FDA AdComm 030403 1 Centocor Presentation REMICADE ® (infliximab)

FDA AdComm 030403 1

Centocor PresentationCentocor Presentation

REMICADE® (infliximab)

FDA AdComm 030403 2

Agenda of SpeakersAgenda of Speakers

REMICADEREMICADE® Jerome A. Boscia, MDJerome A. Boscia, MD Safety Review Safety Review Vice President, Clinical Research & Development Vice President, Clinical Research & Development

CentocorCentocor

Risk Management Risk Management Thomas F. Schaible, PhDThomas F. Schaible, PhDand Efficacy and Efficacy Vice President, Medical AffairsVice President, Medical Affairs CentocorCentocor

FDA AdComm 030403 3

ConsultantsConsultants

Roger Cohen, MDRoger Cohen, MD Paul Stang, PhDPaul Stang, PhD Fox Chase Cancer CenterFox Chase Cancer Center Galt Associates Galt Associates

Fox Chase, PennsylvaniaFox Chase, Pennsylvania Sterling, VirginiaSterling, Virginia

Susan Fisher, PhDSusan Fisher, PhD E. William St. Clair, MD E. William St. Clair, MD University of RochesterUniversity of Rochester Duke University Medical Center Duke University Medical Center Rochester, New YorkRochester, New York Durham, North Carolina Durham, North Carolina

Stephen Hanauer, MDStephen Hanauer, MD Frederick Wolfe, MDFrederick Wolfe, MDUniversity of Chicago Medical CenterUniversity of Chicago Medical Center Arthritis Research Center Arthritis Research Center

Foundation Foundation Chicago, IllinoisChicago, Illinois Wichita, KansasWichita, Kansas

Milton Packer, MDMilton Packer, MDColumbia University College Columbia University College of Physicians and Surgeonsof Physicians and SurgeonsNew York, New York New York, New York

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Burden of DiseaseBurden of Disease

• Rheumatoid Arthritis (RA)– 90% of patients with aggressive disease become

significantly disabled within 20 years– Reduced life expectancy compared with the

general population

• Crohn’s Disease (CD)– Debilitating disease affecting young adults– Detrimental impact on employment and

productivity in 50% of patients– 90% of patients require surgical intervention

FDA AdComm 030403 5

REMICADEREMICADE Overview Overview

• REMICADE is indicated for patients with RA and CD who have had an inadequate response to conventional therapies

• Fulfills previously unmet medical need

• Profound benefit in a majority of patients

• Safety profile continues to be characterized– Arthritis Advisory Committee (AAC)

Safety Update August 2001– New data from clinical trials, registries,

spontaneous adverse event reports

FDA AdComm 030403 6

REMICADEREMICADE®® Experience Experience

• 15 completed clinical trials with ~1700 REMICADE

treated patients and 3445 pt-yrs of follow-up

• 14 ongoing clinical trials with ~3100 REMICADE

treated patients

• Approximately 365,000 patients treated commercially with REMICADE with more than 554,000 pt-yrs since first exposure (~64% in the U.S.)– 198,000 RA patients– 157,000 CD patients

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BackgroundBackground

• Comparisons typically made with the SEER database which represents the general population

• Lymphomas are more common in the overall RA population than in the general population (SIR = 2-3)– Elevated relative risk associated with:• High inflammatory activity (26-fold)• Functional Class III/IV (5-fold)• Small and large joint involvement (9-fold)

• Use of conventional immunosuppressants (e.g. azathioprine) increases risk

• Possible increased risk of lymphoma in CD

Increased Risk of LymphomaIncreased Risk of Lymphoma

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Lymphomas Observed in Lymphomas Observed in REMICADEREMICADE®® RA Clinical Trials RA Clinical Trials

All RA StudiesREMICADE 1298 2458 4 0.63 6.4 (1.7-16)Placebo 430 590 0 0.14 0.0 (0.0-26)

