical ingredients include IVA, TEZ, and lumacaftor (LUM). IVA is a CFTR potentiator that facilitates chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface. TEZ facilitates the cellular processing and trafficking of normal and select mutant forms of CFTR (including F508del-CFTR) to increase the amount of mature CFTR protein delivered to the cell surface. In the triple combination product, ELX is proposed to also increase the delivery and amount of functional CFTR protein at the cell surface, to further enhance chloride ion transport.

IVA monotherapy is currently available for CF patients who have one mutation in the CFTR gene that is responsive to IVA based on clinical and/or in vitro assay data. TEZ/IVA combination therapy is currently approved for patients who are homozygous for the F508del mutation or who have at least one mutation in the CFTR gene that is responsive to TEZ/IVA based on in vitro data and/or clinical evidence of “residual function”. Neither IVA nor TEZ/IVA demonstrated efficacy in CF patients heterozygous for F508del and a MF mutation. Patients with these mutations represent a population with high unmet need for therapies. Nonclinical Pharmacology/Toxicology Vertex conducted a comprehensive program of pharmacology, pharmacokinetics, and toxicology studies to support clinical development and this NDA. Pharmacology studies support the mechanism of action of ELX – facilitates processing and trafficking of CFTR leading to increased chloride transport. Nonclinical studies were conducted to evaluate ELX and the major metabolite (M23). Adequate safety margins for ELX were obtained in all species and studies based on exposures at the recommended human dose. No novel or synergistic toxicities were observed in triple combination studies with IVA and TEZ. The nonclinical team recommends approval with a 2-year carcinogenicity study in rats as a post-marketing requirement. Product Quality The drug product is an immediate release tablet which contains ELX, TEZ, and IVA. Vertex provided data to support the identity, purity, strength, and quality of the new ELX API. The




stability data supports the proposed 24 month expiry for the tablets when packaged in foil-foil blisters and stored at controlled room temperature. Biopharmaceutics issues resulted in two PMCs to monitor the control of both ELX particle size distribution and size distribution. There was internal disagreement regarding the Vertex Ultimately, the Office of New Drug Products Division Director concluded that Vertex’s mitigation strategies for addressing factors potentially impacting drug dissolution and their understanding of and experience with approved continuous manufacturing processes and their controls, were acceptable. The Office of Process and Facilities performed a pre-approval inspection of , a manufacturer of a starting material/intermediate of the ELX synthesis, as this site had not been inspected by the Agency previously. The Vertex, Boston drug product manufacturing site had been inspected recently for the approval of Symdeko (NDA 210491), an IR tablet that is similar to the current triple IR tablet except that it does not contain ELX. Because of this, the shortened review period, and the favorable benefit/risk ratio, a post-approval inspection of Vertex, Boston is planned. All CMC sub-disciplines (API, drug product, process & facilities, and biopharmaceutics) recommended approval. Clinical Pharmacology Dose selection for the combination product was based upon the doses of TEZ and IVA that are approved for CF patients 12 years and older and results of a phase 2 study in CF patients to support the ELX dose. Vertex conducted a phase 2 study (Study 001) that evaluated 4 weeks of treatment with multiple doses of ELX (50 mg, 100 mg, 200 mg) in combination with TEZ/IVA in patients with CF. Results from this study showed that all doses of ELX had a significant treatment effect on FEV1, SwCl, and CFQ-R-RD compared to placebo. While there was not a clear dose response, the 200 mg dose of ELX generally had a numerically greater improvement compared to lower doses. Vertex carried forward this single dose level of ELX (200 mg) in the combination product into the phase 3 program.

Hepatic metabolism and/or excretion are major routes of elimination for ELX, TEZ and IVA. ELX has not yet been studied in patients with hepatic impairment. An increase in exposure of ELX is expected in patients with moderate or severe hepatic impairment; therefore, treatment of patients with moderate or severe hepatic impairment with ELX/TEZ/IVA is not recommended. A post-marketing study in patients with hepatic impairment will be required to evaluate the PK and safety in this patient population and update the product labeling. The clinical pharmacology team recommends approval of this application. Clinical/Statistical – Efficacy To support the efficacy and safety of ELX/TEZ/IVA, Vertex submitted results from two phase 3 efficacy and safety trials, Trial 102 and Trial 103. Trial 102 was a 24-week, randomized, double-blind, placebo-controlled study. Enrolled patients were heterozygous for the F508del mutation and a second MF mutation. Eligible patients were randomized 1:1 to either ELX 200 mg QD/TEZ 100mg QD/IVA 150 mg Q12 or placebo. Given that there are currently no approved therapies for this patient population, the use of a placebo control is acceptable. The primary endpoint


(b) (4)

(b) (4)

(b) (4)



was the absolute change in ppFEV1 from baseline at Week 4. Key secondary efficacy variables included number of exacerbations, SwCl, BMI, and CFQ-R RD score. A total of 405 patients were randomized (29% adolescents 12 to <18 years of age), and 400 patients completed the study. Results from Trial 102 showed that patients treated with ELX/TEZ/IVA had a significant improvement in ppFEV1 at Week 4 compared to patients treated with placebo. The LS mean treatment difference for the ELX/TEZ/IVA group versus placebo for the change from baseline in ppFEV1 at Week 4 was 13.8% (95% CI: 12.1, 15.4; p<0.0001). The review team conducted an exploratory analysis of absolute change from baseline in FEV1 (liters). The LS mean difference in FEV1 between ELX/TEZ/IVA and placebo at Week 24 was 0.51 liters (95% CI: 0.39, 0.63). Key secondary endpoints were supportive of the efficacy of ELX/TEZ/IVA. As described in detail in Section 8.1, treatment with ELX/TEZ/IVA compared to placebo showed the following: • reduction in pulmonary exacerbations through week 24 with a rate ratio of 0.37 (95% CI:

0.25, 0.55) • reduction in SwCl through Week 24 of -42 mmol/L (95%CI: -44, -39) • improvements in CFQ-R RD score through Week 24 of 20 points (95%CI: 18, 23) • improvement in BMI at Week 24 was 1.04 kg/m2 (95%CI: 0.85, 1.23) Trial 103 was a randomized, double-blind, active-controlled, parallel-group, multicenter study in patients with CF who are homozygous for the F508del mutation (F/F genotype). After screening and a 4-week open label TEZ/IVA run-in, eligible patients were randomized to ELX/TEZ/IVA or TEZ/IVA for a 4-week treatment period. Given that TEZ/IVA is currently approved for CF patients with the F/F genotype, using a TEZ/IVA comparator is appropriate for this population. The primary endpoint was the absolute change in ppFEV1 from baseline at Week 4. Key secondary efficacy variables included SwCl and CFQ-R RD score. A total of 108 patients were randomized (28% adolescents 12 to <18 years of age) and 107 patients completed the study. Results from Trial 103 showed that patients treated with ELX/TEZ/IVA had a significant improvement in ppFEV1 at Week 4 compared to patients treated with TEZ/IVA. The LS mean treatment difference for the ELX/TEZ/IVA group versus TEZ/IVA for the change from baseline in ppFEV1 at Week 4 was 10.0% (95% CI: 7.4, 12.6; p<0.0001). Key secondary endpoints were supportive of the efficacy of ELX/TEZ/IVA. As described in detail in Section 8.1, treatment with ELX/TEZ/IVA compared to TEZ/IVA showed the following: • reduction in SwCl at Week 4 of -45 mmol/L (95%CI: -50, -40) • improvements in CFQ-R RD score at Week 4 of 17 points (95%CI: 12, 23) • improvement in BMI at Week 4 was 0.60 kg/m2 (95%CI: 0.41, 0.79)

Overall, results from Trials 102 and 103 showed a statistically significant improvement in the primary endpoint (ppFEV1) and other key secondary endpoints (exacerbations [Trial 102], BMI, CFQ-R-RD, SwCl) in two CF study populations. The results for the primary and key secondary endpoints were not only statistically significant, but clinically meaningful. The submitted data




demonstrated substantial evidence of effectiveness of ELX/TEX/IVA in the CF populations studied. Clinical – Safety The submitted safety data were adequate to assess the safety of ELX/TEZ/IVA in the proposed CF patient population. While the safety database included 619 CF patients who received ELX combination therapy, the primary source of safety data was from Trials 102 and 103, which included 257 patients who received at least one dose of ELX/TEZ/IVA. Trial 102 provides safety data in patients with the longest duration of exposure, 24 weeks. Of note, there is an ongoing OLE study, Study 105, for patients who completed Trials 102 or 103. Review of the safety data identified safety signals that have been seen with other CFTR modulator therapies, including rash and hepatotoxicity, which will be described in the product labeling. Hepatotoxicity has been noted with IVA, TEZ/IVA, and LUM/IVA. Transaminase and total bilirubin elevations occurred more frequently in ELX/TEZ/IVA patients than placebo patients, but there were no Hy’s Law cases. A warning regarding elevation in liver function tests will be included in the product label. The current IVA and TEZ/IVA product labeling has a warning regarding elevated transaminases. As discussed above, given the absence of a dedicated hepatic impairment study, use in patients with moderate and severe hepatic impairment is not recommended. Cataracts have been a concern with VIA based upon juvenile rat studies. A warning regarding the potential risk of cataracts is included in all IVA product labeling. CK elevation was a new safety signal identified in this clinical program, although there were no clear cases of clinical rhabdomyolysis. Information regarding CK elevation will be described in the adverse reactions section of the labeling. The ELX/TEZ/IVA safety profile is generally consistent with other CFTR modulators and the risks can be addressed by product labeling. No safety concerns were identified that should preclude approval or require a REMS. Given the available long term safety data is limited to 24 weeks, a post-marketing commitment for the completion of the OLE study (Study 105) is recommended. The clinical and statistical teams recommend approval. Benefit Risk Assessment Overall, the benefit risk assessment for ELX/TEZ/IVA for the treatment of CF patients aged 12 years and older who have at least one F508del mutation is favorable. Efficacy findings were robust in both studies and clinically meaningful. The safety profile of ELX/TEZ/IVA is generally consistent with other CFTR modulators and the risks can be managed with product labeling. All of the review team members recommend approval and I agree. ELX/TEZ/IVA provides a new therapeutic option for CF patients, particularly for those patients who currently have no CFTR modulator treatment options. Indication The indication proposed by Vertex is broader than the patient populations studied in the clinical program, but the data supports this broader indication. Efficacy findings were generally consistent in both study populations, which included CF patients with one or two F508del




alleles. Trial 102 enrolled patients who were heterozygous for the F508del mutation and a second MF mutation. Exploratory analyses in Trial 102 in the subgroup of patients with Class I mutations (i.e., those predicted to make no CFTR and therefore representing a single F508del) were consistent with the overall population of Trial 102. The second allele is not expected to interfere with the efficacy of ELX/TEZ/IVA, so patients heterozygous for the F508del mutation and another mutation would be expected to benefit from ELX/TEZ/IVA. It is also notable that IVA and TEZ/IVA have demonstrated efficacy in patients with other mutations (e.g., gating, residual function), and we do not anticipate that ELX interacts with TEZ/IVA to reduce the efficacy of these components. The broader indication will allow access to CF patients with at least one F508del mutation who were not evaluated in Trials 102 and 103. However, to provide additional clinical efficacy data that may be used to update product labeling, a post-marketing commitment is recommended to evaluate the efficacy of ELX/TEZ/IVA in CF patients heterozygous for F508del and a second gating / residual function mutation. Combination Rule ELX/TEZ/IVA is a combination product and is subject to the combination rule regulations (21 CFR300.50), which states “two or more drugs may be combined in a single dosage form when each component makes a contribution to the claimed effects”. Establishing the contribution of each component is often demonstrated in clinical studies with a factorial design; however, there can be different approaches to satisfying the combination rule, depending upon the available data. Although Vertex did not conduct full factorial studies in this program, the available clinical and in vitro data support the contribution of the individual components. First, the clinical program provides data to support the contribution of ELX to ELX/TEZ/IVA. TEZ/IVA is already an approved combination product for CF patients with specific mutations. Trial 103 compared ELX/TEZ/IVA to TEZ/IVA and efficacy results demonstrated benefit in the F/F population, showing the contribution of ELX. In F/MF patients, the Agency previously determined lack of efficacy for TEZ/IVA in this population, which is why a placebo group was considered acceptable for Trial 102. Results from Trial 102 showed the efficacy of ELX/TEZ/IVA was significant compared to placebo, thus supporting the contribution of ELX. The pharmacology data provides support for the contribution of each component. Vertex provided extensive in vitro data showing the drug effect on maturation and transport of mature CFTR to the cell surface of HBE cells by WB and chloride transport in HBE cells by Ussing chamber electrophysiology. Both methods represent in vitro models that are biologically relevant to CF. Submitted data included an evaluation of each drug alone, all double combinations, and the triple combination. Review of these data showed greater activity for the three drug combination versus the monocomponents and dual combinations. Overall, the submitted data supports the contribution of each component, satisfying the combination rule (21CFR 300.50).




15 Appendices

15.1. Financial Disclosure

The tables below summarize the financial disclosure checklist for the clinical studies submitted to this NDA. There were several significant payments of other sorts (primarily speaker fees / consultations) and one investigator with equity interest. However, these were unlikely to have had a significant impact upon the conduct of the clinical trials, given that each investigator site enrolled a small number of patients and the pivotal efficacy studies were randomized, double-blinded, and controlled with objective spirometric, nutritional and exacerbation related endpoints. Covered Clinical Study (Name and/or Number): Study 001

Was a list of clinical investigators provided:

Yes No (Request list from Applicant)

Total number of investigators identified: 179

Number of investigators who are Sponsor employees (including both full-time and part-time employees): 0 Number of investigators with disclosable financial interests/arrangements (Form FDA 3455): 1

If there are investigators with disclosable financial interests/arrangements, identify the number of investigators with interests/arrangements in each category (as defined in 21 CFR 54.2(a), (b), (c) and (f)):

Compensation to the investigator for conducting the study where the value could be influenced by the outcome of the study:

Significant payments of other sorts:

Proprietary interest in the product tested held by investigator:

Significant equity interest held by investigator in Sponsor of covered study: 1

Is an attachment provided with details of the disclosable financial interests/arrangements:

Yes No (Request details from Applicant)

Is a description of the steps taken to minimize potential bias provided:

Yes No (Request information from Applicant)

Number of investigators with certification of due diligence (Form FDA 3454, box 3) 0

Is an attachment provided with the reason:

Yes No (Request explanation from Applicant)




Covered Clinical Study (Name and/or Number): Trial 102







Significant payments of other sorts: 3










Covered Clinical Study (Name and/or Number): Trial 103





If there are investigators with disclosable financial interests/arrangements, identify the




number of investigators with interests/arrangements in each category (as defined in 21 CFR 54.2(a), (b), (c) and (f)):


Significant payments of other sorts: 2










Covered Clinical Study (Name and/or Number): Study 105



Total number of investigators identified: 26 (unique to study 105)




Significant payments of other sorts:


Significant equity interest held by investigator in Sponsor of covered study:











15.2. Nonclinical Pharmacology/Toxicology

15.2.1. Excipients

The ELX/TEZ/IVA triple combination is formulated for oral administration as a fixed-dose combination immediate-release film-coated tablet. Each tablet contains 100 mg ELX, 50 mg TEZ, and 75 mg IVA. The dosing regimen consists of two triple combination tablets in the morning and one IVA (150 mg) tablet in the evening. The quantitative composition of the triple combination tablet is shown below. There are no nonclinical safety concerns with the levels of these excipients.

Table 68. Quantitative Composition of ELZ/TEZ/IVA Tablet

Source: Applicant’s submission


(b) (4)

(b) (4)

(b) (4)

(b) (4)



15.2.2. Organic Impurities

Consistent with ICH M7(R1), the Applicant evaluated the mutagenic potential of 64 known and potential impurities using DEREK Nexus 6.0.0 and SARAH Nexus 3.0.0, supplemented by additional proprietary data and expert assessment. A total of 43 structures were predicted to be non-mutagenic by both methods. Consensus positive predictions, along with published positive Ames data, were reported for

. In addition, were considered positive for mutagenic potential on a

weight of evidence basis. Based on information in the NDA submission and response to Information Request received, reviewing chemist Dr. Paresma Patel confirmed that all of these impurities would be adequately purged in the synthetic pathway (i.e., below TTC of µg/day). The group of impurities considered negative on a weight of evidence basis by the Applicant was discussed with reviewing chemist Dr. Paresma Patel. Of these, 6 structures (

) were selected for FDA (Q)SAR consultation. Internal experts agreed with the Applicant’s conclusion that all of these impurities are negative for genotoxic potential. Based on the 200 mg daily dose of ELX, ICH Q3A specifies a drug substance impurity qualification threshold of 0.15% (0.3 mg per day). Therefore, specifications for (NMT %) and unspecified impurities (NMT %) are acceptable. One additional specified impurity is at NMT % ( mg per day) in drug substance and NMT % ( mg per day) as a degradant in drug product. is negative for genotoxic potential based on in silico assessment. The Applicant states that is qualified based on a 28-day mouse toxicology study (VX-445-TX-011). This study was previously reviewed in support of dose selection for the 6-month transgenic mouse carcinogenicity study. The reviewer agrees with the Applicant that the NOAEL in the study was mg/kg/day. was present at % in the drug substance batch used in the study.

