CO-1

Single-Dose Tafenoquine 300 mg for Radical Cure of Plasmodium vivax Malaria

July 12, 2018GlaxoSmithKlineAntimicrobial Drugs Advisory Committee Meeting

CO-2

Introduction

Jörg-Peter KleimMedicine Development Leader, TafenoquineGlaxoSmithKline

CO-3

Global effort to eradicate malaria around world GSK and Medicines for Malaria Venture (MMV) developed

Tafenoquine (TQ) as part of Global Health program Needed for orphan indication in US Tafenoquine would also assist global malaria eradication efforts Aligns with US initiatives and global treatment efforts

Plasmodium vivax Malaria: Global Health Problem

CO-4

Single-dose tafenoquine (TQ) 300 mg in combination with standard chloroquine (CQ) Efficacious treatment for relapse prevention of

P. vivax malaria Similar safety profile to currently-approved primaquine

(PQ) + CQ High treatment compliance

First new treatment for prevention of relapse in > 60 years

Tafenoquine 300 mg

CO-5

Molecular mechanism of action of tafenoquine is unknown P. vivax can hide in patient’s liver for weeks or months Dormant liver stage causes malaria relapses, without need for

another infected mosquito bite Primaquine only current medicine to inactivate dormant liver stage

and prevent relapse 14-day treatment and compliance can be difficult

Tafenoquine offers novel, single-dose treatment for relapse prevention

Tafenoquine Inactivates Dormant Liver Stage

CO-6

Tafenoquine: 8-Aminoquinoline Analogue of Primaquine

PrimaquineHalf-life: 6 hours

TafenoquineHalf-life: 15 days

CO-7

Originally discovered by Walter Reed Army Institute of Research 13 studies support radical cure indication

3 randomized, double-blind studies conducted outside US Pivotal study: Study 582 Part 2 Supportive studies: Study 582 Part 1 and Study 564

20 additional studies analyzed for safety Orphan Drug status (Jan 2013) Breakthrough Therapy designation (Dec 2013)

Tafenoquine Regulatory History

CO-8

Indicated for radical cure (prevention of relapse) of Plasmodium vivax malaria in patients aged 16 years and older

Recommended dosing and administration Single 300 mg dose co-administered with chloroquine

Proposed Indication and Dosing

CO-9

Single-dose TQ 300 mg with standard doses of CQ 70% reduction in risk of recurrence of P. vivax malaria at

6 months compared with chloroquine alone (p < 0.001) Consistent efficacy across supportive studies Acceptable safety profile and similar to 14-day PQ regimen Primary risk: hemolysis in patients with G6PD deficiency

Appropriately managed with labeling and G6PD testing No cases of clinical hemolysis in studies

No increased risk of clinically relevant hemoglobin decline, ophthalmic, CNS, hepatic, or QT prolongation events

Clinical Overview

CO-10

Unmet NeedJ. Kevin Baird, PhDEijkman Oxford Clinical Research UnitUniversity of Oxford

Study Design and Efficacy Results

Justin A. Green, MD, PhDGlaxoSmithKline

Safety Results Alison Webster, MDGlaxoSmithKline

Clinical Perspective Ric Price, MDMenzies School of Health Research

Agenda

CO-11

Additional RespondersGretchen Birbeck, MD, MPH University of Rochester

Medical CenterDepartments of Neurology and Public Health

Christian Baumann, PhD GSK Sr. Director, Global Regulatory Affairs

Navin Goyal, PhD GSK Director, Clinical Pharmacology

Liz Hardaker, MD GSK Medical Director, Global Clinical Safety and Pharmacovigilance

Jim Harvey, PhD GSK Director, Non-clinical Toxicology

Katie Rolfe GSK Director, Statistics and Programming

Maxine Taylor GSK Investigator, Drug Metabolism and Pharmacokinetics

CO-12

Unmet Need

J. Kevin Baird, PhDProfessor of MalariologyEijkman Oxford Clinical Research Unit (Jakarta, Indonesia)University of Oxford

