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Centocor Presentation. REMICADE ® (infliximab). Agenda of Speakers. REMICADE ® Jerome A. Boscia, MD Safety Review Vice President, Clinical Research & Development Centocor Risk Management Thomas F. Schaible, PhD and Efficacy Vice President, Medical Affairs Centocor. Consultants.

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centocor presentation
Centocor Presentation

REMICADE® (infliximab)

agenda of speakers
Agenda of Speakers

REMICADE® Jerome A. Boscia, MD Safety Review Vice President, Clinical Research & Development Centocor

Risk Management Thomas F. Schaible, PhD and Efficacy Vice President, Medical Affairs Centocor

consultants
Consultants

Roger Cohen, MD Paul Stang, PhD Fox Chase Cancer Center Galt Associates Fox Chase, Pennsylvania Sterling, Virginia

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

Stephen Hanauer, MD Frederick Wolfe, MD

University of Chicago Medical Center Arthritis Research Center Foundation Chicago, Illinois Wichita, Kansas

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

burden of disease
Burden 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
remicade overview
REMICADE 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
remicade experience
REMICADE® Experience
  • 15 completed clinical trials with ~1700 REMICADEtreated patients and 3445 pt-yrs of follow-up
  • 14 ongoing clinical trials with ~3100 REMICADEtreated 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
background
Background

Increased Risk of Lymphoma

  • 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
lymphomas observed in remicade ra clinical trials
All RA Studies REMICADE 1298 2458 4 0.63 6.4 (1.7-16)Placebo 430 590 0 0.14 0.0 (0.0-26)

MTX naive early RA REMICADE 743 703 0 0.17 0.0 (0.0-22) Placebo 297 280 0 0.07 0.0 (0.0-52)DMARD resistant RA REMICADE 555 1756 4 0.45 8.9 (2.4-23) Placebo 133 310 0 0.07 0.0 (0.0-52)

Lymphomas Observed in REMICADE® RA Clinical Trials

Pt-Yrs Obs. Exp. SIRNFollow-upCasesSEER* (95% CI)

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

lymphomas observed in remicade 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 Studies REMICADE 2421 4148 6 0.86 7.0 (2.6-15)Placebo 489 691 0 0.15 0.0 (0.0-24)

Lymphomas Observed in REMICADE® CD and All Clinical Trials

Pt-Yrs Obs. Exp. SIRNFollow-upCasesSEER(95% CI)

lymphomas observed in remicade clinical trials
Incidence per 1000 Pt-Yrs Pt-Yrs Obs. Follow-up NFollow-upCases (95% CI)

All RA Studies REMICADE 1298 2458 4 1.63 (1.58-1.68)

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

All Studies REMICADE 2421 4148 6 1.44 (1.41-1.48)

Lymphomas Observed in REMICADE® Clinical Trials
demographics disease characteristics for patients with lymphomas in ra clinical trials
Demographics/Disease Characteristics for Patients 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 trials
Follicular center cell lymphoma

High grade centroblastic/immunoblastic B-cell lymphoma

Mixed cellularityHodgkin’s disease

Mantle cell lymphoma

Lymphomas in RA Trials

Prior

Immuno- REMICADE®Patientsupp.mg/kg

1 MTX 10

2 AZA 10

3 MTX 1

4 MTX 10 AZA

MTX

MTX

etanercept

MTX

Time (Months)

lymphomas in cd trials
Intermediate grade angiocentric B-cell lymphoma

NK Lymphoma

Lymphomas in CD Trials

Prior

Immuno- REMICADE®Patientsupp.mg/kg

1 MTX 10

2 AZA 5

AZA

AZA

Time (Months)

national data bank for rheumatic diseases ndrd
National Data Bank for 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)

National Databank for Rheumatic Diseases

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)

Pt-Yrs Obs. Exp. SIRNFollow-upCasesSEER(95% CI)

*3 patients received both REMICADE and etanercept

lymphomas in ra registry n 18 55716
Lymphomas in RA Registry (N = 18,557)

National Databank for Rheumatic Diseases

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)

REMICADE6465 6537 9* 1.38 (1.35-1.41)

etanercept 3381 5099 8* 1.57 (1.53-1.60)