MTX naive early RAREMICADE 743 703 0 0.17 0.0 (0.0-22) Placebo 297 280 0 0.07 0.0 (0.0-52)

DMARD resistant RAREMICADE 555 1756 4 0.45 8.9 (2.4-23)Placebo 133 310 0 0.07 0.0 (0.0-52)

*SEER = Surveillance, Epidemiology, and End Results*Number expected in age, race, gender-matched general population

Pt-Yrs Obs. Exp. SIR N Follow-up Cases SEER* (95% CI)

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Lymphomas Observed in Lymphomas Observed in REMICADEREMICADE®® CD and All Clinical Trials CD and All Clinical Trials

All CD StudiesREMICADE 1106 1646 2 0.23 8.7 (1.0-31)Placebo 56 95 0 0.01 0.0 (0.0-365)

All RA and CD StudiesREMICADE 2421 4148 6 0.86 7.0 (2.6-15)Placebo 489 691 0 0.15 0.0 (0.0-24)

Pt-Yrs Obs. Exp. SIR N Follow-up Cases SEER (95% CI)

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Lymphomas Observed in Lymphomas Observed in REMICADEREMICADE®® Clinical Trials Clinical Trials

Incidence per 1000 Pt-Yrs

Pt-Yrs Obs. Follow-up N Follow-up Cases (95% CI)

All RA StudiesREMICADE 1298 2458 4 1.63 (1.58-1.68)

All CD StudiesREMICADE 1106 1646 2 1.22 (1.16-1.27)

All StudiesREMICADE 2421 4148 6 1.44 (1.41-1.48)


Demographics/Disease Characteristics for Demographics/Disease Characteristics for Patients with Lymphomas in RA Clinical TrialsPatients with Lymphomas in RA Clinical Trials

• Four RA patients with moderately to severely active disease despite DMARD therapy who developed lymphomas

– Disease duration > 10 years

– Tender joint counts ranged from 22 - 53

– Swollen joint count ranged from 11 - 24

– ESR ranged from 38 - 80 mm/hr


Lymphomas in RA TrialsLymphomas in RA Trials

0 10 20 30

Time (Months)

Follicular center cell lymphoma

High grade centroblastic/immunoblastic B-cell lymphoma

Mixed cellularityHodgkin’s disease

Mantle cell lymphoma

Prior Immuno- REMICADE®

Patient supp. mg/kg

1 MTX 10

2 AZA 10

3 MTX 1

4 MTX 10 AZA

MTX

MTX

MTX etanercept


Lymphomas in CD TrialsLymphomas in CD Trials

0 10 20 30

Time (Months)

NK Lymphoma

Intermediate grade

angiocentric B-cell lymphoma

AZA

AZA

Prior Immuno- REMICADE®

Patient supp. mg/kg

1 MTX 10

2 AZA 5


National Data Bank for National Data Bank for Rheumatic Diseases (NDRD)Rheumatic Diseases (NDRD)

• Long term study of outcomes in 18,557 patients with RA (1998-2002)– RA patients recruited from the practices of

908 U.S. rheumatologists – Biannual assessment– Validation process includes MD, hospital and death

records to maximize accuracy and reliability– ~8% attrition annually


Lymphomas in RA Registry (N = 18,557)Lymphomas in RA Registry (N = 18,557)

No MTX,REMICADE®, or etanercept 3504 7122 5 3.8 1.3 (0.4-3.1)

MTX Alone 6396 12,147 10 6.7 1.5 (0.7-2.7)

REMICADE 6465 6537 9* 3.5 2.6 (1.2-4.9)

etanercept 3381 5099 8* 2.1 3.8 (1.6-7.5)

National Databank for Rheumatic DiseasesNational Databank for Rheumatic Diseases

*3 patients received both REMICADE and etanercept



Lymphomas in RA Registry (N = 18,557)Lymphomas in RA Registry (N = 18,557)

No MTX,REMICADE®, or etanercept 3504 7122 5 0.70 (0.68-0.72)