Table 69. Organic Impurity Levels From a 28-Day Mouse Toxicology Study (VX-445-TX-001) Species ELX dose Impurity level HED Margin

Human 200 mg QD mg/kg/day

NMT % mg/day

mg/kg/day

mg/kg/day -

Mouse mg/kg/day % mg/kg/day

mg/kg/day 2.0

HED: Human equivalent dose (12.3 adjustment factor for mouse) Human body weight 60 kg


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As shown in the table above, the 28-day mouse study provides an acceptable 2-fold safety margin on a body surface area basis compared to the drug substance specifications. Batch analysis and stability data available to date did not raise any concerns and has not been detectable above the Q3A or Q3B reporting thresholds. ICH Q3A calls for a qualification study of 14 to 90 days in duration. Although the Applicant is seeking approval for a chronic indication, the 28-day duration is considered adequate in the context of CF, a serious disease with high unmet medical need. Overall, there are no nonclinical safety concerns with the levels of organic impurities.

15.2.3. Heavy Metals

is a reagent in the synthesis of ELX and is controlled according to ICH Q3D. is a reagent in the synthesis of ELX and is not directly controlled but is indirectly controlled by the ‘residual on ignition’ inorganic impurity specification on NMT %. This limit corresponds to a maximum daily exposure of mg based on the 200 mg daily dose of ELX. ICH Q3D notes the generally low toxicological potential of According to the Agency for Toxic Substances and Disease Registry (U.S. Centers for Disease Control and Prevention), the typical adult dietary intake of is mg/kg/day ( mg/day). Therefore, there is no nonclinical safety concern with the potential levels of in the ELX drug substance.

15.2.4. Residual Solvents

Drug substance specifications are provided for 5 potential residual solvents. The limits for 4 of these ) are set in accordance with ICH Q3C. Reviewing chemist Dr. Paremsa Patel emailed the nonclinical team requesting a toxicological assessment of the Applicant’s prosed limit of NMT ppm for

for which there is Equal or higher limits for this solvent have been accepted for similar Vertex products (i.e., Kalydeco and Orkambi)

. There is no nonclinical safety concern for the proposed

level of .

15.2.5. Other Toxicity Studies

The following studies were submitted and reviewed under the NDA application. These studies evaluated the potential risk of VX-445 not only to patients, but also to manufacturing workers and the environment.

Other Toxicology Study Report Number Review Reference ID

UV Photosafety Studies Multiple-dose phototoxicity study to determine the effects of oral gavage administration on eyes and skin in pigmented rats VX-445-TX-004 4404180

Local Tolerance

Rabbit local tolerance study VRT-1651445-TX-016 Current review


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Other Toxicology Study Report Number Review Reference ID Evaluation of the Eye Hazard Potential of VX-445 using the Bovine Corneal Opacity and Permeability Test (BCOP Test) VX-445-TX-020 Current review

Environmental Impact Environmental Risk Assessment of VX-445 VX-445-TX-022 Current review Phototoxicity Study in Rats (VX-445-TX-004) VX-445 absorbs ultraviolet-visual light at the wavelength ranges between 290 and 700 nm. A phototoxicity study was conducted in Long Evans rats. There was no cutaneous or ocular phototoxicity after a 3-day oral administration of VX-445 at doses up to 40 mg/kg/day, following a single exposure to UVR in female Long-Evans rats. In vitro and In vivo Local Tolerance Studies The potential eye hazard of VX-445 was evaluated by measuring the ability to induce opacity and increase permeability in an isolated bovine cornea (Bovine Corneal Opacity and Permeability test, VX-445-TX-020). Pure VX-445 powder was added on top of the bovine cornea for approximately 240 minutes and did not induce ocular irritation through either corneal opacity or permeability.

A single dose of VX-445 at the concentrations of 0 or 0.1 mg/mL was administrated to New Zealand White albino rabbits through intravenous (IV, 0.5 mL), intra-arterial (IA, 0.5 mL), perivascular (PV, 0.1 mL), and subcutaneous (SC, 0.5 mL) injections (VRT-1651445-TX-016). No test item related systemic or local changes were identified throughout the different groups.

Environmental Impact An environmental risk assessment was performed to evaluate potential environmental risks of VX-445 related to its manufacture and use in the treatment of cystic fibrosis.

As an ionizable molecule, the octanol/water distribution coefficient (Dow) of VX-445 was tested at three pH levels: pH7, 4.5 and 3.6. VX-445 is not identified as a persistent, bioaccumulative, or toxic (PBT) substance. As VX-445 metabolites are expected to be more soluble in water than the parent drug substance, the risk for bioaccumulation of metabolites is considered to be acceptable. The predicted environmental concentration (PEC) was only calculated to the aquatic compartment (PECsurfacewater = μg/L) and was not exceed the action limit of 0.01μg/L. As VX-445 at the maximal recommended human dose generally was not a reproductive or developmental toxicant, it was not expected to affect reproduction of fish or lower organisms. Therefore, an environmental fate and effects assessment was not performed.

15.3. OCP Appendices (Technical Documents Supporting OCP Recommendations)

15.3.1. Individual Studies

Note: In this review, early development names VX-445 is also used to refer to elexacaftor (ELX). All clinical pharmacology studies listed in Table 9 were reviewed in this section.


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In Vitro Studies In vitro studies are listed in the table below.

Table 70. In Vitro Studies (Using Human Biomaterials) of Elexacaftor (VX-445) and Its Major Metabolites

ADME Conclusions Study/Report Absorption VX-445 showed high permeability in the colorectal adenocarcinoma (Caco-2)

cell system M388

Distribution VX-445 does not preferentially partition into red blood cells. The blood:plasma partitioning ratio in human following in vitro incubation at 1 μM was 0.501.

M275

Protein binding is high (>99%) for VX-445 and the major metabolites in human plasma. Human serum albumin is the major human plasma protein for their binding.

O062

In order to calculate the free concentration in the HBE assay, protein binding of VX-445 and M23-VX445 in HBE medium and HBE medium with additional 20% human serum was evaluated by equilibrium dialysis. VX-445 and M23-VX445 are highly bound (> 96.0%) to proteins in HBE media with 20% human serum.

O130

VX-445 protein binding ranged between 74.8 to 81.7% in rat, dog, monkey, and human liver microsomes (0.5 mg/mL). There was no species difference observed.

O111

VX-445 protein binding was 23.2% to 43.8% in rat, dog, monkey, and human hepatocytes (0.5 million cells/mL). There was no species difference observed.

O131

Metabolism When incubated with a panel of 8 recombinant CYPs for 60 minutes, VX-445 was stable (>80% remaining) in the presence of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 (Report M281). VX-445 showed greater turnover in the presence of CYP3A4 (45.6% remaining) and CYP3A5 (45.6% remaining), indicating CYP3A isozymes are likely involved in VX-445 metabolism.

M281

Metabolites of VX-445 were assessed following in vitro incubation with liver microsomes and cryopreserved hepatocytes. Metabolic pathways observed in vitro were pyrrolidine methyl oxidation, pyrazole methyl oxidation, pyrazole N-demethylation, and pyrrolidine cyclization. CYP3A4/5 were the metabolic enzymes identified in vitro as being responsible for the oxidation of VRT-1651445 in humans. In vitro metabolite profiles were qualitatively similar across human, rat, dog, and monkey. No human-specific metabolites were observed in vitro.

M291

Metabolites of VRT-1651445, formed following in vitro incubation with liver microsomes were identified. Metabolic pathways observed in human and mouse liver microsomes were pyrrolidine methyl oxidation, left hand side methyl oxidation, pyrazole methyl oxidation, pyrazole oxidation, pyrazole N-demethylation, amide hydrolysis with pyrrolidine cyclization and pyrrolidine cyclization. In vitro metabolite profiles were qualitatively similar between mouse and human. No human-specific metabolites were observed in vitro.

O033

The metabolic stability of VX-445 was evaluated in human, monkey, dog, and rat liver microsomes. The predicted hepatic clearance expressed as percent hepatic blood flow is 7.08% in human. Overall, these data suggest that the hepatic clearance value in human is predicted to be low (<15% hepatic blood flow).

O241




ADME Conclusions Study/Report Metabolic profile of 14C-VX445 was investigated in plasma, urine and feces samples from the mass balance study 003. See individual study report for study 003 for summary of results.

O229

DDI potential-CYP induction

There is a low potential for VX-445 or M23-445 to induce CYP1A2, CYP2B6, or CYP3A4 based on in vitro induction data in human hepatocytes.

M307 O271

DDI potential-CYP inhibition

VX445 did not inhibit any CYP significantly, with the IC50 values ≥10 μM for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4

M295

M23-VX445 did not inhibit any CYP significantly, with the IC50 values ≥20 μM for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4

O063

DDI potential-Transporter

VX-445 and M23-445 are P-glycoprotein (P-gp) substrates M388 O288

VX-445 and M23-445 are not substrates for the uptake transporters OATP1B3 O225 VX-445 and M23-445 are not substrates for the uptake transporters OATP1B1 O212

O287 VX-445 and M23-445 did not inhibit P-gp, with the IC50 values ≥20 μM M299

O211 VX-445 and M23-445 may inhibit OATP1B1 (R = 1.49 and 1.02, respectively) M292

O195 VX-445 and M23-445 may inhibit OATP1B1 (R = 1.07 and 1.05, respectively) O094

Source: reviewer summary

PHARMACOKINETICS

1. Mass Balance Study Study # 003 Title: A Phase 1, Open-label, Mass Balance Study to Investigate the Absorption, Distribution, Metabolism, and Excretion of 14C-VX-445 Following Single Oral Administration in Healthy Subjects Study period: 15 March 2018- 08 May 2018 Objective: To determine the routes and rate of elimination and recovery of total radioactivity (TRA) after a single oral dose of 200 mg/200 μCi 14C-VX-445 in healthy male subjects To characterize the PK of VX-445 and total radioactivity (TRA) after a single oral dose of 200 mg/200 μCi 14C-VX-445 in healthy male subjects To profile and identify the major metabolites of VX-445 in the urine, plasma, and feces of healthy male subjects following administration of a single oral dose of 200 mg/200 μCi 14C-VX-445 Study design: This was a single-center, open-label, single-dose study in 6 healthy male subjects. Test drug : 14C-VX-445 200 mg/200 μCi was supplied as a powder (Lot G180-007-000) and orally administered as a liquid-filled capsule. Samples:

• Blood sampling for PK and TRA samples: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, and 144 hours postdose, and every 48 hours thereafter until the day of discharge.




• Blood sampling for metabolic profiling: predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 and 144 hours postdose, and every 48 hours thereafter until the day of discharge.

• Urine sampling intervals: predose (up to 12 hours before dosing), 0 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 48, 48 to 72, 72 to 96, 96 to 120, and 120 to 144 hours after study drug administration. Urine was collected every 24 hours thereafter until the day of discharge.

• Feces sampling intervals: A predose feces sample was collected within 24 hours before dosing from all subjects. Postdose feces samples were collected at 0 to 24, 24 to 48, 48 to 72, 72 to 96, 96 to 120, and 120 to 144 hours after study drug administration and every 24 hours thereafter until the day of discharge.

Results The overall mean recovery of radioactivity in urine and feces samples was 87.5% over the 336-hour study, with recovery in individual subjects ranging from 80.7% to 91.2%. Cumulative total, urine, and fecal recovery of [14C] radioactivity following oral administration is shown in Figure 17.

Figure 17. Mean (±SD) Cumulative Percent of Radioactive Dose Recovered in Urine and Feces at Specified Intervals After a Single 200-mg (200-μCi) Oral Dose of 14C-VX-445 to Healthy Male Subjects

Source: Figure 11-2, CSR 003

Absorption The general pattern of the concentration-time profiles was similar among unchanged VX-445 in plasma, TRA in plasma, and TRA in whole blood (Figure 18). Following a single oral dose of 200-mg (200-μCi) 14C-VX-445, the unchanged VX-445 in plasma and the TRA in whole blood and




plasma reached peak concentrations after approximately 7 to 8 hours; the median Tmax was 24 hours for M23-445 in plasma.

Figure 18. Mean Concentration-Time Profiles of Unchanged VX-445 and M23-445 in Plasma and Total Radioactivity in Plasma and Whole Blood at Semi-Log (Lower) Scales

Source: Figure 11-1, CSR 003

Table 71. Pharmacokinetic Parameters for Unchanged VX-445 and M23-445 in Plasma and Total Radioactivity in Plasma and Whole Blood

Source: Table 11-1, CSR 003




Distribution Mean volume of distribution (Vz/F) was 55.6 L. The mean blood-to-plasma ratio of TRA was approximately 60%, indicating no appreciable accumulation of radioactivity in blood cells.

Metabolism VX-445, M23 (pyrazole N-demethylation), M25 (amide hydrolysis and pyrrolidine cyclization), and 2 metabolites of unknown structure (unknowns 1 and 2) were identified in human plasma. The most abundant radioactivity peak observed in plasma was VX-445, accounting for 80.7% of the AUC of total plasma radioactivity, followed by M23 (17.3%), and M25 (1.6%), and unknowns (0.5% combined) in decreasing order of abundance. Relevant ratios based on AUC0-∞ (hereafter referred to as AUC) and Cmax are presented in Table 72. The mean metabolite-to-parent ratio (M23-445/VX-445) in plasma based on AUC was 26%. As determined by the AUC ratio, unchanged VX-445 accounted for approximately 70% of the TRA in plasma after a single dose of 200 mg (200 μCi) 14C-VX-445.

Table 72. Mean (CV%) AUC and Cmax Ratios for M23-445 to Unchanged VX-445 in Plasma, Unchanged VX-445 to TRA in Plasma, and TRA in Blood to TRA in Plasma


In feces, VX-445 accounted for 22.7% of the administered radioactive dose. The most abundant metabolite was M11 (pyrrolidine oxidation and pyrazole Ndemethylation), which contributed to 22.2% of the radioactive dose. Other metabolites that represented at least 2% of the radioactive dose include M20 (18.9%, pyrrolidine oxidative ring-opening) and M17 (9.9%, pyrrolidine oxidative ring-opening and pyrazole Ndemethylation). The combined percentage of the radioactive dose represented by metabolites with unknown structure was 0.8%.

Elimination The mean t1/2 was similar for unchanged VX-445 (20 hours) and its metabolite M23-445 (23 hours) in plasma; the mean t1/2 was similar for TRA in whole blood (30 hours) and in plasma (28 hours), and was slightly longer than the mean t1/2 of unchanged VX-445 in plasma. The mass balance and overall recovery of TRA are summarized in Table 73. Mean recovery of TRA was 0.227% in urine, with 87.3% of the radioactive dose recovered in feces, demonstrating that excretion in urine is very limited and elimination in feces accounted for almost all of the excreted dose (Figure 17). VX-445 was mainly cleared by metabolism in humans, as the mean unchanged parent recovered in excreta accounted for less than 23% of the administered radioactive dose. The most abundant metabolite in feces was M11, which accounted for 22.2% of the administered




radioactive dose, followed by M20 and M17, which accounted for 18.9% and 9.9% of the administered dose, respectively. Urine metabolites were not profiled because only approximately 0.23% of the radioactive dose was recovered in urine. This result indicates that none of the excreted metabolites in urine accounted for more than 0.23% of the administered radioactive dose.

Table 73. Total Percent of Radioactive Dose as 14C-VX-445 or Metabolites of 14C-VX-445 in Pooled Urine at Specified Times After a Single Oral Administration of 14C-VX-445 to Healthy Male Human Subjects


Reviewer comment: Following a single IV dose of [14C]VX-445 to male BDC Sprague Dawley rats, approximately 81.14% of the dosed radioactivity was excreted in the bile, with less found in feces (8.67%) and urine (0.90%). Following a single oral dose of [14C]VX-445 to male BDC Sprague Dawley rats, approximately 61.87% of the dosed radioactivity was excreted in the bile, with less found in feces (20.18%) and urine (0.63%) (study report RPT04494).

In this mass balance study in humans, feces sample were collected 0 to 336 hours after oral dosing, and comprised 87.3% of the administered dose. Less than 10% of the total radioactivity was detected within 24 hours in feces, and may represent unabsorbed ELX passing through the gastrointestinal tract. Most of the radioactivity in feces was detected after 24 hours post dose, with at least half of the total dose excreted as metabolites. This indicated that some drug-related material was excreted via the bile, and biliary excretion is a major route of drug excretion.