CO-13

P. vivax is Most Widespread Human Malaria

1. Price, 2007; Hwang, 2014; 2. World Health Organization, 2017; 3. Center for Disease Control, 2018; 4. Howes, 2016

64% of malaria cases in Americas due to P. vivax2

~200 cases imported to US by travelers in 20153

2.5 billion living at risk of infection1

CO-14

Caused by local transmission by American anopheles mosquitoes

63 outbreaks of malaria in US from 1957–20061

Annual range 1–32 subjects Outbreak reported in Houston in 2017 Frequently raise concerns and require public health resources

While Rare, Small Local Outbreaks Reported in US

1. Filler, CDC, 2006. [includes all malarias]

CO-15

P. vivax Malaria: Parasitic Disease That Can Relapse from Liver Stage

Infected red blood cells

Image adapted from Lima, 2016

Infected hepatocyte

LIVER STAGE

BLOOD STAGE

Gametocytes

Skin

Develops without symptoms

Symptoms of acute malaria attack

Dormant hypnozoite

CO-16

Increasing evidence that burden, economic impact and severity of disease from P. vivax have been underestimated1

Even with access to antimalarials, severe and fatal infections occur1

Splenic rupture, severe anemia, respiratory distress, and possibly coma

Review of > 12,000 P. vivax cases in travelers returning to US2

0.1% resulted in death 1.3% severe cases: acute respiratory distress syndrome,

cerebral malaria, renal or hepatic dysfunction, severe anemia or thrombocytopenia and shock

Symptoms Include Fever, Chills, Vomiting, Malaise, Headache, and Myalgia

1. Price, 2007; 2. Hwang, 2014

CO-17

Risk of Relapse is a Serious Clinical Threat Without Treatment of Liver Stage

Kitchen, in Boyd M, 1949.

Number of Patients

Number of Relapses

0

200

400

600

800

1000

1 to 3 4 to 6 7 to 9 10 to 14 15 to 19 20 to 24 25 to 34 35+

2,495 US soldiers repatriated from Asia Pacific 1943-1945Episodes Incidence

1 to 3 9%4 to 6 13%7 to 9 20%

10 to 14 35%15 to 19 14%20 to 24 6%25 to 34 3%

≥ 35 1%

CO-18

Serious Public Health Threat: > 80% of Clinical Attacks Caused by Relapse

Clinical attacks of P. vivax derived from hypnozoites 98% near Thai-Myanmar

border1

82% in Papua New Guinea2

1. Adekunle, 2015; 2. Robinson, 2015

Placebo (PL)

PQ

0

0.25

0.5

0.75

1

Prop

ortio

n un

infe

cted

by

PCR

CO-19

P. vivax can be refractory to current elimination efforts Persistence of mosquito vectors Relapse from dormant liver stage Can lead to outbreaks where malaria previously eliminated

Suppressive chemoprophylaxis (prevention) widely available in US

Treatment required to prevent local transmission and relapse

Goal of P. vivax Malaria Treatment is Radical Cure

CO-20

Selection of Current US CDC Treatment Options

Center for Disease Control, 2018

Option Blood Stage Treatment

1st Chloroquine (x 3 days)

2nd Atovaquone-proguanil orartemether-lumefantrine

3rd Quinine sulfate combinations (+ doxycycline, tetracycline, or clindamycin)

4th Mefloquine

Liver Stage Treatment

Primaquine phosphate (x 14 days)

CO-21

0.00

0.05

0.10

0.15

0 20 40 60 80 100

Primaquine Effectiveness Dependent on Treatment Adherence

Primaquine treatment compliance as low as 30%1,4

Primaquine efficacy reduced 3- to 4-fold when ≥ 3 of 14 doses missed1,2,3,4

Nelson-Alden Cumulative

Hazard

Time (days)

Log rank test p = 0.021

Directly-observed therapy

Self-administered therapy

1. Abreha, 2017; 2. Takeuchi, 2010; 3. Douglas, 2017; 4. Khantikul, 2009

CO-22

8-aminoquinolines cause hemolysis in G6PD deficiency Identified risk can be mitigated with G6PD testing G6PD deficiency high in many malaria endemic areas Co-incidence with malaria common