MTX Alone 6396 12,147 10 0.82 (0.81-0.84)

REMICADE 6465 6537 9* 1.38 (1.35-1.41)

etanercept 3381 5099 8* 1.57 (1.53-1.60)

National Databank for Rheumatic DiseasesNational Databank for Rheumatic DiseasesIncidence per1000 Pt-Yrs

Pt-Yrs Obs. Follow-up N Follow-up Cases (95% CI)

*3 patients received both REMICADE and etanercept


The Crohn’s Therapy, Resource, Evaluation The Crohn’s Therapy, Resource, Evaluation and Assessment Tool (TREAT) Registry and Assessment Tool (TREAT) Registry

• CD patients ( 18 years) eligible (need to participate for a minimum of 5 years)

• At baseline and every subsequent 6 months: – Patients complete a health status questionnaire – Data collected:

• Demographics and disease characteristics• Medications• Adverse events• Health resource utilization


Lymphomas in Crohn’s Disease RegistryLymphomas in Crohn’s Disease Registry

Treatment Patients Lymphoma

REMICADE® 1108 1

Not exposed 1291 1to REMICADE

TREAT RegistryTREAT Registry


Lymphoma Cases in Spontaneous Lymphoma Cases in Spontaneous Adverse Event ReportingAdverse Event Reporting

• 71 cases of lymphoma have been reported since launch– 45 reports in RA– 20 reports in CD– 6 reports in other diseases


Lymphoma Risk with REMICADELymphoma Risk with REMICADE®®

• Lymphomas are more common in the overall RA population than in the general population (SIR = 2-3)

• In RA clinical trials, a SIR of 6.4 for lymphoma was observed in REMICADE treated patients compared with the general population

– All cases occurred in high risk patients

• In NDRD a SIR of 2.6 for lymphoma was observed in REMICADE treated patients compared with the general population

• Current evidence is insufficient to reach conclusions on whether REMICADE increases the risk of lymphomas


Non-Lymphoma Malignancies in Non-Lymphoma Malignancies in RA and Crohn’s DiseaseRA and Crohn’s Disease

• Large RA cohorts have not reported increased risk of non-lymphoma cancers

• Long-standing CD predisposes to cancer of both the small and large intestine

• Risk of colon cancer in Crohn’s colitis may be comparable to risk in ulcerative colitis

BackgroundBackground


Non-Lymphoma Malignancies* in Non-Lymphoma Malignancies* in REMICADEREMICADE®® Clinical Trials Clinical Trials

All RA StudiesREMICADE 555 1756 11 13.10 0.8 (0.4-1.5)Placebo 133 310 2 2.02 1.0 (0.1-3.6)

All CD StudiesREMICADE 1106 1646 8 4.61 1.7 (0.8-3.4)Placebo 56 95 2 0.18 11.1 (1.3-40.0)

All StudiesREMICADE 1678 3445 19 17.80 1.1 (0.6-1.7)Placebo 192 412 4 2.22 1.8 (0.5-4.6)


*Excludes non-melanoma skin cancers.


Non-Lymphoma Malignancies in Non-Lymphoma Malignancies in Spontaneous Adverse Event ReportingSpontaneous Adverse Event Reporting

• 354 cases of non-lymphoma malignancies have been reported since launch– 230 reports in RA– 68 reports in CD– 15 reports in other diseases– 41 indication not reported


Tuberculosis (TB) UpdateTuberculosis (TB) Update

• Reviewed in detail at August 2001 AAC meeting– Box warning added to prescribing information– Dear Healthcare Professional letter sent

• Implemented education program on TB risk and screening for latent TB– Education provided to 7500 rheumatologists

and gastroenterologists– Follow-up indicates most physicians perform

pre-REMICADE TB screening

• Decreased number of spontaneous reports of TB despite increased patient exposure


Opportunistic Infections inOpportunistic Infections inSpontaneous Adverse Event ReportingSpontaneous Adverse Event Reporting