Conclusions • The mean half-lives of unchanged VX-445 and M23-445 were similar (20 to 23 hours). • The amount of unchanged VX-445 in urine was generally not detectable (i.e., below the

lower limit of quantification), indicating that renal excretion is a negligible route of VX-445 elimination in humans.

• Mean AUC0-∞ values for unchanged VX-445 in plasma were approximately 70% of TRA in plasma, indicating that the majority of circulating TRA was related to unchanged VX-445.

• The mean blood-to-plasma ratio of TRA was approximately 60%, indicating no appreciable accumulation of radioactivity in blood cells.

• The mean metabolite-to-parent (M23-445/VX-445) AUC ratio in plasma was 26%. • The mean overall recovery of radioactive VX-445 was 87.5%, with 87.3% recovered in

feces and approximately 0.23% recovered in urine. • The majority of VX-445 was excreted from the body in feces following oral administration. • 14C-VX-445 accounted for the majority of the total circulating radioactivity in plasma

(80.7%). M23-445 (N-demethylation) accounted for 17.3% of the total circulating radioactivity.




• VX-445 was mainly cleared by metabolism in humans; the unchanged parent recovered in excreta accounted for approximately 23% of the administered radioactive dose.

2. Single and Multiple Ascending Dose Study Trial # 001 Title: A Phase 1/2 Study of VX-445 in Healthy Subjects and Subjects With Cystic Fibrosis Study period: 23 Jan 2017- 27 Mar 2018 Objectives: Parts A, B, and C (Healthy Subjects) Part A: To evaluate the PK, absolute bioavailability, food effect, safety and tolerability of single ascending doses of VX-445 in healthy subjects Part B: To evaluate the PK, safety and tolerability of multiple ascending doses of VX-445 administered in healthy subjects Part C: To evaluate the PK, safety and tolerability of multiple doses of VX-445 daily (qd) in triple combination (TC) with tezacaftor (TEZ) 100 mg qd and ivacaftor (IVA) 150 mg every 12 hours (q12h) for 14 days in healthy subjects Parts D, E, and F (CF Subjects) • To evaluate the PK, safety and tolerability of VX-445 in TC with TEZ/IVA or TEZ/VX-561 in subjects with cystic fibrosis (CF) • To evaluate the efficacy of VX-445 in TC with TEZ/IVA or TEZ/VX-561 in subjects with CF

Study design: Parts A, B, and C (Healthy Subjects) This was a randomized, double-blind, placebo-controlled, single- and multiple-dose, dose-escalation, multi-part study. Doses of VX-445 were administered under fed conditions in all parts/cohorts except Cohort A7, which included a dosing period where VX-445 was also administered under fasting conditions to evaluate the food effect. • Part A: VX-445 single dose escalation including continuous ECG monitoring for extraction and high-precision QTc analysis (Cohorts A1 to A5, dose 20, 60, 120, 240, and 360 mg respectively), and evaluation of food effect and absolute bioavailability (BA) of VX-445 (Cohort A7, oral dose 100 mg, iv dose 20 mg). Subjects were randomized 3:1 to receive VX-445 or placebo in each cohort except Cohort A7. In Cohort A7, all subjects received open-label VX-445. • Part B: VX-445 multiple dose escalation for 10 days, (Cohorts B1 to B4, dose 60, 120, 240, and 340 mg qd respectively). • Part C: VX-445 dose escalation in TC with TEZ/IVA for 14 days, (Cohorts C1 to C3, dose 200, 280, and 100 mg qd respectively). Parts D, E, and F (CF Subjects) This was a randomized, double-blind, parallel-group, multi-part study: • Part D: 2-cohort, placebo-controlled evaluation of VX-445 at multiple dose levels (50, 100, and 200 mg) in TC with TEZ/IVA for 4 weeks in CF subjects with F508del/minimal function mutation (F/MF) genotypes, including a 1 week VX-445 Washout Period • Part E: TEZ/IVA-controlled evaluation of VX-445 200 mg in TC with TEZ/IVA for 4 weeks in CF subjects with F/F genotypes, including a 4-week TEZ/IVA Run-in Period and a 4-week VX-445




Washout Period • Part F: placebo-controlled evaluation of VX-445 200 mg in TC with TEZ/VX-561 for 4 weeks in CF subjects with F/MF genotypes

Table 74. Test product, Trial 001

Sampling Schedule PK Sampling Schedule Part A For Part A1-6, blood samples for PK assessments were collected on Day 1 before dosing (0 hours) and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24 (Day 2), 36 (Day 2), 48 (Day 3), 72 (Day 4), and 96 (Day 5) hours after dosing. For Part A7, blood samples for PK assessments were collected on Days 1 and 7 before dosing (0 hours) and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24 (Days 2, 8), 36 (Days 2, 8), 48 (Days 3, 9), 72 (Days 4, 10), 96 (Days 5, 11), and 120 (Days 6, 12) hours postdose. Blood samples for PK assessments were collected on Day 13 before dosing (0 hours, before the start of the IV infusion) and at 0.5 (after the end of the IV infusion), 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12, 24 (Day 14), 36 (Day 14), 48 (Day 15), 72 (Day 16), and 96 hours (Day 17) after the start of the IV infusion. PK Sampling Schedule Part B Blood samples for PK assessments of VX-445 were collected on Day 1 before dosing (0 hours), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours after dosing. On Days 2, 3, and 4, a blood sample was collected in the morning before dosing. On Day 10, blood samples for PK assessments were collected before dosing (0 hours), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24 (Day 11), 36 (Day 11), 48 (Day 12), 72 (Day 13), and 96 (Day 14) hours after dosing. PK Sampling Schedule Part C Blood samples for PK assessments of VX-445 were collected on Day 1 and Day 7 before dosing (0 hours) and at 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 hours after dosing. The 12-hour sample was collected before the next administered dose if dosing was q12h. On Days 2, 3, 4, 5, and 8, blood samples were collected before (morning) dosing. On Day 14, blood samples were collected


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before dosing (0 hours), and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24 (Day 15), 36 (Day 15), 48 (Day 16), 72 (Day 17), and 96 (Day 18) hours after dosing. Blood samples for PK assessments of TEZ and metabolites, and IVA and metabolites were collected on Day 1 and Day 7 before dosing (0 hours) and at 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 hours after dosing. The 12-hour sample was collected before the next administered IVA dose. On Days 2, 3, 4, 5, and 8, blood samples were collected before (morning) dosing. On Day 14, blood samples were collected before dosing (0 hours), and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24 (Day 15), 36 (Day 15), 48 (Day 16), 72 (Day 17), and 96 (Day 18) hours after dosing. PK Sampling Schedule Part D, E, and F Blood samples were collected for PK analysis of VX-445, TEZ, M1-TEZ, IVA, and M1-IVA in CF patients. See appendix xx for population PK assessment in CF patients. Results: Part A (SAD, food effect, absolute bioavailability) The mean plasma concentration-time profile is shown in Figure 19. The summary of PK parameters for each dose group is provided in Table 75. Following oral administration, VX-445 was readily absorbed with a median Tmax of ~ 4-5 hour in the fed state (20 mg to 360 mg). VX-445 appears to follow single-exponential disposition kinetics in healthy male volunteers (Figure 19). VX-445 exhibited long apparent terminal half-life with a median (range) of 16 to 24 hours over a range of 20 to 360-mg single doses (Table 75). Cmax and AUCinf of VX-445 exhibited approximately dose-proportional increase when administered as single doses of 20 to 360 mg.




Figure 19. Mean VX-445 Plasma Concentration-Time Profiles Following Single Dose Administration of VX-445, Part A (Log-linear Scale)

Source – Figure 11-2, CSR001

Table 75. Summary of the Pharmacokinetic Parameters for ELX Following Single Oral Doses


Table 76 summarizes the PK parameters of a 100 mg dose of VX-445 in the fed versus the fasted state. The median tmax was 5 hours in the fed state compared to 12 hours in the fasted state. Administration of the VX-445 tablet in the fed state with a moderate-fat meal resulted in an




approximately 2.5-fold higher AUC and an approximately 3.6-fold higher Cmax relative to the fasted state.

Table 76. Statistical Analysis of a Food Effect on a VX 445 Tablet Formulation, Part A


Table 77 summarizes the PK parameters of VX-445 following an intravenous infusion. The absolute bioavailability (F) of VX-445 tablet formulation in the fed and fasted state is 80% and 34%, respectively. The t1/2 of VX-445 when administered as an intravenous formulation was comparable to VX-445 administered orally as a tablet formulation in the fed state.

Table 77. Summary of Selected VX-445 PK Parameters After an IV Infusion, Part A


Part B (MAD) Mean VX-445 plasma concentration-time profiles on Days 10 up to 24 hours for all dose levels are shown in Figure 20 and summary PK parameters are listed in Table 78. VX-445 PK after multiple doses was consistent with the single dose PK. The median Tmax was about 4-5 hr and mean t1/2 at steady state ranged from 17.6 to 27.9 hours. The mean accumulation ratio for AUC ranged from 2.04 to 3.67. Based on visual inspection of the trough concentrations from Part B and Part C, VX-445 appeared to reach steady-state by approximately Day 10 to Day 14 following multiple dosing (Figure 21). CL/F of VX-445 did not change after multiple dosing compared to single dose administration. The AUCτ at steady state was consistent with the observed single dose exposures (AUC0-24h

/AUC0-∞). With VX-445 120 mg QD under fed state, the AUCτ at steady state is ~103 μg*h/mL, comparable to AUC0-∞ of 94.6 μg*h/mL after single dose of 120 mg VX-445 administered with food. The PK of VX-445 can therefore be considered time-independent. Cmax and AUCτ of VX-445 exhibited approximately dose-proportional increase when administered as once daily doses of 60 to 340 mg (Table 78). Overall, VX-445 exhibit linear PK.




Figure 20. Mean VX-445 Plasma Concentration-Time Profiles on Day 10 Following Multiple Oral Doses for 10 Days, Part B (Log-linear)

Source: Figure 11-7, CSR001




Figure 21. Mean VX-445 Trough Plasma Concentration-Time Profiles Following Multiple Oral Doses for 10 Days (Part B) and 14 Days (Part C)

Source: Figure 11-8, 11-14, CSR001




Table 78. Summary of Selected VX-445 PK Parameters Following Multiple Oral Doses for 10 Days, Part B

Source: Table 11-5, CSR001

Part C (co-administration with TEZ/IVA) VX-445 exposure when administered in triple combination (TC) with TEZ/IVA was similar to when VX-445 was administered as monotherapy in Part B. A summary of VX-445 and M23-445 PK parameters following multiple doses of VX-445 TC are presented in Table 79. The mean t1/2 for VX-445 at steady state ranged from 24.7 to 28.1 hours and the mean accumulation ratio for AUC on Day 14 ranged from 3.41 to 3.55. A summary of TEZ and IVA parameters following multiple doses of VX-445 TC for 14 days is presented in Table 80. PK parameters of TEZ and IVA and its metabolites were comparable across the cohorts studied regardless of VX-445 dose, and similar to previous studies with SYMDEKO.




Table 79. Summary of Selected VX-445 PK Parameters Following Multiple Oral Doses of VX-445 TC for 14 Days, Part C





Table 80. Summary of Selected TEZ and IVA PK Parameters Following Multiple Oral Doses of VX-445 TC for 14 Days, Part C

Source: Table 11-7, 11-8, CSR 001

Conclusions: ELX has linear PK. Overall, ELX exposure was dose-proportional up to 360 mg. The absolute bioavailability of ELX when administered orally in the fed state is approximately 80%. ELX is absorbed with a median (range) time to maximum concentration (tmax) of approximately 6 hours (4 to 12 hours). ELX exposure (AUC) increases approximately 2.5-fold when administered with a moderate-fat meal relative to fasted conditions. ELX has an apparent terminal half-life ranging from approximately 17.6 to 30.6 hours. With once daily dosing, the mean accumulation ratio of AUC ranged from 2.0 to 3.7. Following co-administration of TEZ/IVA in TC with ELX, both TEZ and IVA exposures were consistent across the ELX doses studied.

3. Multiple Rising Dose Trial # 009 Title: A Phase 1, Randomized, Double-blind, Placebo- and Active-controlled, Thorough QT/QTc Study of VX-445 in Healthy Subjects Study period: 5 Jun 2018- 13 Aug 2018 Objectives:

• To evaluate the effects of therapeutic and supratherapeutic doses of VX-445 on QTcF in healthy subjects




• To evaluate assay sensitivity (i.e., to evaluate the effect of moxifloxacin on QTc in healthy subjects)

• To evaluate the safety and tolerability of therapeutic and supratherapeutic doses of VX-445 in healthy subjects

• To assess the PK of VX-445 and M23-445 • To evaluate the effects of therapeutic and supratherapeutic doses of VX-445 on

heart rate (HR), PR, QRS intervals, and T-wave morphology

QT data were not reviewed here. For QT results, please refer to QT-IRT review by Dr. Janell Chen (DARRTS date September 16, 2019). Study design: This study was a double-blind, randomized, placebo- and active-controlled, multiple-dose, single-center ECG study with a parallel design with nested crossover groups for moxifloxacin and placebo to investigate the effect of VX-445 on QT/QTc intervals in healthy male and female subjects. A total of 64 subjects were enrolled and randomized in a 2:1:1 ratio to Groups 1, 2A, or 2B. All groups in this double-blind study received a total of 16 days study drug treatment in the fed state as follows:

• Group 1: Moxifloxacin-matching placebo on Day 1; VX-445 at the therapeutic dose (200 mg once daily [qd]) on Days 2 through 8; VX-445 at the supratherapeutic dose (400 mg qd) on Days 9 through 15; moxifloxacin-matching placebo on Day 16.

• Group 2A: Moxifloxacin on Day 1; VX-445-matching placebo on Days 2 through 15; moxifloxacin-matching placebo on Day 16.

• Group 2B: Moxifloxacin-matching placebo on Day 1; VX-445-matching placebo on Days 2 through 15; and moxifloxacin on Day 16.

Test product: VX-445 50-mg tablets (Lot 2017037) were administered orally with food at a dose of 200 mg or 400 mg qd. Sampling Schedule Blood PK Sampling Schedule for VX-445: Days 8 and 15 (Day 7 dosing of each dose): Predose (-30 minutes) and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 23.5 hours postdose (Days 9 and 16) Results: Pharmacokinetic results VX-445 was rapidly absorbed in healthy subjects following single and multiple doses of 200 and 400 mg qd with a tmax of approximately 5 hours (Figure 22). VX-445 exposure was generally dose-proportional between doses of 200 and 400 mg qd; M23-445 exposure was slightly greater than dose-proportional. Variability in PK was low. Following the supratherapeutic dose of VX-445, Cmax values reached mean values of 20.9 μg/mL for VX-445 and 8.49 μg/mL for M23-445 (Table 81).




Figure 22. Mean VX-445 Plasma Concentration Versus Time After Therapeutic (200 mg qd) and Supratherapeutic (400 mg qd) Doses of VX-445 for 7 Days

Source: Figure 11-1, CSR009

Table 81. PK Parameters of VX-445 and M23-445 After Therapeutic (200 mg qd) and Supratherapeutic (400 mg qd) Doses of VX-445

Source: 11-1, Study 010 report

4. DDI with Itraconazole, Midazolam, and Digoxin Trial # 006 Title: A Phase 1, Open-label Study to Evaluate the Effect of Itraconazole and Fluconazole on VX-445 Triple Combination Therapy in Healthy Adult Subjects Study period: 09 May 2018- 10 Jul 2018




Objectives: Part A To assess the effect of itraconazole on the PK of a single dose of VX-445/tezacaftor (TEZ)/VX-561 and relevant metabolites Part B (optional) To assess the effect of fluconazole on the PK of a single dose of VX-445/TEZ/VX-561 and relevant metabolites Study design – This was a Phase 1, 2-part, open-label, DDI study. Part A was designed to evaluate the effect of itraconazole on the PK of VX-445/TEZ/VX-561 administered as separate tablets. Optional Part B was designed to evaluate the effect of fluconazole on the PK of VX-445/TEZ/VX-561. Part B was not conducted based on a review of the PK results from Part A. Part A was conducted as shown in Figure 23.

Figure 23. VX18-445-006 Part A Study Design

(Source: Figure 2-1, CSR006)

Test product: VX-445 20-mg tablets (Lot 2016062), TEZ 50-mg tablets (Lot 2016034), and VX-561 50-mg tablets (Lot 2017019) were administered orally as a single dose of VX-445 20 mg/TEZ 50 mg/VX-561 50 mg.




Table 82. Sampling Schedule, Trial 006

Results and Conclusions: PK results Effect of itraconazole on VX-445, TEZ, VX-561, and their respective metabolites: Upon coadministration of VX-445, TEZ and VX-561 as separate tablets with itraconazole, VX-445 exposure (AUC0-∞) increased approximately 2.8-fold, while Cmax remained unchanged. TEZ AUC0-∞ and Cmax increased approximately 4.5-fold and 1.5-fold, respectively (Table 83).