Sex-linked condition Exclude patients from treatment

Diagnostic tests for G6PD deficiency readily available in US

G6PD Testing Can Protect Patients from 8-Aminoquinoline-Induced Hemolysis

CO-23

Untreated liver stage of P. vivax infection causes malaria relapse P. vivax is widespread globally

Cases reported in both endemic areas and countries that have previously eliminated malaria

Primaquine is only treatment option to prevent relapse Poor adherence limits effectiveness

Need for simple, single-dose regimen for radical cure of P. vivax malaria

Successful attack on hypnozoite reservoir of P. vivax likely to result in collapse of transmission cycle

Summary

CO-24

Efficacy

Justin A. Green, MD, PhDProject Physician, TafenoquineClinical DevelopmentGlaxoSmithKline

CO-25

Key Tafenoquine Efficacy Studies

CQ = chloroquine x 3 days TQ = tafenoquine single dose PQ = primaquine x 14 days

Study Phase Treatment Groups N Role

Study 582 Part 1 Phase 2b

CQTQ 50 mg + CQTQ 100 mg + CQTQ 300 mg + CQTQ 600 mg + CQPQ 15 mg + CQ

545557575650

Dose finding

Study 582 Part 2 Phase 3CQTQ 300 mg + CQPQ 15 mg + CQ

133260129

Pivotal

Study 564 Phase 3 TQ 300 mg + CQPQ 15 mg + CQ

16685 Supportive

CO-26

Clinical Pharmacology of Tafenoquine 300 mg

Administer with food Increased absorption Improved GI tolerability

Linear PK up to 1200 mg t1/2 ~15 days No impact of age, race, weight,

gender, or G6PD deficiency on PK Slow metabolism

No major circulating metabolites0 1 2 3 4 5 6 7 8 9 10

Time (weeks)

300

100

50

20

5

TQ Conc.

(ng/mL)

CO-27

Study 582 (Part 1): Rationale for 300 mg Single Dose TQ Treatment

0%

20%

40%

60%

80%

100%

0 30 60 90 120 150 180 210

Recurrence-free (%)

N at riskPQ + CQ 50 49 44 37 37 37 11 0CQ 54 52 39 31 26 24 11 0

TQ 600 mg + CQTQ 300 mg + CQPQ + CQ

TQ 50 mg + CQTQ 100 mg + CQ

CQ

Time (days)

TQ 50 mg + CQ 55 54 46 43 34 32 8 0TQ 100 mg + CQ 57 55 46 38 33 30 7 0TQ 300 mg + CQ 57 56 56 53 50 50 18 0TQ 600 mg + CQ 56 55 53 50 49 46 11 0

CO-28

90% recurrence-free efficacy in TQ arm with 30% treatment difference to CQ

Study overpowered for efficacy comparisons Original sample size: N=600

Slow recruitment and global shortage of study chloroquine Smaller sample size negotiated Still powered for significance

Study 582 (Part 2): Statistical Analysis Plan

CO-29

Study 582 (Part 2) Design: Multi-Center, Double-Blind, Placebo-Controlled Study

Randomized N=522

CQ N=133

TQ 300 mg + CQN=260

PQ + CQ N=129

TQ: Day 1 or 2

Followed for 6 months

CQ: Days 1 to 3 Followed for 6 months

PQ: Days 1–14

Followed for 6 months

CQ: Days 1 to 3

CQ: Days 1 to 3

Placebo

CO-30

Microscopically diagnosed P. vivax malaria at screening No mixed malaria infections ≥ 16 years old No severe P. vivax malaria (WHO criteria) Corrected QT interval (QTcF) < 450 msec at screening Screening hemoglobin (Hb) concentration ≥ 70 g/L No G6PD enzyme level < 70%

Study 582 (Part 2): Key Inclusion / Exclusion Criteria

CO-31

Recurrence-free efficacy at 6M: CQ vs TQ 300 mg + CQ (mITT*) Recurrence includes relapse and reinfection