Incidence per 1000 Pt-Yrs Pt-Yrs Obs. Follow-up NFollow-upCases (95% CI)

*3 patients received both REMICADE and etanercept

the crohn s therapy resource evaluation and assessment tool treat registry
The Crohn’s Therapy, Resource, Evaluation 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 registry
Lymphomas in Crohn’s Disease Registry

TREAT Registry

TreatmentPatientsLymphoma

REMICADE® 1108 1

Not exposed 1291 1 to REMICADE

lymphoma cases in spontaneous adverse event reporting
Lymphoma Cases in Spontaneous Adverse 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 remicade
Lymphoma 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 ra and crohn s disease
Non-Lymphoma Malignancies in RA and Crohn’s Disease

Background

  • 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
non lymphoma malignancies in remicade 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)

Non-Lymphoma Malignancies* in REMICADE® Clinical Trials

Pt-Yrs Obs. Exp. SIRNFollow-upCasesSEER(95% CI)

*Excludes non-melanoma skin cancers.

non lymphoma malignancies in spontaneous adverse event reporting
Non-Lymphoma Malignancies in Spontaneous 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 update
Tuberculosis (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 in spontaneous adverse event reporting
Adverse EventReports

Pneumocystis carinii pneumonia 38

Histoplasmosis 30

Listeriosis 28

Atypical mycobacteria 26

Aspergillosis 24

CMV infections 16

Systemic candidiasis 13

Coccidioidomycosis 13

Opportunistic Infections inSpontaneous Adverse Event Reporting

Approximately 365,000 Patients Treated

opportunistic infections risk management
Opportunistic Infections – Risk 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
Heart Failure

Hospitalization and Death in the ATTACH Trial (Phase II)

REMICADE®

Placebo5 mg/kg10 mg/kg

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

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 prescribing information
REMICADE® Prescribing Information

Heart Failure

  • 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
new onset heart failure in all completed clinical trials
New-onset Heart Failure in All Completed Clinical Trials

PlaceboAll 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 spontaneous adverse event reporting
New-onset Heart Failure in Spontaneous 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 speakers31
Agenda of Speakers

REMICADE® Jerome A. Boscia, MD Safety Review Vice President, Clinical Research & Development Centocor

Risk Management Thomas F. Schaible, PhD and Efficacy Vice President, Medical Affairs Centocor

continuing safety commitment
Continuing 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
status ongoing safety commitment
Study Status Status TrialDescriptionAug 01Feb 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 RA despite MTX

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

Status – Ongoing Safety Commitment

Phase III/IV Trials - RA

status ongoing safety commitment34
Study Status Status TrialDescriptionAug 01Feb 03

ACCENT I REMICADE® Enrollment Marketing maintenance complete approval in active (580 pts) (June 2002) luminal CD

ACCENT II REMICADE Enrollment BLA submitted maintenance complete priority in fistulizing CD (306 pts) review

Status – Ongoing Safety Commitment

Phase III Trials – Crohn’s Disease

status ongoing safety commitment35
Status Status Registry DescriptionAug 01Feb 03

NDRD (Wolfe) RA registry 3100 pts 6280 pts

TREAT CD registry 1200 pts 5004 pts

Status – Ongoing Safety Commitment

Patient Registries

remicade ongoing safety commitment
Number of Patients

REMICADE Non-REMICADE TreatedComparators

ASPIRE ~750 ~300 START 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

REMICADE®–Ongoing Safety Commitment
safety commitment new programs
Safety Commitment – New Programs

Patient Registries

  • 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
safety commitment new programs38
Safety Commitment – New Programs

Additional Lymphoma Follow-up

  • 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
risk management physicians using remicade
Risk Management – Physicians 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 conclusions
Safety 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)
clinical benefit in rheumatoid arthritis
ATTRACT Clinical Benefit in Rheumatoid Arthritis

ACR20 at Week 30

All patients received concomitant MTX

impact on radiographic progression
ATTRACTImpact on Radiographic Progression

Median Change in Modified Sharp Score through 2 Years

All patients received concomitant MTX

improvement in physical function
ATTRACTImprovement in Physical Function

Improvement in HAQ Averaged over Time through 2 Years

benefit risk of remicade therapy
Benefit:Risk of REMICADE® 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
ad