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, MD Columbia University College of Physicians and Surgeons New 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
British Medical Journal: Buckley, CD

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 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

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. Lymphomas Observed in REMICADE® RA Clinical Trials
Pt-Yrs Obs. Exp. SIR N Follow-up Cases SEER* (95% CI)
All RA Studies REMICADE (1.7-16) Placebo (0.0-26)
MTX naive early RA REMICADE (0.0-22) Placebo (0.0-52) DMARD resistant RA REMICADE (2.4-23) Placebo (0.0-52)
*SEER = Surveillance, Epidemiology, and End Results *Number expected in age, race, gender-matched general population

9. Lymphomas Observed in REMICADE® CD and All Clinical Trials
Pt-Yrs Obs. Exp. SIR N Follow-up Cases SEER (95% CI)
All CD Studies REMICADE (1.0-31) Placebo ( )
All RA and CD Studies REMICADE (2.6-15) Placebo (0.0-24)

10. Lymphomas Observed in REMICADE® Clinical Trials
Incidence per Pt-Yrs Pt-Yrs Obs. Follow-up N Follow-up Cases (95% CI)
All RA Studies REMICADE ( )
All CD Studies REMICADE ( )
All Studies REMICADE ( )

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
Swollen joint count ranged from
ESR ranged from mm/hr

12. Lymphomas in RA Trials Time (Months) 1 MTX 10 2 AZA 10 3 MTX 1
Prior
Immuno- REMICADE® Patient supp. mg/kg
1 MTX 10
2 AZA 10
3 MTX 1
4 MTX AZA
MTX
Follicular center cell lymphoma
High grade centroblastic/ immunoblastic B-cell lymphoma
Mixed cellularity Hodgkin’s disease
Mantle cell lymphoma
MTX
MTX
etanercept
Time (Months)

13. Lymphomas in CD Trials Time (Months) 1 MTX 10 2 AZA 5 Prior
Immuno- REMICADE® Patient supp. mg/kg
1 MTX 10
2 AZA 5
AZA
NK Lymphoma
Intermediate grade angiocentric B-cell lymphoma
AZA
Time (Months)

14. National Data Bank for Rheumatic Diseases (NDRD)
Long term study of outcomes in 18,557 patients with RA ( )
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
Pt-Yrs Obs. Exp. SIR N Follow-up Cases SEER (95% CI)
No MTX, REMICADE®, or etanercept ( )
MTX Alone , ( )
REMICADE * ( )
etanercept * ( )
*3 patients received both REMICADE and etanercept

16. Lymphomas in RA Registry (N = 18,557)
National Databank for Rheumatic Diseases
Incidence per Pt-Yrs Pt-Yrs Obs. Follow-up N Follow-up Cases (95% CI)
No MTX, REMICADE®, or etanercept ( )
MTX Alone , ( )
REMICADE * 1.38 ( )
etanercept * 1.57 ( )
*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
Treatment Patients Lymphoma
REMICADE®
Not exposed 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. Non-Lymphoma Malignancies* in REMICADE® Clinical Trials
Pt-Yrs Obs. Exp. SIR N Follow-up Cases SEER (95% CI)
All RA Studies REMICADE ( ) Placebo ( )
All CD Studies REMICADE ( ) Placebo ( )
All Studies REMICADE ( ) Placebo ( )
*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. Opportunistic Infections in Spontaneous Adverse Event Reporting
Approximately 365,000 Patients Treated
Adverse Event Reports
Pneumocystis carinii pneumonia 38
Histoplasmosis 30
Listeriosis 28
Atypical mycobacteria 26
Aspergillosis 24
CMV infections 16
Systemic candidiasis 13
Coccidioidomycosis 13

26. Opportunistic Infections – Risk Management
Histoplasmosis and coccidioidomycosis cases occurred primarily in endemic areas
For patients who have resided in histoplasmosis or coccidioidomycosis endemic areas
Careful Benefit:Risk assessment prior to REMICADE® treatment
Careful monitoring of patients during and after REMICADE therapy
Route of administration allows for regular follow-up