Adverse Event Reports

Pneumocystis carinii pneumonia 38

Histoplasmosis 30

Listeriosis 28

Atypical mycobacteria 26

Aspergillosis 24

CMV infections 16

Systemic candidiasis 13

Coccidioidomycosis 13

Approximately 365,000 Patients TreatedApproximately 365,000 Patients Treated


Opportunistic Infections – Opportunistic Infections – Risk ManagementRisk Management

• Histoplasmosis and coccidioidomycosis casesoccurred primarily in endemic areas

• For patients who have resided in histoplasmosis or coccidioidomycosis endemic areas

– Careful Benefit:Risk assessment prior toREMICADE® treatment

• Careful monitoring of patients during and afterREMICADE therapy

– Route of administration allows for regular follow-up


Heart Failure

Hospitalization for HF

0 - 28 wks 5 (10%) 3 (6%) 11 (21%)

Death

0 - 28 wks 0 (0.0%) 1 (2.0%) 3 (5.9%)

0 - 52 wks 4 (8.2%) 4 (8.0%) 8 (15.7%)

REMICADE®

Hospitalization and Death in the ATTACH Trial (Phase II)Hospitalization and Death in the ATTACH Trial (Phase II)

Placebo 5 mg/kg 10 mg/kg

(n = 49) (n = 50) (n = 51)


REMICADEREMICADE®® Prescribing Information Prescribing Information

• Contraindications– Patients with Class III/IV heart failure

• Warnings– Use with caution in patients with

Class I/II heart failure– Dose should not exceed 5 mg/kg– Closely monitor patients and discontinue

REMICADE if new or worsening symptoms of heart failure appear

Heart FailureHeart Failure


New-onset Heart Failure in New-onset Heart Failure in All Completed Clinical TrialsAll Completed Clinical Trials

Placebo All REMICADE®

Patients treated 192 1678

Average weeks 40.6 52.8 of follow-up

New-onset heart failure 4 (2.1%) 3 (0.2%)


New-onset Heart Failure in New-onset Heart Failure in Spontaneous Adverse Event ReportingSpontaneous Adverse Event Reporting

• 158 spontaneous adverse event reports of heart failure– 28 patients with no known history of heart failure,

acute precipitating event, or risk factor– Confounded by incomplete information and lack

of a control group


Agenda of SpeakersAgenda of Speakers

REMICADEREMICADE® Jerome A. Boscia, MDJerome A. Boscia, MD Safety Review Safety Review Vice President, Clinical Research & Development Vice President, Clinical Research & Development

CentocorCentocor

Risk Management Risk Management Thomas F. Schaible, PhDThomas F. Schaible, PhDand Efficacy and Efficacy Vice President, Medical AffairsVice President, Medical Affairs CentocorCentocor


Continuing Safety CommitmentContinuing Safety Commitment

• Centocor is committed to obtaining long-term prospective safety information

– Progress since August 2001 AAC

• Ongoing safety assessment programs

• New programs

– Expansion of safety databases

– Specific follow-up on lymphoma cases

• Programs collect data in patients receiving and not receiving REMICADE

– Important to differentiate safety signals


Study Status Status Trial Description Aug 01 Feb 03

ASPIRE REMICADE® ~700 pts Enrollment complete+ MTX in (1049 pts)early RA

START REMICADE 0 pts Enrollment complete+ MTX safety (1083 pts)in active RAdespite MTX

iRAMT REMICADE 0 pts Enrollment complete + MTX safety (210 pts)and efficacy with MTX tapering

Status – Ongoing Safety CommitmentStatus – Ongoing Safety Commitment

Phase III/IV Trials - RAPhase III/IV Trials - RA


Study Status StatusTrial Description Aug 01 Feb 03

ACCENT I REMICADE® Enrollment Marketingmaintenance complete approvalin active (580 pts) (June 2002)luminal CD