Analyzed using 2 methodologies1. Survival analysis (WHO1) Time to first recurrence Kaplan-Meier and Cox proportional hazards

2. Categorical analysis (FDA) Logistic regression Missing = failure

Study 582 (Part 2): Primary Efficacy Endpoint

*mITT: microbiological intent-to-treat1. World Health Organization, 2003

CO-32

mITT Population CQ

N=133TQ 300 mg + CQ

N=260PQ + CQN=129

Completed 97% 96% 95%

Reason for study withdrawal

Lost to follow-up 2% 2% 2%

Physician decision < 1% < 1% 0

Withdrawal by patient < 1% 2% 3%

Study 582 (Part 2): Disposition

CO-33

Study 582 (Part 2): Demographics Balanced Across Treatment Groups

mITT Population CQ

N=133TQ 300 mg + CQ

N=260PQ + CQN=129

Age, mean 35 years 35 years 35 yearsMale 73% 75% 77%Background [Region]

Multiple [Brazil] 35% 37% 36%Native American [Peru] 32% 31% 32%Asian [SE Asia] 20% 19% 20%Black [Ethiopia] 11% 11% 10%White [Brazil] 2% 2% 2%

Min. G6PD enzyme activity 72.6% 70.2% 70.4%

CO-34

Study 582 (Part 2): Baseline Disease Characteristics

mITT Population CQ

N=133TQ 300 mg + CQ

N=260PQ + CQN=129

Previous malarial episode 80% 84% 84%

Asexual parasite count* 5,615 x 106/L 5,314 x 106/L 4,380 x 106/L

Gametocyte parasite count* 55 x 106/L 54 x 106/L 31 x 106/L

*Median counts. Day 1 Assessment 1 value used as Baseline

CO-35

Tafenoquine = 100% compliance (n/N = 260/260) Primaquine = 96% compliance (n/N = 124/129) Assessed by pill counts (≥ 12 pills taken)

Study 582 (Part 2): High Compliance

CO-36

Study 582 (Part 2): Primary Endpoint Met (Survival Analysis), Recurrence-Free Efficacy Over 6 Months

62.4% TQ 300 mg + CQ69.6% PQ + CQ

27.7% CQ

0%

20%

40%

60%

80%

100%

0 30 60 90 120 150 180 210

Recurrence-free (%)

N at riskCQ 133 125 77 61 48 41 7 0TQ 300 mg + CQ 260 251 244 217 183 163 27 0

Time (days)

PQ + CQ 129 124 112 101 91 87 10 0

mITT TQ 300 mg + CQ vs CQHR (95% CI) 0.299 (0.222, 0.404)

p-value < 0.001

PQ + CQ vs CQ0.262 (0.178, 0.387)

< 0.001

Recurrence = reinfection or relapse

CO-37

Study 582 (Part 2): Primary Endpoint Met (Categorical Analysis), Significant Reduction in Odds of RecurrencemITT PopulationCategorical (missing = failure)

CQ N=133

TQ 300 mg + CQN=260

PQ + CQN=129

Recurrence-free at 6 months 26% 60% 64%Odds ratio vs CQ alone(95% CI) - 0.241

(0.152, 0.382)0.198

(0.117, 0.335)p-value - < 0.001 < 0.001

CO-38

Factors analyzed include Gender, age, BMI, region, parasite genotype, exposure

Conclusions PK/PD analyses demonstrated AUC > 56 μg*hr/mL

greatest predictor of positive treatment outcome > 95% of patients in Phase 3 achieved this exposure

Reinfection more likely to explain recurrences than relapse

Analysis of Apparent Treatment Failures

CO-39

Efficacy Results in Other Key Studies

CO-40

Study 582 (Part 1): Efficacy at 6 Months

Recurrence-free (%)

Time (days)

89.2% TQ 300 mg + CQ

77.3% PQ + CQ

37.5% CQ

0%

20%

40%

60%

80%

100%

0 30 60 90 120 150 180 210

N at riskCQ 54 52 39 31 26 24 11 0TQ 300 mg + CQ 57 56 56 53 50 50 18 0PQ + CQ 50 49 44 37 37 37 11 0