27. Heart Failure Hospitalization and Death in the ATTACH Trial (Phase II)
REMICADE®
Placebo 5 mg/kg 10 mg/kg
(n = 49) (n = 50) (n = 51)
Hospitalization for HF
wks 5 (10%) 3 (6%) 11 (21%)
Death
wks 0 (0.0%) 1 (2.0%) 3 (5.9%)
wks 4 (8.2%) 4 (8.0%) 8 (15.7%)
The ATTACH trial was a randomized, placebo-controlled, pilot trial designed to evaluate, in a preliminary fashion, the effect of REMICADE in patients with Class III/IV heart failure due to systolic dysfunction. One hundred and fifty patients were randomized to receive placebo, REMICADE 5 mg/kg, or REMICADE 10 mg/kg at 0, 2, and 6 weeks following randomization. The protocol-specified follow-up period was 28 weeks. In addition, survival status at 1 year was determined in all patients.
This slide displays the number of patients who were hospitalized for worsening heart failure through 28 weeks and the number who died through both 28 weeks and 1 year, along with the corresponding Kaplan-Meier event rates.
At 28 weeks, the rates of hospitalization for worsening heart failure were similar in the placebo and 5 mg/kg groups, but increased in the 10 mg/kg group. At this same timepoint, there was the suggestion of a dose-response with respect to death. However, by one year there were similar death rates in the placebo and 5 mg/kg groups, with a persistent increase in the 10 mg/kg group. None of these differences achieved statistical significance.
[Note to Jerry: As you know, the composite of death + hospitalization for worsening heart failure in the 10 mg/kg group at 28 weeks did have a nominal p value of This is not shown on the slide.]

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
The REMICADE prescribing information was updated in March, 2002, at which time all ATTACH patients had completed 38 weeks of follow-up but 1-year mortality follow-up was still ongoing.
Because of the suggestion of a dose-response in the mortality data at both 28 and 38 weeks [1-2-7 deaths at 38 weeks in PI; data not shown on previous slide], it was decided to contraindicate REMICADE at any dose in patients with Class III/IV heart failure. Although no data in patients with Class I/II heart failure were available, avoidance of doses greater than 5 mg/kg was recommended in these patients.
Now that complete results of the ATTACH trial are available, including mortality data through 1 year, the prescribing information is being updated.
At 1 year, there was evidence of an adverse effect only with the 10 mg/kg dose of REMICADE. Therefore, the new proposed label contraindicates only higher doses of REMICADE, ie greater than 5 mg/kg, in patients with Class III/IV heart failure.
Although the 5 mg/kg REMICADE dose was not associated with an increase in hospitalization or death in the ATTACH trial, the effect of longer term treatment is unknown. In the ATTACH trial, patients received only 3 doses over 6 weeks. Because of this uncertainty, as well as the absence of controlled clinical trial data on REMICADE in patients with milder heart failure, the new proposed Warnings section advises extreme caution when using REMICADE in any patient with heart failure and only after consideration of other treatment options. And again, dose should not exceed 5 mg/kg.

29. New-onset Heart Failure in All Completed Clinical Trials
Placebo All REMICADE® Patients treated
Average weeks of follow-up
New-onset heart failure 4 (2.1%) 3 (0.2%)
p 242