Table 83. Geometric Least Squares Mean (GLSM) Ratios and 90% CI for VX-445, TEZ, VX-561, and Their Respective Metabolites With (TP 2) and Without (TP 1) Itraconazole





5. DDI with Oral Contraceptives Trial # 002 Title: A Phase 1, Open-label, 2-period, Fixed-sequence Study to Evaluate the Effect of VX-445 Triple Combination Therapy on the Pharmacokinetics of Oral Contraceptives in Healthy Female Subjects Study period: 24 Jan 2018- 07 Apr 2018 Objectives:

• To assess the effect of VX-445/tezacaftor (TEZ)/ivacaftor (IVA) on the PK of levonorgestrel (LN) and ethinyl estradiol (EE)

• To assess the safety of coadministration of VX-445/TEZ/IVA in combination with LN/EE in healthy female subjects

• To assess plasma steady state PK of VX-445, TEZ, and IVA during coadministration with LN/EE in healthy female subjects

Test product: VX-445 50-mg tablets (lot 2017037), IVA 150-mg tablets (lot 3140699R), TEZ 100-mg/IVA 150-mg FDC tablets (lot 2017016), and LN 150-μg/EE 30-μg FDC tablets (lots 7502F001B and 7502F002B) Study design –This was a Phase 1, open-label, DDI study to evaluate the effect of VX-445/TEZ/IVA on the PK of oral contraceptives. A total of 16 subjects were enrolled in the study. Subjects received LN/EE for 3 weeks, followed by coadministration of LN/EE and VX-445/TEZ/IVA for 10 days.

Figure 24. Study Design Scheme

Source: Figure 9-1. CSR 002

Sampling Schedule PK Sampling Schedule LN and EE PK • PK samples were collected on Days 21 before the morning dose, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours after the morning dose. And on Day 31 before the morning dose, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 (i.e., Day 32) hours after the morning dose. Also, PK samples were collected before dosing on Days 22, 26, 29, and 30.




ELX, TEZ, IVA, and their metabolites • PK samples were collected on Day 31 before the morning dose, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 (i.e., Day 32) hours after the morning dose. Also, PK samples were collected before dosing on Days 22, 26, 29, and 30. Results and Conclusions PK results Administration of VX-445/TEZ/IVA in combination with oral contraceptives did not impact the PK of EE or LN. Mean plasma EE and LN concentration-time profiles on Days 21 and 31 are presented in Figure 25 and Figure 26. EE and LN exposures in healthy subjects after co-administration with VX-445/TEZ/IVA were similar compared to administration of EE and LN alone. The results of the statistical analysis of VX-445/TEZ/IVA coadministration on LN/EE exposures are provided in Table 84. LN AUC0-24h increased by 23% and EE AUC0-24h increased by 33% when coadministered with VX-445/TEZ/IVA. Increases in LN and EE exposures of this magnitude are not expected to be clinically relevant. PK parameter estimates for VX-445, TEZ, and IVA are presented in Table 85). The exposure of VX-445, TEZ, and IVA is similar to that observed in other studies.

Figure 25. Mean EE Plasma Concentration Time Profiles After Administration of LN/EE Alone (Day 21) and After LN/EE+VX-445 TC (Day 31)

Source: Figure 11- 1, CSR002




Figure 26. Mean LN Plasma Concentration Time Profiles After Administration of LN/EE Alone (Day 21) and After LN/EE+VX-445 TC (Day 31)

Source: Figure 11- 2, CSR002

Table 84. Statistical Analysis of LN and EE Exposures After Administration of LN/EE Alone and After LN/EE+VX-445 TC





Table 85. Mean VX-445, TEZ, IVA Exposures after Administration of LN/EE+VX-445 TC

* VX-445 TC: VX-445 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h Source: Table 11-3, CSR 002

Conclusions: No significant DDI between EE/LN and VX-445/TEZ/IVA was observed when oral contraceptive was co-administered with VX-445/TEZ/IVA in healthy subjects. VX-445/TEZ/IVA was safe and well tolerated when administered concurrently with OC.

6. Relative Bioavailability and Food Effect Trial # 005 Title: A Phase 1, Open-label, Randomized, Crossover Study to Evaluate the Relative Bioavailability and Food Effect of a Fixed-dose Combination Tablet of VX-445, Tezacaftor, and VX-561 in Healthy Subjects Study period: 09 Jan 2018- 24 Jun 2018 Objectives Part A Cohorts A1: To evaluate the relative bioavailability of a FDC tablet of VX-445/tezacaftor (TEZ)/VX-561 compared to VX-445, TEZ, and VX-561 co-administered as separate tablets Cohort A3 : To evaluate the relative BA of FDC tablets of VX-445/TEZ/ivacaftor (IVA) compared to VX-445 co-administered with TEZ/IVA FDC tablets Part B To evaluate the effect of food on the relative BA of VX-445/TEZ/VX-561 administered as an FDC tablet. Study design and treatment schedule This was a Phase 1, 2-part, open-label, randomized, crossover study in healthy subjects. In Part A, Cohort A1 evaluated VX-445/TEZ/VX-561 as an FDC tablet compared to VX-445, TEZ, and VX-561 co-administered as separate tablets. Optional Cohort A3 evaluated VX-445/TEZ/IVA as an FDC tablet compared to VX-445 co-administered with a TEZ/IVA FDC tablet. In Part B, study drug was administered under different fed and fasted conditions to evaluate the food effect on




the relative BA of VX-445/TEZ/VX-561 FDC tablets. Fed conditions included moderate-fat (approximately 20g of fat) and low-fat (approximately 7g of fat) meals.

Table 86. Trial 005 Design





Table 87. Test Product VX-561, a Deuterated Isotope of IVA With a Specific Pattern of 9 Substituted Deuteriums

PK Sampling Schedule For each period, blood PK samples for VX-445, TEZ, VX-561, and IVA (if applicable) were collected predose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12 (Days 1, 11, and 21), 24 (Days 2, 12, and 22), 48 (Days 3, 13, and 23), 72 (Days 4, 14, and 24), 96 (Days 5, 15, and 25), 120 (Days 6, 16, and 26), and 144 (Days 7, 17, and 27) hours postdose. Results and Conclusions Relative Bioavailability of the FDC Formulation Compared to Separate Tablets The FDC formulation demonstrated similar bioavailability compared to the separate tablet formulations of VX-445, TEZ, and VX-561. For both VX-445 and TEZ, the PK parameters and time course of exposure were generally similar after administration of VX-445/TEZ/VX-561 as an FDC tablet compared to separate tablets. VX-561 exposure (Cmax and AUC0-∞) was slightly higher after administration of VX-445/TEZ/VX-561 as an FDC tablet than as separate tablets. The geometric mean ratios for Cmax and AUC of the FDC relative to separate tablets were both approximately 100% under fed conditions (Table 88).




Table 88. Relative Bioavailability Assessment of VX-445, TEZ, and VX-561 Exposures After Administration in Part A, Cohort A1


Relative Bioavailability of the FDC Formulation Compared to Separate Tablets The VX-445/TEZ/IVA FDC formulation demonstrated similar bioavailability compared to the separate tablet formulations of VX-445 and TEZ/IVA. TEZ exposures were similar after administration of both VX-445/TEZ/IVA formulations; the geometric least squares mean ratios differed by <3% for both AUC0-∞ and Cmax. VX-445 exposures decreased slightly (15% for AUC0-∞ and 27% for Cmax) when VX-445/TEZ/IVA was administered as an FDC tablet compared to VX-445 co-administered with a TEZ/IVA FDC tablet, whereas IVA exposures increased slightly (12% for AUC0-∞ and 11% for Cmax) with the VX-445/TEZ/IVA FDC tablet formulation (Table 89).

Table 89. Relative BA Assessment of VX-445, TEZ, and IVA Exposures After Administration in Part A, Cohort A3


Effect of Food on the FDC Formulation Table 90 summarizes the PK parameters of VX-445, TEZ, and VX-561 after single-dose administration of VX-445 200 mg/TEZ 100 mg/VX-561 150 mg as FDC tablets in the fasted state or with a low-fat or moderate-fat meal.




For TEZ, the PK parameters and time course of exposure were generally similar after administration of VX-445/TEZ/VX-561 in the fasted state or after a low-fat or moderate-fat meal. VX-445 and VX-561 exposures (Cmax and AUC0-∞) were both higher after administration of VX-445/TEZ/VX-561 in the fed state compared with the fasted state; the increases in exposure were higher after study drug administration with a moderate-fat meal than with a low-fat meal (Table 90). VX-445 exposures after administration of a VX-445/TEZ/IVA FDC tablet with a moderate-fat meal showed an approximately 1.9-fold (AUC0-∞) to 3.9-fold (Cmax) increase compared with the fasted state. VX-561 exposures after administration of a VX-445/TEZ/IVA FDC tablet with a moderate-fat meal showed an approximately 3.1-fold (AUC0-∞) to 6.2-fold (Cmax) increase compared with the fasted state (Table 91).

Table 90. Summary of VX-445, TEZ, and VX-561 PK Parameters After Administration in Part B, Evaluating Food Effect





Table 91. Relative BA Assessment of VX-445, TEZ, and VX-561 Exposures as FDC Tablet With a Moderate-fat Meal Compared to Under Fasted Conditions


Conclusions The VX445/TEZ/IVA FDC formulation demonstrated similar bioavailability compared to the separate tablet formulations of VX-445 and TEZ/IVA. Relative to the fasted state, administration with a low-fat meal resulted in AUC0-∞ increases of approximately 1.4-fold and 2.1-fold for VX-445 and VX-561, respectively. Administration with a moderate-fat meal resulted in AUC0-∞ increases of approximately 1.9-fold and 3.1-fold for VX-445 and VX-561, respectively, relative to the fasted state. TEZ exposure was unchanged by administration with a low-fat or moderate-fat meal relative to fasted conditions.

Reviewer comment: The food effect for VX-561 (deuterated ivacaftor) is similar to what has been observed for ivacaftor in previous studies. The food effect for TEZ and VX-445 is also similar to what has been observed in previous studies. Due to the significant food effect for ivacaftor, TRIKAFTA is recommended to be taken with fat-containing food. VX-445/TEZ/IVA was administered with fat containing food in all phase 2 and 3 studies.

The phase 3 formulation is VX-445 100 mg/TEZ 50 mg/IVA 75 mg FDC. It is the same as the to-be-marketed formulation. The exposure of VX-445, TEZ and IVA in phase 3 studies is consistent with the phase 2 study (Study 001), where separate tablets were administered.

15.3.2. Physiologically Based Pharmacokinetic (PBPK) Modeling Review

Executive Summary The objective of this review is to evaluate the adequacy of the Applicant’s following physiologically based pharmacokinetic (PBPK) analyses report O318 “physiologically based pharmacokinetic analyses of VX-445” and response to relevant information requests (IRs). Specifically, the modeling analyses were used to evaluate the effect of moderate CYP3A inhibitors on the PK of VX-445 (elexacaftor) and provide dose adjustment recommendations in the presence of CYP3A inhibitors.




The Division of Pharmacometrics has reviewed the report, supporting modeling files, and response to our information requests submitted on September 5, 2019, and concluded that the Applicant’s physiologically based pharmacokinetic (PBPK) analyses are adequate to evaluate the effects of moderate CYP3A inhibitors on the PK of VX-445.

Background Submitted is elexacaftor (VX-445)/tezacaftor/ivacaftor tablets (fixed dose combination); ivacaftor tablets co-packaging indicated for the treatment of cystic fibrosis (CF) in patients aged 12 years and older who have at least one F508del mutation in the CFTR gene. The proposed dosage is two tablets (each containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) in the morning and one tablet (containing ivacaftor 150 mg) in the evening 12 hours apart taken with fat-containing food.

In vitro phenotyping study with 8 recombinant CYP enzymes for 60 minutes showed VX-445 was stable (>80% remaining) in the presence of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6, and 46% remaining in the presence of CYP3A (Report M281).

VX-445 and its major metabolite, M23-445, have low potential to inhibit all CYP enzymes evaluated in human liver microsomes (Reports M295 and O063), and low potential to induce CYP1A2, CYP2B6, or CYP3A4 based on in vitro induction data in human hepatocytes (Reports M307 and O271). VX-445 and M23-445 are P-glycoprotein (P-gp) substrates but are not substrates for the uptake transporters OATP1B1 or OATP1B3. Based on in vitro results, VX-445 and M23-445 have a low potential to inhibit P-gp (Summary of Clinical Pharmacology Studies).

Human ADME study (Study 003) conducted in the fed state showed that VX-445 was mainly cleared by CYP metabolism. The unchanged parent recovered in the excreta accounted for approximately 23% of the administered radioactive dose with a mean of 0.228% of the dose recovered in urine over 336 hours.

M23-445 (N-demethylation) was identified as the only major metabolite with similar potency to VX-445 in F/MF HBE cells. The mean metabolite-to-parent (M23-445/VX-445) AUC ratio in plasma was 26% (Study 003). The mean metabolite-to-parent AUC ratio at steady-state ranged from approximately 35% to 50% (Studies 001 and 009).

This review focuses on evaluating the effect of CYP3A inhibitors on the PK of VX-445. The DDI liability assessment for the other two active ingredients, tezacaftor and ivacaftor was conducted previously in NDA 210491 (ivacaftor; ivacaftor, tezacaftor copackage), and NDA 203188 (ivacaftor).

Methods Software

Simcyp® Version 17.1 (Certara) was used for PBPK analyses by the Applicant and the reviewer.




PBPK model development The VX-445 PBPK model consists of a first-order absorption and a minimal PBPK model. The distribution parameters (Vss [volume of distribution at steady-state], Vsac [volume of distribution of the single adjusted compartment], and Q [intercompartmental clearance]) were obtained based on observed PK profiles following intravenous (IV) dosing (Study 001). The absorption parameters were optimized by fitting absorption parameters (fa [fraction available from dosage form], ka [first-order absorption rate constant], and Tlag [lag time]) to the PK profile following a 360 mg single oral dose (Study 001) under fed condition with fixed distribution parameters and clearance fixed to its reported value of CL/F. The elimination of VX-445 consists of CYP3A (fmCYP3A = 67%) and biliary excretion (33%) pathways based on in vitro and human ADME studies. Table 92 summarizes model input parameters for VX-445.

Table 92.Model Input Parameters for VX-445

Source: Appendix A of Report O318 Errata 1




Reviewer comments: The active metabolite, M23-445, was not incorporated into the PBPK analyses. The Applicant indicated that there was insufficient information to build the model and M23-445 was not considered to contribute significantly to the overall efficacy.

VX-445 is a P-gp substrate and weak inhibitor. The efflux ratio was 14.9 based on the permeability study in Madin-Darby Canine Kidney (MDCK) cells overexpressing human MDR1 (P-gp) at 1 µM concentration (Report M388). The efflux ratio was 0.46 at 5 µM concentration in Caco-2 cells where digoxin showed an efflux ratio of 13.8. VX-445 is classified as a highly permeable compound in Caco-2 cells at 5 µM concentration (Report M388). The model did not incorporate P-gp as a substrate nor as an inhibitor. It is unlikely that not incorporating P-gp-mediated DDI will affect CYP3A-mediated DDI evaluation because (1) the absolute bioavailability was approximately 80% under fed condition suggesting limited role of gut P-gp in absorption, and (2) the measured unchanged VX-445 in feces was approximately 23% suggesting limited role of liver P-gp in elimination.

The VX-445 model incorporated the interaction parameters for CYP2C8 and CYP2C9. Among the evaluated perpetrators, verapamil and its metabolite, norverapamil, are partially eliminated by CYP2C8. The reviewer conducted simulations to evaluate the effect of CYP2C8 inhibition on the PK of verapamil and norverapamil by turning on and off the CYP2C8 inhibition. Simulations suggested that incorporation of CYP2C8 and CYP2C9 inhibition functions in the VX-445 model does not affect the PK of verapamil and norverapamil.

Clinical data suggested the VX-445 exposure was similar in the presence and absence of tezacaftor/ivacaftor. Therefore, it is acceptable that the PBPK model and analyses did not incorporate tezacaftor/ivacaftor.

PBPK model validation Clinical PK and DDI studies used to support the model development, validation and application are listed in in Table 93.