CO-41

Study 564: Comparable Efficacy to Primaquine

0%

20%

40%

60%

80%

100%

0 30 60 90 120 150 180 210

Recurrence-free (%)

Time (days)N at riskTQ 300 mg + CQ 166 161 156 143 131 115 19 0PQ + CQ 85 83 74 69 64 60 9 0

72.7% TQ 300 mg + CQ75.1% PQ + CQ

CO-42

TQ 300 mg single-dose co-administered with CQ significantly reduced risk of P. vivax recurrence compared to CQ alone Consistent efficacy across studies

Reduction in recurrence numerically comparable with PQ

Efficacy Summary: Tafenoquine an Effective Treatment for Radical Cure of P. vivax Malaria

CO-43

Safety

Alison Webster, MDHead of Clinical, Global HealthGlaxoSmithKline

CO-44

Well-characterized and similar to already approved primaquine Safety data from placebo-controlled studies Adverse events of special interest across development Proposed post-approval plans

Tafenoquine Safety Agenda

CO-45

Safety ExposuresDataset / Subjects Total Tafenoquine Dose N

All studies / All treated

Any 4,129

< 300 mg 392

= 300 mg 810

> 300 mg 2,927

All primary studies / P. vivax infected = 300 mg 483

Placebo-controlled studies / P. vivax infected = 300 mg 317

CO-46

Placebo-controlled StudiesCQ

N=187TQ 300 mg + CQ

N=317PQ + CQN=179

Any AE 68% 64% 60%

Any SAE 5% 7% 6%

Any fatal SAE 0 0 0

Any AE leading to study withdrawal 0 0 0

Any AE leading to study drug discontinuation 3% 4% < 1%

Safety Overview

CO-47

Placebo-controlled StudiesCQ

N=187TQ 300 mg + CQ

N=317PQ + CQN=179

Any AE 68% 64% 60%Pruritus 14% 13% 9%Headache 21% 12% 13%Dizziness 9% 9% 8%Nausea 8% 8% 7%Vomiting 5% 8% 9%Diarrhea 5% 6% 5%Viral upper respiratory tract infection 5% 6% 7%Myalgia 12% 5% 7%Abdominal pain upper 10% 5% 8%Pharyngitis 4% 5% 6%Pyrexia 12% 4% 9%Chills 11% 2% 7%

Overall AEs Across 6 Months of Follow-Up in ≥ 6% of Patients in Any Arm

CO-48

Overall AEs ≥ 5% Reported During First 29 Days

Placebo-controlled StudiesCQ

N=187TQ 300 mg + CQ

N=317PQ + CQN=179

Any AE 48% 50% 49%Pruritus 13% 12% 9%Dizziness 3% 8% 6%Nausea 6% 6% 4%Hemoglobin decreased 2% 5% 2%Headache 6% 5% 5%Vomiting 4% 5% 6%Abdominal pain upper 7% 4% 7%

CO-49

AEs Leading to Discontinuation of Study Drug Across 6 Months

Placebo-controlled StudiesCQ

N=187TQ 300 mg + CQ

N=317PQ + CQN=179

Any AE leading to study drug discontinuation 3% 4% < 1%

Hemoglobin decreased 1% 3% 0

ECG QT prolonged 2% 0 < 1%

P. falciparum infection 0 < 1% 0

CO-50

Hemoglobin decrease definition in Phase 3 ≥ 30% or > 30 g/L from baseline or decrease in absolute

hemoglobin < 60 g/L in first 15 days Otherwise did not meet standard SAE criteria None life-threatening or required hospitalization

Resolved without intervention None classified as severe hemoglobin AEs

Protocol-Defined SAEs of Hemoglobin Decline

CO-51

SAEs in ≥ 2 Patients Across 6 Months

*Hemoglobin decreased protocol-defined SAE: ≥ 30% or > 30 g/L from baseline or decrease in absolute hemoglobin < 60 g/L in first 15 days

