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Centocor Presentation

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

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  1. Centocor Presentation REMICADE® (infliximab)

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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)

  10. 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

  11. 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

  12. 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)

  13. 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)

  14. 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

  15. 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

  16. 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

  17. 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

  18. Lymphomas in Crohn’s Disease Registry TREAT Registry TreatmentPatientsLymphoma REMICADE® 1108 1 Not exposed 1291 1 to REMICADE

  19. 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

  20. 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

  21. 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

  22. 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.

  23. 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

  24. 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

  25. 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

  26. 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

  27. 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%)

  28. 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

  29. 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%)

  30. 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

  31. 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

  32. 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

  33. 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

  34. 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

  35. 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

  36. 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

  37. 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

  38. 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

  39. 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

  40. 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)

  41. Efficacy

  42. ATTRACT Clinical Benefit in Rheumatoid Arthritis ACR20 at Week 30 All patients received concomitant MTX

  43. ATTRACT Impact on Radiographic Progression Median Change in Modified Sharp Score through 2 Years All patients received concomitant MTX

  44. ATTRACT Improvement in Physical Function Improvement in HAQ Averaged over Time through 2 Years

  45. Clinical Benefit in Crohn’s Disease

  46. ACCENT I Maintenance of Clinical Remission in Crohn’s Disease Week 30 FDA AdComm 030403 46

  47. Clinical Benefit in Fistulizing Crohn’s Disease Response through Week 18

  48. 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

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