Table 93. Human PK Data Used for VX-445 PBPK Model Development and Validation Study No. Study description Roles in PBPK analyses Model objective

003 Human ADME study 200 mg in the fed condition

To allocate clearance to each pathway Development

001-Cohort A7 (IV)

PK in healthy subjects following 20 mg IV administration

To obtain CLiv, and minimal PBPK model parameters, Vss, Vsac, and Q Development

001-Cohort A5 (360 mg SD)

PK in healthy subjects following 360 mg single-dose oral administration in the fed condition

To obtain absorption parameters, fa, ka, Tlag, and CL/F Development

006 DDI study with itraconazole To obtain fmCYP3A Development

001 PK in healthy subjects following SD from 20 to 360 mg or MD from 60 to 340 mg QD in the fed condition

To validate model performance in predicting PK Validation

IV: intravenous; SD: single dose, MD: multiple dose

Perpetrator Models Simcyp default inhibitor models, itraconazole (fasted solution), fluconazole, erythromycin, and verapamil, were used to predict strong and moderate CYP3A inhibition effects on VX-445 PK.




These inhibitor models were validated by the software developer by comparing the simulated and observed PK profiles of the inhibitors following multiple dose administration and their effects on the PKs of other CYP3A substrates. Table 94 summarized the predicted and observed DDI effects of inhibitors on various CYP3A substrates.

Table 94. Predicted and Observed CmaxR and AUCR for Perpetrator Models Regarding the CYP3A Pathway

Perpetrator Substrate Observed Predicted Pred. / Obs. CmaxR AUCR CmaxR AUCR CmaxR AUCR

Itraconazole

Midazolam 2.56 5.75 2.48 5.3 0.97 0.92 Midazolam 3.41 10.77 2.82 11.03 0.83 1.02 Midazolam 2.91 5.17 3.02 7.97 1.04 1.54 Zolpidem 1.10 1.34 1.18 1.68 1.07 1.25

Fluconazole Midazolam 2.30 3.73 1.95 3.14 0.85 0.84 Triazolam 1.47 1.63 1.38 1.71 0.94 1.05 Triazolam 1.40 2.05 1.64 2.42 1.17 1.18

Erythromycin Midazolam 2.70 4.41 2.84 7.84 1.05 1.77 Triazolam 1.77 3.65 1.93 4.03 1.09 1.10 Alprazolam 1.18 2.47 1.07 2.62 0.90 1.06

Verapamil Midazolam 1.97 2.92 2.10 3.32 1.07 1.14 Source: Simcyp model files, CmaxR and AUCR are mean Cmax and AUC ratios when the substrate was given with/without a perpetrator.

PBPK model application The developed PBPK models were used to simulate the effects of itraconazole (200 mg every 24 hours or QD, solution, fasting), fluconazole (200 mg QD), erythromycin (500 mg every 6 hours or QID), and verapamil (80 mg every 8 hours or TID) on the PK of VX-445.

Reviewer comment: In the clinical DDI study (Study #006), itraconazole (solution) was taken in the fasted condition and VX-455 was taken one hour later with food. In the Applicant’s PBPK analyses, the simulation dosing intervals were matched with the clinical setting and the ‘fed’ condition was selected. The substrate model (VX-445) and the inhibitor models (itraconazole, fluconazole, and erythromycin) consisted of a first-order absorption model, and therefore, selection of ‘fasted’ or ‘fed’ does not affect the PK simulation. Verapamil in Simcyp V17 consisted of a mechanistic absorption model (Advanced Dissolution, Absorption and Metabolism (ADAM) Model). The reviewer conducted simulations under fasted and fed conditions for verapamil, and the simulated PK profiles and DDI effects were similar. The reviewer also conducted additional simulations to evaluate the effects of fluconazole at 400 mg QD dose level, and verapamil at 120 mg TID dose level. Results 1. Can the VX-445 PBPK model describe the PK of VX-445? Yes. As described previously, the VX-445 PBPK model was developed based on the human ADME study, and PK studies following 20 mg IV dosing and 360 mg single oral dosing of VX-445 under fed condition. The fixed dose combination drug is recommended to be taken with food. The PBPK model was then used to predict PK following single- and multiple- dose




administration of VX-445 without further modification (Table 87). The Applicant compared the simulated with observed mean PK parameters (Cmax, AUCinf for single dose administration, and AUCtau for multiple dose administration) following single- dose (20 mg – 360 mg), or multiple- dose (60 mg – 340 mg, day 10) administration. The reviewer confirmed the Application’s simulation results and conducted additional simulations comparing the predicted with the observed PK parameters on day 1 following multiple- dose (60 mg – 340 mg) administration, and PK parameters on days 1, 7, and 14 following multiple- dose (100 mg, 200 mg, and 280 mg, Study 001 Part C) administration. For all dosing regimens, the predicted/observed PK parameter ratios are generally within the range of 0.73 to 1.5 (Figure 27) except for Cmax on day 1 following 340 mg QD administration where the predicted / observed mean Cmax was 0.55 (result not shown). Clinical single dose ascending study showed that mean Cmax and AUC of VX-445 increased approximately dose proportionally following single doses from 20 to 360 mg (Study 001). Multiple dose ascending study showed that VX-445 exposure increased slightly greater than dose proportional from 60 to 340 mg QD. Although the model did not incorporate non-linear mechanism, the model was able to predict the Cmax and AUCinf following single- and multiple-dose administration with the predicted vs. observed ratios less than 2-fold.

Figure 27. Simulated and Observed VX-445 PK Parameters (A) Cmax (B) AUC of SAD and MAD Studies

Source: Figure 7-1 of Report O318

2. Can the VX-445 PBPK model be used to assess the effects of moderate CYP3A inhibitors on the PK of VX-445?

Yes. The fraction of VX-445 being metabolized by CYP3A (fmCYP3A) was determined by comparing the predicted effects with the in vivo DDI study with itraconazole. An fmCYP3A of 67% was obtained based on this approach. An fmCYP3A of 74% was estimated based on the human ADME study. In both approaches, the rest of clearance was assigned to biliary clearance. Sensitivity analysis was conducted for fmCYP3A in the range of 55% to 85%.




The Applicant’s VX-445 PBPK model was able to describe the observed DDI effect of itraconazole on VX-445 PK. The predicted CmaxR and AUCR were 1.1 and 2.87, respectively, while the observed CmaxR and AUCR were 1.05 and 2.83, respectively (Table 6-3 of Report O318, Version 1.0). The predicted Cmax and AUCinf of VX-445 were in the range of 0.8 to 1.5 of the observed values following single dose administration of 20 mg VX-445 in the presence and absence of itraconazole (simulated by the reviewer using the submitted workspace).

Based on the fmCYP3A of 67%, the Applicant simulated the effects of moderate CYP3A inhibitors, fluconazole (200 mg QD), erythromycin (500 mg QID), and verapamil (80 mg TID) on the PK of VX-445. The reviewer conducted additional simulations to evaluate the effects of fluconazole and verapamil at higher dose levels on the PK of VX-445. Overall, the simulated increase in AUCinf in the presence of a moderate CYP3A inhibitor was in the range of 1.88- to 2.5- fold (Table 95).

Table 95. Summary of Observed (Itraconazole) and Simulated Effects of Strong and Moderate CYP3A Inhibitors on the PK of VX-445

Dosage CmaxR AUCinfR VX-445, 20 mg SD + Itraconazole, 200 mg QD (observed) 1.05 2.83

VX-445, 20 mg SD + Itraconazole, 200 mg QD 1.10 2.87 VX-445, 20 mg SD + Fluconazole, 200 mg QD 1.07 1.88 VX-445, 20 mg SD + Fluconazole, 400 mg QD 1.08 2.31 VX-445, 20 mg SD + Erythromycin, 500 mg QID 1.08 2.33 VX-445, 20 mg SD + Verapamil, 80 mg TID 1.07 2.21 VX-445, 20 mg SD + Verapamil, 120 mg TID 1.08 2.50

Source: Tables 6-3 and 6-4 of Report O318, reviewer’s analysis using submitted models

Based on the observed and simulated effects of strong and moderate CYP3A inhibitors, the Applicant proposed to reduce the dose of VX-445 to twice per week when it is co-administered with a strong CYP3A inhibitor or once every 48 hours when it is co-administered with a moderate CYP3A inhibitor. As shown in Table 96, when VX-445 is co-administered with itraconazole, the predicted 7-day exposure was 91% of the predicted 7-day exposure following 200 mg QD without itraconazole. When VX-445 was co-administered with a moderate CYP3A inhibitor, the predicted 2-day exposure was 1.03 to 1.34- fold of the predicted 2-day exposure following 200 mg QD without an inhibitor. It should be noted that the dose adjustment for strong CYP3A inhibitors was based on itraconazole where a 2.8-fold increase in AUC was observed. And the dose was reduced from once daily to twice weekly, i.e. a 3.5-fold decrease. There are other strong CYP3A inhibitors may have lower inhibition potential than itraconazole. In those cases, the exposure to VX-445 could be even lower using the proposed dose adjustment regimen with a strong CYP3A inhibitor. Nevertheless, the drug may still be efficacious based on dose/exposure-response relationship (refer to Section 15.3.4, Pharmacokinetics Review).




Table 96. Summary of Observed and Simulated Mean Steady-State PK of VX-445 in the Presence and Absence of a CYP3A Inhibitor Following Proposed Dose Adjustment Regimens

Dosage Cmax, ss (µg/mL)

Cmin, ss (µg/mL)

7-day AUCss (µg*hr/mL)

2-day AUCss (µg*hr/mL)

VX-445, 200 mg QD, observed 9.13 4.64 1127 322 VX-445, 200 mg QD, predicted 8.49 4.80 1028 294 VX-445, 200 mg twice / week + Itraconazole, 200 mg QD 8.36 3.48 933 Not Calculated

VX-445, 200 mg once / 48 hours + Fluconazole, 200 mg QD 8.58 4.2 1080 300

VX-445, 200 mg once / 48 hours + Fluconazole, 400 mg QD 9.94 5.48 1303 366

VX-445, 200 mg once / 48 hours + Erythromycin, 500mg QID 9.62 5.55 1307 360

VX-445, 200 mg once / 48 hours + Verapamil, 80 mg TID 9.70 5.30 1282 353

VX-445, 200 mg once / 48 hours + Verapamil, 120 mg TID 10.57 6.17 1405 395

Source: Tables 9-1, 9-2, 9-3, and 9-4, reviewer’s analysis using submitted models

Conclusions The Applicant’s VX-445 PBPK model is adequate to evaluate the effects of moderate CYP3A inhibitors on the PK of VX-445. The model did not incorporate the active metabolite, M23-445. Therefore, the dose adjustment regimens were proposed based on the change in the parent drug only. The proposed dosing regimens for DDI scenarios with strong and moderate CYP3A inhibitors were consistent with those for tezacaftor/ivacaftor tablets.

15.3.3. In Vitro Data To Meet Combination Guidance Criteria

The proposed drug is a combination of the investigational drug ELX with previously approved drugs IVA and TEZ. IVA is effective on some CFTR variants where sufficient mature protein is expressed at the cell surface. The drug acts directly on channel function to increase the channel open probability. TEZ acts as a molecular chaperone to increase the fraction of mature CFTR protein on the cell surface. ELX also acts as a molecular chaperone but binds to a different site on CFTR from TEZ. The F508del variant results in multiple defects in how the CFTR protein functions. Western blot data show that only around 10% of the wild type amount of mature protein is found on patient-derived HBE cells. In addition, single channel electrophysiology data show that the rare F508del CFTR channels found on the cell surface are mostly in the closed state. The combination of IVA and TEZ is approved for treatment of homozygous F508del and “residual function” patients but the clinical effectiveness leaves room for improvement. The addition of ELX as a second molecular chaperone is proposed to increase the clinical response over the IVA/TEZ formulation.




The FDA has a guidance on the codevelopment of two or more drugs for use in combination.11 This guidance includes three specific criteria that should be met. Criteria #1: “Sponsors should develop evidence to support the biological rationale for the combination in an in vivo (preferable) or in vitro model relevant to the human disease or condition the product is intended to treat.” Disease-causing gene variants have a variety of consequences. In a subset of variants, a full-length protein is made but is not stable enough to survive QC checks in the endoplasmic reticulum and so little CFTR protein is found on the cell surface. WB technology is a well-established method to measure the relative amount of immature protein (B-band) or mature protein (C-band). This method was used in the evaluation of IVA alone and in the evaluation of the IVA/TEZ combination. This method is reported as the fraction of mature protein of total CFTR protein. In healthy controls the value is around 0.88 compared to around 0.10 in untreated homozygous F508del patients. This method should report changes in response to TEZ, ELX, or both. The functional measurement of chloride channel activity is done using electrophysiology methods. The Ussing chamber measures the aggregate current across a monolayer of cells expressing the ion channel of interest. Data from the Ussing chamber method was used to support the in vitro expansion of approval for IVA and for IVA/TEZ. Criteria #2: “The model should compare the activity of the combination to the activity of the individual drugs.” The Applicant evaluated the in vitro effect of each single drug, all dual combinations and the triple drug combination. Experiments were performed using WB methods to evaluate molecular chaperone activity. In addition, Ussing chamber electrophysiology experiments were performed to evaluate the effects on chloride channel currents for all single and combination conditions. All experiments were performed using HBE cells from CF donors. See below for details of the experiments. Criteria #3: “The model should demonstrate that the combination has substantial activity and provides greater activity, a more durable response (e.g., delayed resistance), and/or a better toxicity profile than the individual new investigational drugs.” The Applicant performed WB experiments to study the ability of drugs and drug combinations to increase the amount of mature CFTR protein in HBE cells from two donors. The WB data shows the effects of each individual drug, all dual combinations and the triple combination. The results presented were obtained using cells from two donors. One was an F508del/G542X heterozygote, and the other donor was homozygous F508del/F508del. The G542X variant

11 FDA Guidance for Industry: Codevelopment of two or more new investigational drug for use in combination. June 2013.




introduces a stop codon resulting in an inactive protein ~1/3 of full length. Each experiment was performed three times with six replicate wells per condition in each run.

Table 97. Applicant’s Western Blot Data from Report M379 for the Homozygous Donor

Raw densitometry data for the experiments from the homozygous donor were obtained and independently reanalyzed. The data for calculated mature fraction (C/C+B) are shown in the table below. The reanalyzed data agree with the Applicant’s results for mean (C/C+B) within rounding errors (Table 91).

Table 98. FDA Reanalysis of Effect of Drugs on the Mature Fraction of CFTR in HBE Cells from the F508del/F508del Donor

Treatment

Mature Fraction (C/C+B) Mean Std Dev Mean

Addition Mean /

Addition IVA loss % IVA loss

DMSO 0.108 0.033 1 µM IVA 0.091 0.027 18 µM TEZ 0.308 0.088 2 µM VX445 0.410 0.089 TEZ + IVA 0.236 0.083 0.400 59% -0.072 -23.4% VX445 + IVA 0.390 0.083 0.502 78% -0.020 -4.8% VX445 + TEZ 0.699 0.064 0.719 97% VX445+TEZ+IVA 0.664 0.065 0.810 82% -0.035 -5.0% WT CFTR* 0.882 0.029 IVA effect: -0.042 -11.1%

*Data from TEZ/IVA NDA. Main experiment data from 3 experiments with 6 technical replicates per experiment. Mean Addition is the sum of the mature fraction for each single drug. Mean/Addition is the observed combination mean/Mean Addition and expressed as a percent. Two primary conclusions can be drawn from Table 92. First that ELX and TEZ combine in an apparently additive fashion. Based on its mechanism of action, IVA is not expected to have any significant effect on mature fraction of CFTR. The second conclusion is that IVA has a small but




consistently negative effect on mature fraction. This IVA effect is a known issue with the drug and has been mechanistically explored in two publications.12,13 Results from the experiment with HBE cells from an F508del/G542X donor produced results similar to those above. Again, the combination of TEZ and ELX was additive showing independence of functional effect.

Table 99. FDA Reanalysis of Effect of Drugs on the Mature Fraction of CFTR in HBE Cells From the F508del/G542X Donor

Treatment

Mature Fraction (C/C+B) Mean Std Dev Mean

Addition Mean /

Addition IVA loss % IVA loss

DMSO 0.168 0.075 1 µM IVA 0.168 0.077 18 µM TEZ 0.327 0.026 2 µM VX445 0.428 0.039 TEZ + IVA 0.234 0.032 0.495 47% -0.093 -28.4% VX445 + IVA 0.412 0.036 0.596 69% -0.016 -3.7% VX445 + TEZ 0.699 0.047 0.755 93% VX445+TEZ+IVA 0.679 0.037 0.923 74% -0.020 -2.9% WT CFTR* 0.882 0.029 IVA effect: -0.043 -11.7%

The Applicant used well established WB technology to measure the effect of all three drugs alone, in all possible dual combinations and in the full triple combination. The molecular chaperones TEZ and ELX showed approximately additive effects on the mature fraction of CFTR on donor HBE cells.