ACCENT II REMICADE Enrollment BLA submittedmaintenance complete priorityin fistulizing CD (306 pts) review


Phase III Trials – Crohn’s DiseasePhase III Trials – Crohn’s Disease



Status StatusRegistry Description Aug 01 Feb 03

NDRD (Wolfe) RA registry 3100 pts 6280 pts

TREAT CD registry 1200 pts 5004 pts

Patient RegistriesPatient Registries


REMICADEREMICADE®® ––Ongoing Safety CommitmentOngoing Safety Commitment

Number of Patients

REMICADE Non-REMICADE Treated Comparators

ASPIRE ~750 ~300START 1083 ~330iRAMT 210 0 PROMPT 553 0ACCENT I 580 0ACCENT II 306 0NDRD Registry 6280 ~12,000TREAT Registry 2684 2299Long-term safety 1165 124

follow-up

Total ~13,000 ~15,000


Safety Commitment – New ProgramsSafety Commitment – New Programs

• APART registry

– 2500-patient RA registry in U.S.

• European RA registries

– Registries in Spain, Germany, Sweden and UK

• European CD registry

– 4000-patient registry

• All registries enroll REMICADE and non-REMICADE treated patients

Patient RegistriesPatient Registries


Safety Commitment – New ProgramsSafety Commitment – New Programs

• Registries provide sources to obtain additional details on reported lymphomas

– Compare lymphoma profiles with REMICADE +/- immunosuppressants (MTX, AZA)

– More fully characterize lymphomas

• Initiate surveillance in multiple healthcare delivery systems

– Further quantify lymphoma risk and contributing factors

Additional Lymphoma Follow-upAdditional Lymphoma Follow-up


Risk Management – Risk Management – Physicians Using REMICADEPhysicians Using REMICADE®®

• REMICADE is used primarily by and continues to be promoted to sub-specialists

– Best able to make Benefit:Risk decisions

• This sub-specialist population is readily targeted by risk management initiatives

– e.g. REMICADE TB education program


Safety Commitment ConclusionsSafety Commitment Conclusions

• Conduct risk management programs as specific safety issues arise

• Expand prospective safety databases

– Phase III/IV clinical studies, international patient registries, long-term safety follow-up

– Follow-up in REMICADE® and non-REMICADE treated patients (approaching 30,000)


EfficacyEfficacy


ATTRACTATTRACT

ACR20 at Week 30ACR20 at Week 30

Clinical Benefit in Rheumatoid ArthritisClinical Benefit in Rheumatoid Arthritis

All patients received concomitant MTX


Impact on Radiographic ProgressionImpact on Radiographic Progression

Median Median Change in Modified Sharp Score through 2 YearsChange in Modified Sharp Score through 2 Years

ATTRACTATTRACT

All patients received concomitant MTX


ATTRACTATTRACT

Improvement in HAQ Averaged over Time through 2 YearsImprovement in HAQ Averaged over Time through 2 Years

Improvement in Physical FunctionImprovement in Physical Function


Clinical Benefit in Crohn’s DiseaseClinical Benefit in Crohn’s Disease

Maintenance of Clinical Remission Maintenance of Clinical Remission in Crohn’s Diseasein Crohn’s Disease

ACCENT IACCENT I

Week 30Week 30



Clinical Benefit in Fistulizing Clinical Benefit in Fistulizing Crohn’s DiseaseCrohn’s Disease

Response through Week 18Response through Week 18


Benefit:Risk of REMICADEBenefit:Risk of REMICADE®® Therapy Therapy

• REMICADE is highly effective in RA and CD patients who have failed conventional therapies

• Treatment related serious adverse events are infrequent

• Centocor remains committed to continuing safety assessment and risk management programs as needed

• Benefit:Risk for REMICADE in both RA and CD continues to be excellent

FDA AdComm 030403 1 Centocor Presentation REMICADE ® (infliximab)

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Transcript of FDA AdComm 030403 1 Centocor Presentation REMICADE ® (infliximab)