Placebo-controlled StudiesCQ

N=187TQ 300 mg + CQ

N=317PQ + CQN=179

Any SAE 5% 7% 6%

Hemoglobin decreased* 2% 5% 2%

QT prolongation 3% < 1% 2%Any SAEs (excluding hemoglobin decreased) 4% 3% 4%

CO-52

Hematologic events Ophthalmic events CNS events Hepatic events Other events (QT and hypersensitivity)

Adverse Events of Special Interest

CO-53

Relative Risk

Placebo-Controlled Studies: AESIs Comparison at 6 Months TQ + CQ vs CQAESI Incidence

Hematological events

Ophthalmic events

Psychiatric disorders

Nervous system disorders

Hepatobiliary disorders

Renal and urinary disorders

0 10 20 30Percent

CQ (N=187)TQ + CQ (N=317)

0.01 0.1 1 10 100Risk Ratio (95% CI)

CO-54

Placebo-Controlled Studies: No Clinically Relevant Effect on Hemoglobin

60

80

100

120

140

160

180

200

Day 1 Day 3 Day 5 Day 8 Day 11 Day 15 Day 22 Day 29 Day 60 Day 90 Day 120

Hemoglobin (g/L)

CQ 187 187 186 185 184 186 184 183 181 181 132TQ 300 mg + CQ 317 315 313 312 310 310 308 309 309 308 251PQ + CQ 179 179 177 175 173 173 173 172 173 168 123

CQ TQ 300 mg + CQ PQ + CQ

CO-55

Hemoglobin declines in G6PD-normal patients not drug-induced hemolytic events No evidence from any laboratory markers

Data suggest underlying infection and subsequent rehydration could be contributing factors

All declines resolved without intervention Hemoglobin nadir in same range in patients with / without SAE

Placebo-Controlled Studies: Hemoglobin Declines Do Not Fall to Levels of Clinical Concern

CO-56

Study 564 design TQ 300 mg + CQ vs PQ + CQ

Primary endpoint Decrease in hemoglobin of ≥ 30% or > 30 g/L from

baseline, or absolute level < 60 g/L

Study 564: Focusing on Hematologic Safety

CO-57

No evidence of hemolysis from laboratory markers No patients required blood transfusion Majority of hemoglobin drops in both treatment groups small (< 20 g/L) and

with no clinical sequelae

Study 564:No Clinically Relevant Hemoglobin Decline

TQ 300 mg + CQN=166

PQ + CQN=85

Hemoglobin decline95% CI

4 (2.4%)0.94, 6.03

1 (1.2%)0.21, 6.37

Difference in proportion 95% CI

1.23% -4.16, 4.98

CO-58

Across primary studies no evidence of retinal toxicity or corneal changes associated with vision changes

Adverse events associated with ocular changes Infrequent and similar across treatment groups

All events mild or moderate in severity All resolved No ophthalmic SAEs Onset within first 29 days

All Primary Studies: No Ophthalmic SAEs for Tafenoquine 300 mg Single Dose

CO-59

N=330 TQ, N=168 placebo No changes to ophthalmic safety parameters using highly

sensitive techniques Eye disorder AEs observed in lower proportion of patients on

tafenoquine vs placebo

Study 807: Ophthalmic Events with Tafenoquine 300 mg Single Dose Compared with Placebo

CO-60

No serious CNS AEs reported in > 800 individuals at proposed treatment dose

Observed effects mild to moderate and resolved No subjects withdrew from studies or discontinued treatment

due to CNS AEs

CNS Safety for Tafenoquine 300 mg Single Dose

CO-61

Placebo-Controlled Studies: CNS AEs Over 6 Months

Placebo-controlled StudiesCQ

N=187TQ 300 mg + CQ

N=317PQ + CQ

N=179Any nervous system AE 27% 18% 20%

Headache 21% 12% 13%Dizziness 9% 9% 8%Migraine < 1% < 1% 0Syncope 0 < 1% < 1%Tremor 0 < 1% < 1%Burning sensation 0 0 < 1%Dysesthesia 0 0 < 1%Somnolence 0 < 1% 0