Ussing chamber recordings of chloride transport FDA requested original electrophysiology recordings of chloride transport measured from HBE cells of F508del/F508del and F508del/MF donors for independent analysis to understand the effect of ELX by itself and in combination with TEZ and/or IVA. The Applicant submitted a total of 92 files, each containing experiments conducted using a 96-well platform instrument. The data were generated using cultured HBE cells from 3 F508del/F508del and 4 F508del/MF donors. Method. HBE cells were incubated with ELX either alone or in combination with either 18 µM TEZ and/or 1 µM IVA on the basal lateral side of the cells for 18-24 hours at 37°C. Following drug incubation, Ussing chamber electrophysiology was used to measure potency and efficacy

12 Meng X, Wang Y, Wang X, Wrennall JA, Rimington TL, Li H, Cai Z, Ford RC, Sheppard DN. (2017) Two small molecules restore stability to a subpopulation of the cystic fibrosis transmembrane conductance regulator with the predominant disease-causing mutation. J Biol Chem 292, 3706-3719. DOI: 10.1074/jbc.M116.751537. 13 Veit G, Avramescu RG, Perdomo D, Phuan PW, Bagdany M, Apaja PM, Borot F, Szollosi D, Wu YS, Finkbeiner WE, Hagedus T, Verkman AS, Lukacs GL. (2014) Some gating potentiators including VX-770, diminish ΔF58-CFTR functional expression. Sci Transl Med 6, 246ra97. DOI: 10.1126/scitranslmed.3008889.




of ELX either alone or in combination with 18 µM TEZ and/or 1 µM IVA. During recording, concentrations of ELX, TEZ, and IVA were all added back to the basal lateral side of the membrane. Ion secretion by HBE cells were then recorded under voltage clamp mode at -68 mV as the short circuit current. Once a stable baseline short circuit current was established, 20 µM forskolin was added to the apical surface of the cells to activate CFTR. Following stabilization of forskolin-activated current, an inhibitor cocktail of BPO, GlyH-101, and CFTR inhibitor 172 (each at 20 µM) was added to block all CFTR-mediated current. For each 96-well experiment, the Applicant tested all drug combinations plus controls, presumably generated from subjects without CF. Figure 28 below shows FDA’s analysis.

Figure 28. Concentration-Response Graphs in F508del/F508del and F508del/MF HBE Cells Treated With ELX, TEX, and/or IVA. Data Shown as Mean ± Sem, and Handled Using Naïve Pooling Approach Without Accounting for Donor or Recording Plate Differences

Results. The results showed that ELX concentration-dependently enhances chloride transport in F508del/F508del-HBE and F508del/MF-HBE cells, and that this effect is larger than that achieved by TEZ alone, IVA alone, and TEZ+IVA combined (see chloride transport without ELX above). Note that the numerical values for drug effects shown in Figure A differed quantitatively from the submitted non-clinical study report M387. In reviewing the submitted raw data, the FDA scientist discovered a number of wells in the 96-well platform exhibited problematic recordings, likely due to compromised membrane integrity to start with or sudden change during the recording process, systematic drift in the short circuit current, edge effect (i.e., same drug(s) tested on the membranes at the edges of the 96 wells exhibiting smaller




effects in comparison with the same drugs tested on the membranes at the center of the plate), and atypical augmentation in response to forskolin. In FDA’s analysis, recording wells that contained compromised membranes were excluded based on reviewer’s criteria. For future submissions, the Applicant is requested to clarify whether all wells in all plates were used for data analysis, or whether some data quality criteria were applied. Concentration-response graphs shown in Figure 28 were fit with the standard Hill equation without constraints to estimate EC50 (potency) and minimal or base and maximal chloride transport (the latter used to infer efficacy). These results are shown in Table 100 below, demonstrating that ELX+IVA+TEZ combination treatment is more potent and efficacious than effects due to TEZ alone, IVA alone, and TEZ+IVA combined. Again, FDA’s analysis differed numerically from Applicant’s values in M387. In the future, the Applicant is requested to clarify data analysis plan in the non-clinical study reports to document how data were handled/pooled (i.e., whether and how donor and plate differences were accounted for) and the formula used to fit the concentration-response graphs. The Applicant’s cooperation on these requests would help to expedite FDA review process.

Table 100. Potency (EC50) and Efficacy (Maximal Chloride Transport Derived From Fitting Concentration Response Graphs) of ELX Alone and in Combination with TEZ and/or IVA

Drugs

EC50 (µM) Base chloride transport (µA/cm2)

Max chloride transport (µA/cm2)

FF

ELX only 1.66 ± 0.40 7.9 ± 0.5 29.2 ± 1.5 ELX + 18 µM TEZ 0.46 ± 0.14 16.4 ± 1.5 48.1 ± 2.3 ELX + 1 µM IVA 0.54 ± 0.18 13.7 ± 2.7 69.4 ± 4.6 ELX + 18 µM TEZ+ 1 µM IVA 0.09 ± 0.04 25.4 ± 5.8 81.0 ± 3.8

FmF

ELX only 4.31 ± 1.38 6.0 ± 0.2 21.1 ± 1.4 ELX + 18 µM TEZ 1.42 ± 0.42 9.7 ± 0.7 37.5 ± 2.1 ELX + 1 µM IVA 1.18 ± 0.43 9.9 ± 1.5 52.7 ± 4.3 ELX + 18 µM TEZ+ 1 µM IVA 0.27 ± 0.09 17.0 ± 2.8 61.2 ± 3.3

Conclusions The Applicant designed and executed in vitro assays to evaluate the effect of each drug alone, all double combinations and the triple combination. The WB assays demonstrate an additive effect for the combination of TEZ and ELX on CFTR mature fraction. IVA had a small and consistently negative but not statistically significant effect on CFTR mature fraction. The Ussing chamber electrophysiology experiments showed that ELX concentration-dependently enhances chloride transport in F508del/F508del-HBE and F508del/MF-HBE cells, and that this effect is larger than that achieved by TEZ alone, IVA alone, and TEZ+IVA combined. Further, ELX+IVA+TEZ combination treatment is more potent and efficacious than effects due to TEZ alone, IVA alone, and TEZ+IVA combined. Overall, the Applicant performed in vitro WB experiments and Ussing chamber electrophysiology experiments using single drugs, all possible pairwise combinations as well as the full triple combination.




15.3.4. Pharmacometrics Review

Population Pharmacokinetics/Pharmacodynamics (PK/PD) analysis I

Introduction Population PK/PD analysis of ELX uses pooled data from one Phase 1/2 and two Phase 3 trials in patients with cystic fibrosis (CF).

The main objectives of this analysis were the following: 1. To characterize the pharmacokinetic disposition of ELX and summarize the predicted

AUC, Cmax, and Tmax at the Phase 3 dose of 200 mg qd;

2. To evaluate the efficacy of ELX/TEZ/IVA combination therapy with regard to ppFEV1 and summarize the predicted ppFEV1 at the Phase 2 doses;

3. To evaluate the efficacy of ELX/TEZ/IVA combination therapy with regard to SwCl and summarize the predicted SwCl at the Phase 2 doses; and

4. To characterize the impact of ELX on TEZ and IVA PK considering ELX is a weak CYP3A inducer, and summarize the predicted AUCs in CF patients when administered with ELX 200 mg qd.

Model development

Data The study design, study population, and PK/PD measures varied among the 3 clinical trials. Brief descriptions of the studies included are presented in Table 101.

The data file for ELX and M23-455 population PK model contained 2794 ELX concentrations from 167 subjects and 1609 M23-445 concentrations, a major metabolite, from 112 subjects. In addition, for updating the TEZ and the IVA population PK models, the data file included 1851 TEZ concentrations from 119 subjects and 1591 IVA concentrations from 98 subjects.

CF subjects from Parts D and E of Study 001 were included in population exposure-response modeling. In addition, Phase 3 data from Studies 661-106 (F/F) and 661-107 (F/MF) were included in these analyses to anchor the ELX exposure-response analyses in the presence of TEZ/IVA. Table 102 provides summary statistics of the baseline demographic covariates in the analysis dataset.

Table 101. Studies Included in Population PK/PD Analysis Study Design PK measures PD measures Phase 1/2 first-in-human and proof-of-concept study 001

Parts A, B, and C were conducted in healthy subjects. Parts D, E, and F were conducted in CF subjects. For the CF cohorts, subjects received ELX qd and TEZ qd/IVA q12h or placebo in Parts D and E. Subjects received ELX qd and TEZ qd/VX-561 qd in Part F. Parts D and F enrolled CF subjects with

plasma concentrations of ELX, M23-445, TEZ, and IVA

ppFEV1 and SwCl




Study Design PK measures PD measures F/MF genotypes and Part E enrolled CF subjects with F/F genotype. ELX formulation was administered (tablet or IV) in each cohort.

Phase 3 661-107 CF subjects with F/MF were randomized to receive TEZ 100 mg qd + IVA 150 mg q12h or matched placebo.

plasma concentrations of TEZ, and IVA

ppFEV1 and SwCl

Phase 3 661-106 CF subjects with F/F were randomized to receive TEZ 100 mg qd + IVA 150 mg q12h or matched placebo.

plasma concentrations of TEZ, and IVA

ppFEV1 and SwCl

Source: PM reviewer

Table 102. Baseline Demographic Covariates for PK/PD Analysis for ppFEV1 (Upper) and SwCI (Lower)




Table 97 (continued). Baseline Demographic Covariates for PK/PD Analysis for ppFEV1 (Upper) and SwCI (Lower)

Source: Applicant’s Population PKPD report o166, Table 7-4 & 7-5

Elexacaftor population PK model A one-compartment model was chosen. Absorption was modeled using two simultaneous processes: (1) a zero-order delivery to the absorption compartment followed by first-order absorption and (2) a zero-order delivery to the central compartment. All model parameters were log transformed. Inter-individual variability (IIV) was incorporated on clearance, central volume, the infusion duration to the depot compartment (D1), and the fraction of dose directly entering the central compartment (FS). FS was constrained to lie between zero and one. Sex and race were observed to potentially have effects on clearance, whereas renal function (as determined by EGFR), AST, age, and weight had minor effects on clearance. Weight and sex exhibited effects on central volume, although the sex effect is likely mediated by differences in weight. Adding an effect of female sex on CL resulted in a modest objective function improvement, as did blocking the OMEGA matrix to account for correlation between D1 and FS. The ELX PK model was evaluated via visual and numerical predictive checks.

M23-445 population PK model The metabolite data were fit sequentially using the empirical Bayes estimates from the ELX parent models. A two-compartment model was selected. The model included time-dependence of clearance (CL), the effect of weight on the central and peripheral volumes, and the effect of sex on central volume to improve model fits. A correlation between the IIV for CL and V was estimated via including a block OMEGA matrix. The final model was further evaluated by visual inspection of diagnostic plots.

Tezacaftor population PK model in the presence of ELX The previously developed TEZ population pharmacokinetic model (Report N279) was used to investigate the effect of the TEZ exposure in the presence of ELX. The prior TEZ model is




consistent with the CF PK data from Study 001, suggesting that ELX has a minimal impact on TEZ PK in CF subjects. Comparison of TEZ exposure in the presence or absence of ELX from the F/F triple combination cohort was further explored.

Ivacaftor population PK model in the presence of elexacaftor The previously developed IVA population pharmacokinetic model (Report N279) was used to investigate the effect of the IVA exposure in the presence of ELX. The prior IVA model is consistent with the steady-state PK data from Study 001, suggesting that ELX has a minimal impact on IVA PK at steady-state. Comparison of IVA exposure in the presence or absence of ELX from the F/F triple combination cohort was further explored.

PK/PD model

The model evaluation results demonstrated that the ELX population PK model provided a reasonable description of the data. CF subject data were included from Parts D and E of Study 001 for exposure-response modeling. Phase 3 data from Studies 661-106 (F/F) and 661-107 (F/MF) were included in these analyses to anchor the ELX exposure-response analyses in the presence of TEZ/IVA. An indirect response with an Emax model parameterized in terms of baseline ppFEV1, maximal increase in ppFEV1 (Emax), and ELX concentration required to achieve 50% of Emax (EC50) was used to describe the relationships between ELX exposure (Caveg) and ppFEV1/SwCI for each genotype (F/MF and F/F). Cavg was selected as the PK exposure metric.

Simulations were conducted using parameters obtained from the bootstrap analysis of the exposure-response model for ppFEV1 and SwCl, respectively, to explore the dose-response relationship for the ppFEV1 response at week 4 and the SwCI at the ELX doses of 50 mg, 100 mg, and 200 mg qd.

Results Elexacaftor population PK model

The PK final model parameter estimates for healthy subjects and CF subjects are shown in Table 103.




Table 103. Elexacaftor Population Pharmacokinetic Final Model Parameter Estimates for Healthy Subjects (Left) and CF Subjects (Right)

Source: Applicant’s Population PKPD report o166, Table 7-7

The model evaluation results demonstrated that the ELX population PK model provided a reasonable description of the data.

M23-445 population PK model The model provided an adequate description of the M23-445 concentration data, as judged by visual inspection of diagnostic plots.

Tezacaftor population PK model in the presence of elexacaftor The prior TEZ model is consistent with the CF PK data from Study 001, suggesting that ELX has a minimal impact on TEZ PK in CF subjects. As shown in Figure 29, the comparison of TEZ exposure in the presence or absence of ELX from the F/F triple combination cohort further supports that ELX has minimal impact on steady-state TEZ exposures in CF subjects.




Figure 29. Comparison of TEZ Exposure in the Presence or Absence of ELX From the F/F Triple Combination Cohort

Source: Applicant’s Population PKPD report o166, Figure 7-19

Ivacaftor population PK model in the presence of elexacaftor The prior IVA model is consistent with the steady-state PK data from Study 001, suggesting that ELX has a minimal impact on IVA PK at steady state. As shown in Figure 30, the comparison of IVA exposure in the presence or absence of ELX from the F/F triple combination cohort further supports that ELX has minimal impact on steady-state IVA exposures in CF subjects.




Figure 30. Comparison of IVA Exposure in the Presence or Absence of ELX from the F/F Triple Combination Cohort.


PK/PD model One thousand trials of 3,000 patients per trial were simulated across different ELX doses. The mean dose-response relationship for each trial was determined, and then the median and 95% confidence interval was calculated. Uncertainty in the PK/PD model parameters was incorporated by simulating the trials using parameters obtained from the bootstrap analysis of the exposure-response model for ppFEV1 and SwCl, respectively. PK parameters were simulated from the final ELX PK model using patient demographics sampled from the Phase 3 Study 661-107.

The dose-response simulations for ppFEV1 and SwCI are shown in Figure 31 and Figure 32.




Figure 31. Dose-Response Simulations for ppFEV1


Figure 32. Dose-Response Simulations for Sweat Chloride





Population PK analysis II (Model Update)

Introduction

This population PK analysis is to evaluate the ELX population PK developed previously (Report 0166) using Phase 3 data (VX17-445-102 and VX17-445-103). The objectives of this analysis were:

• To evaluate the ELX population PK developed previously (Report O166) using Phase 3 data (VX17-445-102 and VX17-445-103);

• To summarize the PK exposures of VX-445 and its major metabolite M23-445 (AUC0-24h, Cmax, Cmin, Cavg, and effective half-life) by study; and

• To evaluate the following covariate effects for the parent compound (ELX) and its major metabolite (M23-445) on their respective AUC0-24h and Cmax: age, weight, sex, race, and renal impairment stages.

Analyses

Data Brief descriptions of the studies (VX17-445-102 and VX17-445-103) are presented in Table 104.

Table 104. Studies Included in Population PK Analysis Study Design PK measures PD measures Phase 3 445-102 CF subjects with F/MF were randomized to

receive two fixed-dose combination (FDC) film-coated tablets (100mg ELX/50mg TEZ/75mg IVA) in the morning and one film-coated IVA tablet in the evening (N=180) or matched placebo (N=180).

plasma concentrations of ELX, and M23-445 pre-dose on Day 1, Week 4, Week 8, Week 12, and Week 16.

ppFEV1 and SwCl

Phase 3 445-103 CF subjects with F/F were randomized to receive two fixed-dose combination (FDC) film-coated tablets (100mg ELX/50mg TEZ/75mg IVA) in the morning and one film-coated IVA tablet in the evening (N=50) or matched placebo +TEZ/IVA (N=50).

plasma concentrations of ELX, and M23-445 pre-dose on Day 1, Week 4.

ppFEV1 and SwCl

Source: PM reviewer

Method The previously developed ELX and M23-445 population PK models were evaluated with the Phase 3 data. Then these models were used to obtain the post-hoc model parameters (empirical Bayes estimates) for all subjects from the Phase 3 studies (VX17-445-102 and VX17-445-103). The effects of covariates including age, weight, sex, race and renal impairment based on eGFR on the PK for the parent compound (ELX) and its active metabolite (M23-445) were evaluated using simulations of ELX and M23-445 Week 4 PK exposure metrics calculated from the empirical Bayes estimates. Graphical evaluation of liver enzyme levels (AST and ALT) on the PK for ELX and M23-445 were also conducted.