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
Centocor has been closely monitoring reports of heart failure in association with REMICADE. Data sources include our clinical trial database, an ongoing registry of rheumatoid arthritis patients, and J&J’s Integrated Pharmacovigilance System, which contains all spontaneous post-marketing reports. Particular attention has recently been focused on new-onset heart failure, ie, the appearance of heart failure in a patient with no known history of heart failure.
Reports of heart failure in clinical trials other than ATTACH have been infrequent. This is probably due, at least in part, to the exclusion of patients with significant underlying cardiac disease at entry. Pooled data from 14 completed Centocor-sponsored trials demonstrated no increase in the incidence of heart failure among REMICADE-treated patients compared with placebo-treated patients. None of the patients reporting heart failure had a prior history of heart failure.
The infliximab Rheumatoid Arthritis Registry project was begun in December 2000 and is administered by the Arthritis Research Center Foundation and the National Databank for Rheumatic Disease under the direction of Dr Frederick Wolfe. This project provides for additional data collection and follow-up on REMICADE-treated patients that are entered into the National Databank on Rheumatic Disease, a large registry that was created over 20 years ago. Dr. Wolfe recently analyzed data on 13, 171 registry patients, including over 4000 REMICADE-treated patients. After adjusting for differences in demographic and disease characteristics, rates of both total and incident cases of heart failure were similar among REMICADE-treated and control patients.
Finally, as of October 31, 2002, there were 158 spontaneous post-marketing reports of heart failure from health professionals. Of these, 59 patients had no known history of heart failure and no apparent acute precipitating event, such as infection, myocardial infarction, or pulmonary embolism. Twenty-eight of these 59 patients had no reported risk factors for the development of heart failure (eg, hypertension, coronary artery disease, diabetes, valvular heart disease, pulmonary disease). Interpretation of these data are, however, significantly confound by incomplete and, at times, inconsistent information, as well as lack of a control group.
Although no increase in new-onset heart failure has been observed in Centocor-sponsored clinical trials or in a recent analysis of the National Databank for Rheumatic Disease, we cannot entirely exclude the possibility that REMICADE may rarely precipitate heart failure in a patient with no prior history of the disease and no acute precipitating event. Centocor will continue to closely monitor all reports of heart failure in association with REMICADE use. (Hopefully, we will have reached closure on any label changes related to new-onset HF so that a definitive statement can be made here.)

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. Status – Ongoing Safety Commitment
Phase III/IV Trials - RA
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 RA despite MTX
iRAMT REMICADE 0 pts Enrollment complete MTX safety (210 pts) and efficacy with MTX tapering

34. Status – Ongoing Safety Commitment
Phase III Trials – Crohn’s Disease
Study Status Status Trial Description Aug 01 Feb 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

35. Status – Ongoing Safety Commitment
Patient Registries
Status Status Registry Description Aug 01 Feb 03
NDRD (Wolfe) RA registry 3100 pts 6280 pts
TREAT CD registry 1200 pts 5004 pts

36. REMICADE® – Ongoing Safety Commitment
Number of Patients
REMICADE Non-REMICADE Treated Comparators
ASPIRE ~750 ~300 START 1083 ~330 iRAMT PROMPT ACCENT I ACCENT II NDRD Registry 6280 ~12,000 TREAT Registry Long-term safety follow-up
Total ~13,000 ~15,000

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. Clinical Benefit in Rheumatoid Arthritis
ATTRACT
Clinical Benefit in Rheumatoid Arthritis
ACR20 at Week 30
The results of the 30-week primary endpoint, proportion of patients achieving an ACR 20 response, are shown here. The proportion of patients in all REMICADE in combination with methotrexate dosing regimens achieving an ACR 20 response rate ranged between 50 and 58%, compared to 20% in the methotrexate control group. The differences between the REMICADE groups and the methotrexate group were highly statistically significant.
All patients received concomitant MTX

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

44. Improvement in Physical Function
ATTRACT
Improvement in Physical Function
Improvement in HAQ Averaged over Time through 2 Years
The results of the primary endpoint at 102 weeks of change in HAQ score averaged over time through week 102 is shown here. Patients receiving methotrexate in combination with placebo infusions had a median improvement of 0.1 in their HAQ score compared to patients receiving REMICADE in combination with methotrexate who had a median improvement of 0.3 to 0.4 in their HAQ score over time through 102 weeks. The differences between all 4 active treatment groups and the methotrexate control group were all highly statistically significantly different.

45. Clinical Benefit in Crohn’s Disease
The clinical benefit of REMICADE was initially demonstrated in a Phase III trial comparing a single REMICADE 5 mg/kg dose to placebo at week 4. Eighty-one percent of patients treated with a single dose of REMICADE 5 mg/kg achieved clinical response by week 4 compared to 16% of patients treated with placebo. In addition, 48% of 5 mg/kg REMICADE patients achieved clinical remission vs. 4% of placebo patients. Both improvements were highly statistically significant with p <

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

47. Clinical Benefit in Fistulizing Crohn’s Disease
Response through Week 18
Composite slide showing patients in fistula response and complete response at week 54.

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