Any psychiatric AE 3% 4% 4%Insomnia 3% 4% 4%Anxiety 0 < 1% 0

CO-62

Placebo-Controlled Studies: CNS AEs in First 29 Days

Placebo-controlled StudiesCQ

N=187TQ 300 mg + CQ

N=317PQ + CQ

N=179Any nervous system AE 10% 11% 10%

Dizziness 3% 8% 6%Headache 6% 5% 5%Syncope 0 < 1% 0Tremor 0 < 1% < 1%Dysesthesia 0 0 < 1%Migraine < 1% 0 0Somnolence 0 < 1% 0

Any psychiatric AE 3% 4% 4%Insomnia 3% 4% 4%Anxiety 0 < 1% 0

CO-63

All received dose of TQ > 300 mg All recovered 3 of 4 had history of pre-existing psychiatric disorder HV - 350 mg: acute psychotic episode (severe)* HV - 500 mg: psychotic episode (severe)* HV - 600 mg: depressed mood (mild) P. vivax patient - TQ 600 mg + CQ: depressed mood (mild)*

Single-Dose Tafenoquine: Psychiatric Disorders Across Program

*History of pre-existing psychiatric disorderHV = healthy volunteer

CO-64

Across development program Transient, sporadic, reversible increases in liver transaminases No Hy’s Law cases

2 patients fulfilled lab criteria of ALT ≥ 3x and bilirubin ≥ 2x ULN with alternative causes 27 year-old female on day 89 diagnosed with hepatitis E 29 year-old male on day 22 with concomitant herbal medicine use

No Signal of Liver Toxicity With Tafenoquine (Placebo-Controlled, from Day 3)

CQN=187

TQ 300 mg + CQ N=317

PQ + CQ N=179

ALT ≥ 3x ULN 14 (7%) 15 (5%) 7 (4%)

ALT ≥ 5x ULN 4 (2%) 6 (2%) 3 (2%)

Bilirubin ≥ 2x ULN 10 (5%) 10 (3%) 4 (2%)

ALT ≥ 3x and bilirubin ≥ 2x ULN 0 2 (< 1%) 0

CO-65

TQT Study Maximum effect on QTcF < 10 msec at supratherapeutic

dose of 1200 mg compared to placebo Study 491 Co-administration of tafenoquine with chloroquine No additional effect on QTcF observed

Placebo-controlled studies No differences observed

Multiple Studies Demonstrate No QT Prolongation for Tafenoquine 300 mg

CO-66

Both had urticaria / angioedema Healthy volunteers in same study Delay of onset and duration not consistent with anaphylaxis Both subjects recovered Treated with antihistamines and steroids No alternative explanation identified TQ proposed label to include precaution for hypersensitivity

Two Subjects with Delayed Hypersensitivity

CO-67

Enhanced pharmacovigilance in US Post-marketing requirement Active follow-up of US patients in collaboration with CDC

Observational studies of real-world TQ use in endemic countries

WHO, MHRA*, Bill and Melinda Gates Foundation Smart Safety Surveillance

Proposed Post-Approval Activities to Include Active Enhanced Pharmacovigilance

*UK Medicines and Healthcare Products Regulatory Agency

CO-68

Safety profile well-characterized and similar to primaquine No evidence that TQ exacerbated effects of CQ Known risk of hemolysis in G6PD-deficient patients managed

G6PD testing proposed in label No clinical hemolytic events in G6PD-normal patients Observed hemoglobin declines, not clinically meaningful No evidence of retinal toxicity CNS AEs mild to moderate and resolved

Label to include precaution for patients with history of serious psychiatric disorders

Safety Summary of Tafenoquine 300 mg Single Dose

CO-69

Tafenoquine:Pivotal Advance in Malaria Therapeutics

Ric Price, MDProfessor of Global HealthSenior Principal Research FellowMenzies School of Health Research

CO-70

Incidence of Malaria (per patient-year)