Results The previously developed ELX and M23-445 population PK models (Report O166) adequately predicted both the central tendency of the Phase 3 data (102 and 103) based on the model diagnostics and the prediction-corrected visual predictive check (pcVPC). In addition, the Week 4 ELX and M23-445 predicted exposures from the Phase 3 CF subjects were consistent with those from the Phase 1/2 CF subjects. The PK parameters Cmax (mcg/mL) and AUC0_24h (mcg·h/mL) for ELX are 8.66 (2.05) and 162 (48.1) respectively. None of the selected covariates affected the ELX or M23-445 exposures to a clinically relevant extent. Exploratory analyses of the PK-PD data for SwCl and ppFEV1 indicated that the clinical dose of 200 mg qd ELX resulted in the plateau region of the selected exposure-response relationship. Based on population PK analysis, exposure of ELX and its metabolite was similar in patients with mild renal impairment (N=35, eGFR 60 to less than 90 mL/min/1.73 m2) relative to patients with normal renal function (N=214, eGFR 90 mL/min/1.73 m2 or greater) with median AUC0_24 at 164 and 156 μg*hr/mL respectively. In CF subjects with moderate renal impairment, the median AUC0_24 was 197 μg*hr/mL (N=2, eGFR 30-59 mL/min/1.73m2). Graphical evaluation of liver enzyme levels (AST and ALT) on the PK for ELX and M23-445 did not show any trend (data not shown). Following oral administration of ELX/TEZ/IVA to patients 12 to less than 18 years of age in trials 445-102 and 445-103, the mean (±SD) AUCss was 149 (38.7) mcg·h/mL for ELX, similar to the AUCss in adult patients. Overall, none of the effects on exposure for the covariates: age, weight, sex, and mild renal impairment were determined to be clinically significant for either ELX or M23-445. Exposure of ELX and M23-445 was similar in adolescents relative to adults with CF.

Population PK analysis III (Tezacaftor and Ivacaftor Models Update)

Introduction This population PK analysis is to evaluate population PK of TEZ and IVA in the presence of ELX in Phase 3 Studies VX17-445-102 and VX17-445-103 (refer to report p044). The objectives of this analysis were:

• To characterize the population pharmacokinetic (PK) of TEZ, tezacaftor metabolite 1 (M1-TEZ), and IVA in adolescent and adult cystic fibrosis (CF) subjects receiving the triple combination of ELX/TEZ/IVA.

• To estimate Bayesian-predicted steady-state exposures of TEZ, M1-TEZ, and IVA in individual patients when dosed in combination with ELX.




Analyses

Data

Population PK data sets for TEZ, M1-TEZ, and IVA were developed from pooled data across two phase 3 studies (VX17-445-102 and VX17-445-103) and one phase 1/2 study (VX16-445-001). The TEZ and M1-TEZ population PK data sets were comprised of 409 CF subjects contributing a total of 2648 TEZ observations and 2643 M1-TEZ observations for model estimation. The IVA population PK data set was comprised of 388 CF subjects contributing a total of 2385 IVA observations for model estimation.

Method

Modeling for all 3 analytes (TEZ, M1-TEZ and IVA) was conducted using previously developed Population PK models described in the Vertex Report O350 and addendum. Two stages of model fitting were performed for each model: 1) The adequacy of the previous models to predict the phase 3 data was evaluated using MAXEVAL=0 in NONMEM and; 2) Obtain population PK models for all analytes through re-estimation of the full dataset.

Individual steady-state exposures of TEZ, M1-TEZ, and IVA were simulated using the empirical Bayes estimates (EBEs) to characterize the TEZ, M1-TEZ, and IVA PK in the presence of ELX.

Results

Model assessment resulted in the same conclusion for TEZ, M1-TEZ, and IVA; the selected final model provided an adequate description of the data for the intended purpose of the model to perform individual simulations. The results are consistent with the prior finding with phase 1/2 data only. The PK parameters Cmax (mcg/mL) and AUC0_24h (mcg·h/mL) for TEZ are 6.77 (1.47) and 94.5 (24.0), respectively; the PK parameters Cmax (mcg/mL) and AUC0_24h (mcg·h/mL) for IVA are 1.24 (0.34) and 11.7 (4.01), respectively.

Following oral administration of ELX/TEZ/IVA to patients 12 to less than 18 years of age in trials 445-102 and 445-103, the mean (±SD) AUCss was 96.0 (23.4) mcg·h/mL and 10.6 (3.35) mcg·h/mL, respectively, for TEZ and IVA, similar to the AUCss in adult patients.

15.4. Clinical Appendix

15.4.1. Supportive Tables, Trial 102

Table 105. Trial 102, Study Assessments: Treatment Period and Safety Follow-up Visit

Event/Assessmenta

Day

1

Day 15

(± 3 Days)

Week

4 (± 5

Days)

Week

8 (± 5

Days)

Week

12 (± 5

Days)

Week

16 (± 5

Days)

Week

20 (± 5

Days)

Week

24 (± 5

Days)

ETT

Visitb

Safety F/U Visit 28 (± 7) Days After the Last Dose of Study

Drug (If

Applicable)c

Clinic visit X X X X X X X X X Telephone contact X d I&E Criteria X CFQ-R e X X X X X X X X TSQM e X X X




Event/Assessmenta

Day

1

Day 15

(± 3 Days)

Week

4 (± 5

Days)

Week

8 (± 5

Days)

Week

12 (± 5

Days)

Week

16 (± 5

Days)

Week

20 (± 5

Days)

Week

24 (± 5

Days)

ETT

Visitb

Safety F/U Visit 28 (± 7) Days After the Last Dose of Study

Drug (If

Applicable)c

Weight and height f X X X X X X X X X OE X g X g Complete PEh x x X x Pregnancy testingi Urine Urine Urine Urine Urine Urine Urinej Urine Urine Urine ECGl, VS, Pulse oximetrym, Spirometryn X X X X X X X X X

Sweat chlorideo X X X X X X Urinalysis X X X X Hematology, serum chemistry X p X X X X X X X X Coagulation X p X X X PK samplingq X X X X X X DNA sample (optional) X Blood sample for RNA X X X Blood biomarker, Sputum, Inflammatory mediator samplesr

X X

Medical historys X

Randomizationt X

Study drug dosingu Day 1 through evening before Week 24

Study drug count X X X X X X X X

Other events related to

outcomev

Continuous from signing of ICF through completion of study participation

Medications, treatments, procedures review

Continuous from signing of ICF through completion of study participation

AEs and SAEsw Continuous from signing of ICF through completion of study participation

a. All assessments will be performed before dosing unless noted otherwise. b. If the subject prematurely discontinues study treatment, an ETT Visit should be scheduled as soon as possible after the

decision to discontinue treatment. Subjects who prematurely discontinue treatment will continue to complete all scheduled study visits for assessments following completion of the ETT Visit

c. The Safety Follow-Up Visit required for all subjects, unless the subject completes the Week 24 Visit and has enrolled in a separate open-label study within 28 days after the last dose of study drug. If an ETT Visit occurs 3 weeks or later following the last dose of study drug, then the ETT Visit replaces the Safety Follow-up Visit.

d. Telephone contact will be made to assess the subject’s status, any AEs, concomitant medications, treatments, and procedures.

e. The CFQ-R, followed by the TSQM (only subjects aged ≥12 years to <18 years at the date of informed consent will complete the TSQM), must be completed before any other assessments scheduled at relevant visits.

f. Weight and height will be measured with shoes off. Following screening, height will be collected only for subjects ≤21 years of age on the date of informed consent.

g. Subjects who are <18 years of age on the date of informed consent and who have completed at least 12 weeks of study drug treatment will have a single ophthalmologic examination conducted by a licensed ophthalmologist or optometrist at completion of study participation, except for those subjects who have withdrawn consent or assent. This examination should be completed within 4 weeks before the Week 24 Visit, unless the subject prematurely discontinues study drug, in which case this examination should occur by the Safety Follow-up Visit (or ETT Visit for subjects who do not complete a Safety Follow-up Visit).

h. Subjects will have a complete physical examination. Symptom-directed physical examinations will occur at any time during the study if deemed necessary by the investigator.




i. Any female subject who does not meet the criteria for non-childbearing potential is considered to be of childbearing potential and must have pregnancy tests at the indicated time points.

j. At Week 20, when there is no clinic visit, a urine pregnancy test will be performed with a home kit provided by the study site. Results will be reported to the site by telephone.

k. Blood samples for FSH will be measured as needed. l. All standard 12-lead ECGs will be performed after the subject has been at rest for at least 5 minutes. ECGs will be collected

before dosing (as applicable). Additionally, at the Day 15 Visit, postdose ECG assessments will be performed at 2 hours and 4 hours after the morning dose of study drug.

m. Vital signs and pulse oximetry will be collected before dosing and after the subject has been at rest for at least 5 minutes. n. Spirometry assessments must be performed before study drug dosing and should be performed pre-bronchodilator at

approximately the same time at each visit. o. SwCl collection before study drug dosing. At each time point, 2 samples will be collected, 1 from each arm (left and right). p. Blood samples will be collected before the first dose of study drug. q. PK samples will be collected predose on Day 1, Week 4, Week 8, Week 12, and Week 16. A PK sample will be collected at 2

hours after the morning clinic dose on Day 1. Approximately 40 subjects enrolled in the study will have 4 postdose samples taken at 2, 4, 6, and 8 hours after the morning clinic dose at Week 4. All remaining subjects will have 1 postdose sample taken at 1 hour after the morning clinic dose at Week 4. Vertex will manage the allocation of the 40 subjects providing more intensive PK sampling across study sites. If study drug is not administered at the Week 4 Visit (i.e., due to study drug interruption or permanent discontinuation), a single PK blood sample will be collected at the visit. At the ETT Visit, a single PK blood sample will be collected.

r. Sputum will be collected from subjects who can produce a sample spontaneously. The sputum sample will be processed for microbiology analysis and sputum biomarkers.

s. Data on hospitalizations and intravenous antibiotic therapies administered during the 12 months prior to the signing of the ICF will be collected.

t. Randomization may occur on either Day -1 or Day 1, after all eligibility criteria are confirmed. u. The final dose of study drug will be administered the evening before the Week 24 Visit. v. Other events related to outcome include assessments relating to PEx, administration of antibiotic therapy for

sinopulmonary signs/symptoms, and hospitalizations for CF w. SAEs that occur after completion of study participation and are considered related to study drug will be reported to Vertex

GPS within 24 hours.




Table 106. Eligible CFTR Mutations, Trial 102 MF Mutation Category Mutation

Nonsense mutations Q2X S4X W19X G27X Q39X W57X E60X R75X L88X E92X Q98X Y122X E193X W216X

L218X Q220X Y275X C276X Q290X G330X W401X Q414X S434X S466X S489X Q493X W496X C524X

Q525X G542X G550X Q552X R553X E585X G673X Q685X R709X K710X Q715X L732X R764X R785X

R792X E822X W882X W846X Y849X R851X Q890X S912X Y913X Q1042X W1089X Y1092X W1098X R1102X

E1104X W1145X R1158X R1162X S1196X W1204X L1254X S1255X W1282X Q1313X Q1330X E1371X Q1382X Q1411X

Canonical splice mutations 185+1G→T 296+1G→A 296+1G→T 405+1G→A 405+3A→C 406-1G→A 621+1G→T 711+1G→T

711+5G→A 712-1G→T 1248+1G→A 1249-1G→A 1341+1G→A 1525-2A→G 1525-1G→A

1717-8G→A 1717-1G→A 1811+1G→C 1811+1.6kbA→G 1811+1643G→T 1812-1G→A 1898+1G→A 1898+1G→C

2622+1G→A 2790-1G→C 3040G→C

(G970R) 3120G→A 3120+1G→A 3121-2A→G

3121-1G→A 3500-2A→G 3600+2insT 3850-1G→A 4005+1G→A 4374+1G→T

Small (≤3 nucleotide) insertion/deletion (ins/del) frameshift mutations

182delT 306insA 306delTAGA 365-366insT 394delTT 442delA 444delA 457TAT→G 541delC 574delA 663delT 849delG 935delA

1078delT 1119delA 1138insG 1154insTC 1161delC 1213delT 1259insA 1288insTA 1343delG 1471delA 1497delGG 1548delG 1609del CA

1677delTA 1782delA 1824delA 1833delT 2043delG 2143delT 2183AA→Ga 2184delA 2184insA 2307insA 2347delG 2585delT 2594delGT

2711delT 2732insA 2869insG 2896insAG 2942insT 2957delT 3007delG 3028delA 3171delC 3171insC 3271delGG 3349insT 3659delC

3737delA 3791delC 3821delT 3876delA 3878delG 3905insT 4016insT 4021dupT 4022insT 4040delA 4279insA 4326delTC

Non-small (>3 nucleotide) insertion/deletion (ins/del) frameshift mutations

CFTRdele1 CFTRdele2 CFTRdele2,3 CFTRdele2-4 CFTRdele3-10,14b-16 CFTRdele4-7 CFTRdele4-11 CFTR50kbdel CFTRdup6b-10 CFTRdele11 CFTRdele13,14a CFTRdele14b-17b

CFTRdele16-17b CFTRdele17a,17b CFTRdele17a-18 CFTRdele19 CFTRdele19-21 CFTRdele21 CFTRdele22-24 CFTRdele22,23 124del23bp 602del14 852del22 991del5

1461ins4 1924del7 2055del9→A 2105-2117del13insAGAAA 2372del8 2721del11 2991del32 3121-977_3499+248del2515 3667ins4 4010del4 4209TGTT→AA

Missense mutations that • Are not responsive in vitro to TEZ, IVA, or TEZ/IVA and • % pancreatic insufficient >50% and SwCl- >86 mmol/L

A46Db G85E R347P L467Pb I507del N1303K

V520F A559Tb R560T R560S A561E

Y569Db L1065P R1066C L1077Pb M1101K

CFTR: cystic fibrosis transmembrane conductance regulator; IVA: ivacaftor; SwCl: sweat chloride; TEZ: tezacaftor Source: Appendix A Protocol VX17-445-102, Version 3.0.




Applicant Citation: obtained from CFTR2.org [Internet]. Baltimore (MD): Clinical and functional translation of CFTR. The Clinical and Functional Translation of CFTR (CFTR2), US Cystic Fibrosis Foundation, Johns Hopkins University, the Hospital for Sick Children. Available at: http://www.cftr2.org/. Accessed 15 February 2016. Applicant Notes: % pancreatic insufficient: percentage of F508del-CFTR heterozygous patients in the CFTR2 patient registry who are pancreatic insufficient; SwCl: mean sweat chloride of F508del-CFTR heterozygous patients in the CFTR2 patient registry. a Also known as 2183delAA→G. b Unpublished data.

Table 107. Liver Function Test Values for Subject 102-

Study Day or Visit/ Reference Point

ALT (NR: 0 to

20 U/L)

AST (NR:

0 to 31 U/L)

ALP (NR: 50 to 162 U/L)

Total BILI (NR:

0 to 20.5 µmol/L)

Direct BILI (NR:

0 to 8.6 µmol/L)

Indirect BILI (NR:

0 to 12 µmol)

GGT (NR:

4 to 24 U/L)

Screening 36 (H) 48 (H) 344 (H) 18.4 6.3 12.1(H) 14

Day 1 (first dose) 33 (H) 46 (H) 415 (H) 22.4 (H) 8.9 (H) 13.5 (H) 14

Day 13 84 (H) 106 (H) 351 (H) 23.6 (H) 8.7 (H) 14.9 (H) 16

Day 16; unscheduled 63 (H) 60 (H) 332 (H) 24.5 (H) 9.3 (H) 15.2 (H) 16

Day 27 53 (H) 79 (H) 344 (H) 35.5 (H) 11.5 (H) 24 (H) 16

Day 55 45 (H) 59 (H) 381 (H) 30.6 (H) 11.5 (H) 19.1 (H) 15

Day 90 59 (H) 71 (H) 408 (H) 32.1 (H) 10.5 (H) 21.6 (H) 15

Day 111 59 (H) 65 (H) 398 (H) 35.6 (H) 12 (H) 23.6 (H) 15

Day 169 36 (H) 46 (H) 374 (H) 42.8 (H) 10.5 (H) 32.3 (H) 15 Source: CSR page 1124 ALT: alanine transaminase; ALP: alkaline phosphatase; AST: aspartate transaminase; BILI: bilirubin; GGT: gamma-glutamyl transferase; H: high; L: low; ND: not done; NR: normal range

Table 108. Liver Function Test Values for Subject 102-

Study Day or Visit/ Reference Point

ALT (NR: 0 to

55 U/L)

AST (NR: 5 to

34 U/L)

ALP (NR: 40 to 150 U/L)

Total BILI (NR:

0 to 20.5 µmol/L)

Direct BILI (NR:

0 to 8.6 µmol/L)

Indirect BILI (NR:

0 to 12 µmol)

GGT (NR: 12 to

64 U/L)

Screening 14 14 88 45.4 (H) 5.2 40.2 (H) 11 (L)

Day 1 (first dose) ND 14 93 ND ND ND 11 (L)

Day 18a 34 27 92 89.8 (H) 5.7 84.1 (H) 12

Day 22; unscheduled -- 32 90 -- -- -- 14

Day 35 26 23 95 52 (H) 5.8 46.2 (H) 12

Day 64 ND ND 107 ND ND ND 10 (L)

Day 68; unscheduled 17 17 96 46.5 (H) -- -- 10 (L)

Day 82 16 18 102 53.8 (H) 4.4 49.4 (H) 9 (L)

Day 120 ND ND 100 ND ND ND 10 (L)

Day 154b; unscheduled 16 18 93 26.8 (H) 10.8 (H) 16 (H) 10 (L)

Day 167 97(H) 118 (H) 104 61.2 (H) 5.4 55.8 (H) 11 (L) Source: CSR page 1127 ALT: alanine transaminase; ALP: alkaline phosphatase; AST: aspartate transaminase; BILI: bilirubin; GGT: gamma-glutamyl transferase; H: high; L: low; ND: not done; NR: normal range a Last on-treatment date before first interruption; study drug interruption began on 22 November 2018.