0.00.20.40.60.81.01.21.41.6

Survived Dead

Risk and frequency of relapse varies with origin of infection1

Relapses can occur every 21 to 42 days Each episode associated with further

hemolysis and cumulative risk of anemia2

Morbidity and mortality likely function of incidence density3

Clinical trials focus on incidence risk of infection

Predominant Morbidity and Mortality of P. vivax Related to its Propensity to Recur

1. White, Malaria Journal 2011 ; 2. Douglas et al PLoS Med 2013; 3. Patriani Under Review 2018

P. falciparum P. vivax

MixOther

CO-71

Primaquine Radical Cure

“Group recommends that intensive research be carriedout with a view to developing an anti-relapse drug freefrom side effects and radically curative at a single dose orat most after a three day treatment”

1963

No optimal dosing regimen

Clinicians reluctant to prescribe PQ

Patients don’t take complete course

55 years later

CO-72

Clinical Trial: Patients Don’t Complete 14-Day Regimen for Acute Febrile Illness

Abreha et al Plos Med 2017* > 10/14 doses taken

Primaquine efficacy related to total mg/kg dose ingested

Complete Course *

Incomplete Course

Unsupervised Course

73.7%

63.2%

92.0%

Duration of Follow-up (days)

Efficacy

1.00

0.75

0.50

0.25500 100 150 200

CO-73

0.0

0.2

0.4

0.6

0.8

1.0

0 30 60 90 120 150 180 210

Study 582 (Part 2): Tafenoquine Efficacy is Similar to 14-Day Course of Primaquine

TQ 300 mg + CQPQ + CQ

Recurrence-free Probability

Time (days)

CQ

Actual efficacy of PQexpected to be

lower due toreduced adherence

CO-74

Reality: Patients Don’t Complete Unsupervised 14-Day Regimen for Acute Febrile Illness

1. Douglas et al PLoS Med 2017

Papua, Indonesia1

Pharmacy Records 2004-2013: 46,221 Patients treated with 14 days unsupervised primaquine

No PQHigh DoseLow Dose

Months of Follow-up

Risk of P. vivax

Recurrence

Overall Effectiveness:10.0% [95%CI 0.05-0.14]*

0.4

0.3

0.2

0.1

0.0

0 123 6 9

*after controlling for age, gender, ethnicity

CO-75

Primaquine exposure in > 36 million individuals1,2

219 SAEs - mostly severe hemolysis1 (none in G6PD normal individuals)

14 deaths: 12 hemolysis, 1 hepatic necrosis, 1 unknown Risk = 1 in 621,428

Safety Well-Characterized and Identified Risks Manageable

Population SAEs Risk

MDA 15–30 mg daily 9 million16 severe hemolysis2 methemoglobinemia1 severe urticaria

1.8 per million

Patients 15–30 mg daily 24 severe hemolysis1 neuropsychiatric3

1. WHO Safety of 8 aminoquinolines 2014; 2 Ashley MalJ 2014; 3 Schlossberg Annals Int Med 1980

CO-76

Hemolysis is attributable to both parasitemia and treatment

Radical cure prevents early recurrence, providing faster hematological recovery

Risk of Early Hemolysis Outweighed by Fewer Episodes of Recurrent Parasitemia

Pooled Individual Data Analysis1

29 clinical trials with 3421 patients

1. Commons et al SubmittedTime (days)

11.5

12.0

12.5

13.0

13.5

14.0

0 7 14 21 28 35 42

PrimaquineNo primaquine

Hemoglobin(g/dL)

CO-77

Radical cure essential for control and elimination of P. vivax

Radical cure has potential to reduce direct and indirect morbidity and mortality

AEs of PQ and TQ well-identified and manageable

Primaquine radical cure is a broken strategy

Single-dose radical cure with tafenoquine represents pivotal advance in malarial therapeutics

Conclusions

CO-78

Single-Dose Tafenoquine 300 mg for Radical Cure of Plasmodium vivax Malaria

July 12, 2018GlaxoSmithKlineAntimicrobial Drugs Advisory Committee Meeting

CO-79

Backup Slides Shown

CO-80

CO-81

CO-82