(b) (6)

(b) (6)



b Study drug was resumed on this day.

Table 109. Summary of Respiratory-related Adverse Events: Trial 102, Safety Set

Preferred Term

Placebo N=201 n (%)


Subjects reporting at least 1 respiratory-related AE 113 (56) 72 (36)

Cough1 87 (43) 40 (20)

Sputum increased 39 (19) 40 (20)

Hemoptysis 28 (14) 11 (5)

Dyspnea2 16 (8) 14 (7)

Pulmonary function decreased3 13 (6) 0

Wheezing4 8 (4) 7 (3)

Lower respiratory tract congestion 4 (2) 4 (2)

Pleuritic pain 2 (1) 1 (<1)

Pulmonary pain 1 (<1) 1 (<1)

Increased bronchial secretion 1 (<1) 1 (<1)

Hyperventilation 0 1 (<1)

Sputum discolored 4 (2) 0

Rales 3 (1) 0

Increased viscosity of bronchial secretion 2 (1) 0

Dyspnea exertional 1 (<1) 0

Pulmonary hemorrhage 1 (<1) 0

Respiratory-related severe (Grade 3) AE 1 (<1) 2 (1)

Respiratory-related SAE 4 (2) 2 (1)

Respiratory-related AE leading to treatment interruption 0 1 (<1)5

Respiratory-related AE leading to treatment discontinuation 0 0

AE: adverse event, SAE: serious adverse event, ELX: elexacaftor, TEZ: tezacaftor, IVA: ivacaftor, n: number of subjects in subset, N: total subjects in trial arm. Subjects counted once per preferred term category. 1 Includes PT: cough, productive cough 2 Includes PT: dyspnea, respiration abnormal, chest discomfort 3 Includes PT: pulmonary function test decreased, forced expiratory volume decreased 4 Includes PT: Asthma, wheezing, bronchospasm, bronchial hyperreactivity

5 Hemoptysis Source. Reviewer calculated in JMP 12.0 using ADAE dataset selecting subjects: AEHLT (Breathing abnormalities, Bronchospasm and obstruction, Coughing and associated symptoms, Lower Respiratory tract signs and symptoms, respiratory and pulmonary function diagnostic procedures), by USUBJID, TRT01A, AEDECOD, AESER, AEACN

15.4.2. Supportive Tables, Trial 103

Table 110. Study Assessments, Trial 103

Event/Assessmenta TEZ/IVA Run-in Period

(4 Weeks) Treatment Period (4 Weeks) ETT

Visitb Safety FU Visit 28 (± 7) Days After the Last Dose of Study

Drug (If Applicable)c

Day -28 ± 1 Day

Day -14 (Day -15

to Day -3)

Day 1d

Day 15

± 3 Days

Week 4 ± 5 Days

Clinic visit X X X X X X X




Event/Assessmenta TEZ/IVA Run-in Period

(4 Weeks) Treatment Period (4 Weeks) ETT

Visitb Safety FU Visit 28 (± 7) Days After the Last Dose of Study

Drug (If Applicable)c

Day -28 ± 1 Day

Day -14 (Day -15

to Day -3)

Day 1d

Day 15

± 3 Days

Week 4 ± 5 Days

Inclusion and exclusion criteria confirmation

X

CFQ-Re X X X X X

TSQMe X X X

Weight and heightf X X X X X X

Physical examinationg Abbreviated Complete Complete Complete

Pregnancy testingh Urine Urine Urine Serum Serum

Standard 12-lead ECGi X X X X X X

Vital signsj X X X X X X

Pulse oximetryj X X X X X X

Spirometryk X X X X X X

Sweat chloridel X X X X X

Urinalysis X X X X X

Hematology Xm Xm X X X X

Coagulation Xm Xm X X X

Serum chemistry Xm Xm X X X X

PK samplingn X X X

DNA sample (optional) X

Inflammatory mediator samples X X

Blood biomarker samples X X

Blood sample for RNA X X

Sputum sampleo X

Collection of prior hospitalizations and IV antibiotic therapiesp

X

Run-in TEZ/IVA dosingq Day -28 to evening on Day -1

Run-in TEZ/IVA drug count X X X

Randomizationr X

Randomized study drug dosings Day 1 through evening before the Week 4 Visit

Randomized study drug count X X X X

Other events related to outcomet Continuous from signing of ICF through completion of study participation

Medications review Continuous from signing of ICF through completion of study participation

Treatments and procedures review Continuous from signing of ICF through completion of study participation

AEs and SAEsu Continuous from signing of ICF through completion of study participation

a. All assessments will be performed before dosing unless noted otherwise. b. If the subject prematurely discontinues study drug treatment, an ETT Visit should be scheduled as soon as possible after

the decision to discontinue treatment. Subjects who prematurely discontinue treatment during the Treatment Period will continue to complete all scheduled study visits for assessments following completion of the ETT Visit

c. The Safety Follow-Up Visit is required for all subjects, unless the subject completes the Week 4 Visit and has enrolled in a separate open-label study within 28 days after the last dose of study drug. If an ETT Visit occurs 3 weeks or later following the last dose of study drug, then the ETT Visit replaces the Safety Follow-up Visit.




d. To enter the Treatment Period, conditions for entry must be satisfied. e. The CFQ-R, followed by the TSQM (only subjects aged ≥12 years to <18 years at the date of informed consent will

complete the TSQM), must be completed before any other assessments scheduled at relevant visits. f. Weight and height will be measured with shoes off. Following screening, height will be collected only for subjects ≤21

years of age on the date of informed consent. g. Symptom-directed physical examinations will occur at any time during the study if deemed necessary by the investigator. h. Any female subject who does not meet the criteria for non-childbearing potential is considered to be of childbearing

potential and must have pregnancy testing at the indicated time points. i. All standard 12-lead ECGs will be performed after the subject has been at rest for at least 5 minutes. ECGs will be collected

before dosing (as applicable). Additionally, at the Day 15 Visit, postdose ECG assessments will be performed at 2 hours and 4 hours after dosing.

j. Vital signs and pulse oximetry will be collected before dosing and after the subject has been at rest for at least 5 minutes. k. Spirometry assessments must be performed before study drug dosing and should be performed pre-bronchodilator at

approximately the same time at each visit. l. Sweat chloride collection will occur before study drug dosing. At each time point, 2 samples will be collected, 1 from each

arm (left and right). m. Blood samples will be collected before the first dose of study drug in each study period. n. The Day 1 predose PK sample must be collected before dosing. The Week 4 predose PK sample must be collected within 60

minutes before dosing for subjects who are receiving their first dose of study drug in an open-label study on the same day as the Week 4 Visit. For subjects who are not entering an open-label study on the same day as the Week 4 Visit, the Week 4 sample should be collected approximately 12 hours after the evening dose of IVA on the day prior to the Week 4 Visit.

o. Sputum will be collected from subjects who can produce a sample spontaneously. The sputum sample will be processed for microbiology analysis and sputum biomarkers.

p. Data on hospitalizations and intravenous antibiotic therapies administered during the 12 months prior to the signing of the ICF will be collected.

q. For the Run-in Period, TEZ/IVA should be administered. The final dose during the Run-in Period will be administered on Day -1, the evening before the Day 1 Visit.

r. Randomization may occur on either Day -1 or Day 1, after conditions for entry into the Treatment Period have been satisfied. Randomization must occur before the first dose of study drug in the Treatment Period.

s. For the Treatment Period, the randomized study drug regimen should be administered. The final dose of study drug in the Treatment Period will be administered the evening before the Week 4 Visit.

t. Other events related to outcome include assessments relating to PEx, administration of antibiotic therapy for sinopulmonary signs/symptoms, and hospitalizations for CF.

u. SAEs that occur after completion of study participation and are considered related to study drug will be reported to Vertex GPS within 24 hours.




Table 111. Respiratory-related Adverse Events, Trial 103, Safety Set

Preferred Term

TEZ/IVA N=52 n (%)


Subjects reporting at least 1 TEAE 11 14

Cough1 4 (8) 9 (16)

Dyspnea2 1 (2) 4 (7)

Sputum increased 3 (6) 3 (5) Hemoptysis 5 (10) 2 (4) Increased bronchial secretion 0 1 (2) Sputum discolored 0 1 (2) Sputum retention 0 1 (2) Wheezing3 0 1 (2)

Subjects counted once per preferred term category. Source. Reviewer calculated in JMP 12.0 using ADAE dataset selecting subjects: AEBODSYS (Respiratory, thoracic and mediastinal disorders) AEHLT (Breathing abnormalities, Bronchospasm and obstruction, coughing and associated symptoms, Lower Respiratory tract signs and symptoms, or respiratory and pulmonary function diagnostic procedures), by USUBJID, TRT01A, AEDECOD. 1Includes the following PT: cough, productive cough 2Includes PT dyspnea, respiration abnormal 3Includes PT Asthma, wheezing, bronchospasm, bronchial hyperreactivity

15.4.3. Supportive Tables, Study 105

Table 112. Study 105 Schedule of Assessments

Event/Assessmenta

Treatment Period

Day 1b

Day 15 (± 3

Days)

Weeks 4, 8, 16, 24, 36 (± 5 Days)

Weeks 12, 20, 28, 32, 40, 44, 52, 56,64, 68, 76,

80, 88, 92 (± 5 Days)

Week 48

(± 5 Days)

Weeks 60, 72, 84

(± 5 Days)

Week 96

(± 5 Days)

ETT Visitc

Safety FU Visit 28

(± 7 Days) After Last

Dosed Clinic visit X X X X X X X X

Telephone contact Xk

ICF and assent (when applicable)

Xe

Inclusion and exclusion criteria confirmation

X

CFQ-Rf X Weeks 4, 8, 24

X Week 72 X X X

Weight and heightg X X X X X X X X

Ophthalmologic examinationh

X Xi Xi Xi

Complete physical examinationj

X X X

Pregnancy testk Urine Urine Urine Urine Urine Serum Serum Serum

FSHl

Standard 12-lead ECGm X X Weeks 8, 24 X Week 72 X X X

Vital signsn X X X X X X X X

Pulse oximetryn X X X X X X X X

Spirometryo X X X X X X X X




Event/Assessmenta

Treatment Period

Day 1b

Day 15 (± 3

Days)

Weeks 4, 8, 16, 24, 36 (± 5 Days)

Weeks 12, 20, 28, 32, 40, 44, 52, 56,64, 68, 76,

80, 88, 92 (± 5 Days)

Week 48

(± 5 Days)

Weeks 60, 72, 84

(± 5 Days)

Week 96

(± 5 Days)

ETT Visitc

Safety FU Visit 28

(± 7 Days) After Last

Dosed SwClp X X Weeks 4,

8,16, 24 X

Urinalysis X X X X X X X

Hematology X X X X X X X X

Coagulation X Week 24 X Week 72 X X X

Serum chemistry X X X X X X X X

PK samplingq Week 4

Inflammatory mediator samples

X Week 24 X

Blood biomarker samples X Week 24 X

Sputum samplesr X Week 24 X

Study drug count X X X X X X X

Study drug dosings Day 1 through evening before Week 96 Visit

Other events related to outcomet,u

Continuous from signing of the ICF through completion of study participation

Medications review Continuous from signing of the ICF through completion of study participation

Treatments and procedures review

Continuous from signing of the ICF through completion of study participation

AEs and SAEsu Continuous from signing of the ICF through completion of study participation

AE: adverse event; BMI: body mass index; CF: cystic fibrosis; CFQ-R: CF Questionnaire-Revised; ETT: Early Termination of Treatment; FSH: follicle stimulating hormone; GPS: Global Patient Safety; ICF: informed consent form; PEx: pulmonary exacerbation(s); PK: pharmacokinetic; SAE: serious adverse event; SwCl: sweat chloride; FU: follow-up a. All assessments will be performed before dosing unless noted otherwise. b. The Day 1 Visit of this study will be on the same day as the last scheduled visit of the parent study. Subjects will NOT have

to repeat any Day 1 assessments that were specified to be performed at the last scheduled visit in the parent study. Subjects who were enrolled and remained clinically stable but had Day 1 study drug administration procedures delayed by no more than 7 days for reasons not related to their clinical status will have to repeat the safety and spirometry assessments that were specified to be performed at the Day 1 Visit before receiving their first dose of study drug. Subjects who have not received the first dose of study drug within 7 days of the last dose of study drug in the parent study, or subjects who had Day 1 study drug administration procedures delayed by no more than 7 days for a reason related to clinical status, will have to repeat all Day 1 assessments.

c. If the subject prematurely discontinues study drug treatment, an ETT Visit should be scheduled as soon as possible after the decision to discontinue treatment.

d. The Safety Follow-up Visit is required for all subjects. For subjects who complete an ETT Visit 3 weeks or later following the last dose of study drug, the ETT Visit will replace the Safety Follow-up Visit.

e. The ICF and, when appropriate, assent form, can be signed up to 28 days prior to Day 1. f. The CFQ-R must be completed before the start of any other assessments scheduled at relevant visits. g. Weight and height will be measured with shoes off. Height will be collected only for subjects ≤21 years of age (on the date

of informed consent in the parent study). For subjects >21 years of age, the height value obtained from the Screening Visit in the parent study will be used for BMI calculations.

h. Ophthalmologic examinations will only be conducted on subjects <18 years of age (on the date of informed consent in the parent study) by a licensed ophthalmologist or optometrist.

i. A single ophthalmologic examination is required at completion of study participation for subjects <18 years of age (on the date of informed consent in the parent study) except for those subjects who have withdrawn consent or assent. Ophthalmologic examinations are only required if the cumulative drug exposure (in the parent study and current study) is at least 12 weeks since the last study ophthalmologic examination.

j. Subjects will have a complete physical examination. Symptom-directed physical examinations will occur at any time during the study if deemed necessary by the investigator.




k. Pregnancy tests will be performed for all female subjects of childbearing potential. At assessment time points when telephone contact takes the place of a clinic visit, a urine pregnancy test will be performed with a home kit provided by the study site. Results will be reported to the site by telephone.

l. Blood samples for FSH will be measured. m. All standard 12-lead ECGs will be performed after the subject has been at rest for at least 5 minutes. ECGs will be collected

before dosing (as applicable). n. Vital signs and pulse oximetry will be collected before dosing and after the subject has been at rest for at least 5 minutes. o. Spirometry assessments must be performed before study drug dosing and should be performed pre-bronchodilator at

approximately the same time each visit. p. Sweat chloride collection will occur before study drug dosing. At each time point, 2 samples will be collected, 1 from each

arm (left and right). q. PK samples will be collected predose on Week 4 only as described in. r. Sputum will be collected from subjects who can produce a sample spontaneously. The sputum sample will be processed

for microbiology analysis and sputum biomarkers. s. The final dose of study drug will be administered the evening before the Week 96 Visit. t. Other events related to outcome include assessments relating to PEx, administration of antibiotic therapy for

sinopulmonary signs/symptoms, and hospitalizations for CF. u. SAEs that occur after completion of study participation and are considered related to study drug will be reported to Vertex

GPS within 24 hours.


--------------------------------------------------------------------------------------------This is a representation of an electronic record that was signedelectronically. Following this are manifestations of any and allelectronic signatures for this electronic record.--------------------------------------------------------------------------------------------/s/------------------------------------------------------------

STACY J CHIN10/21/2019 12:56:48 PM

SALLY M SEYMOUR10/21/2019 01:06:32 PM

MARY T THANH HAI10/21/2019 01:19:22 PM

Signature Page 1 of 1


APPLICATION NUMBER · VX-445 Major Human Active Metabolite (M23, VRT -1654549) TK and Safety...

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Transcript of APPLICATION NUMBER · VX-445 Major Human Active Metabolite (M23, VRT -1654549) TK and Safety...