1. sNDA 21-156: CELEBREX TM INDICATION Reduction and Regression of Adenomatous Colorectal Polyps in Familial Adenomatous Polyposis Patients FDA ODAC Presentation December 14, 1999 Bethesda, MD

2. CDER/DODP Review Team Medical Reviewers: Judy H. Chiao, M.D. Julie Beitz, M.D. (TL) Statisticians: John Lawrence, Ph.D. Gang Chen, Ph.D. (TL) Biopharm:John Duan, Ph.D. Atiqur Rahman, Ph.D. (TL) Pharm/Tox:Wendelyn Schmidt, Ph.D. Paul Andrews, Ph.D. (TL) Chemistry:Sung Kwang Kim, Ph.D. Rebecca Wood, Ph.D. (TL) GI Consultants: James Lewis, M.D (SGE), Mark Avigan, M.D., John Senior, M.D. (FDA) CSO:Paul Zimmerman DSI: Gus Turner, Ph.D.

3. FDA Presentation Outline Regulatory requirements for accelerated approval GI Issues in FAP FDA Review of Study 001 Conclusions Unresolved Issues and Points to Consider

4. Accelerated Approval Requirements Serious or life-threatening illness Meaningful therapeutic benefits over existing treatments Surrogate endpoints likely to predict clinical benefit in the above patient population Post-marketing studies to demonstrate clinical benefit must be carried out with “due diligence”

5. Familial Adenomatous Polyposis Genotype vs. Phenotype Autosomal dominant genetic disease with 80-100% penetrance Germline mutation of APC gene (tumor suppressor gene) –Attenuated FAP (AFAP) is a heterogeneous clinical entity, characterized by fewer than 100 colorectal polyps and later age of onset of colon cancer –AFAP is associated with 3’ or 5’APC mutations

6. Familial Adenomatous Polyposis Clinical Phenotype Hallmark of FAP colorectal polyposis –>100 colorectal adenomatous polyps (tubular adenomas); 100% colon cancer unless the colon is removed 45 y/o: 83% developed cancer 50 y/o: 93% developed cancer –Upper GI polyps and increased risk for periampullary cancer –Extraintestinal manifestations

7. Familial Adenomatous Polyposis Current Management Prophylactic colectomy could prevent colon cancer in persons known to be at risk of FAP

8. Familial Adenomatous Polyposis Types of Prophylactic GI Surgery Subtotal Colectomy w/ Ileorectal Anastomosis Need vigilant f/u q 6-12 mos Risk of rectal cancer 13-25% at 20 yrs Repeated polypectomies causing scarring 25-30% may need rectal stump removed

9. Familial Adenomatous Polyposis Types of Prophylactic GI Surgery Colectomy with Mucosal Proctectomy followed by Ileoanal Anastomosis ? Functionally less desirable Polyps in the pouch: ? malignant potential

10. Familial Adenomatous Polyposis Unresolved GI Issues Upper GI polyps in 30-100% –Difficult to manage –Risk of death from duodenal cancer >rectal cancer

11. Study 001 in FAP Patients Study Design: Randomized, DB, placebo- controlled 3-arm study (placebo vs. 100 mg bid vs. 400 mg bid); N=83 Hypothesis: Celebrex  colorectal polyps Primary efficacy endpoint: mean percent change in the number of colorectal polyps Secondary efficacy endpoint: mean percent change in the duodenal plaque- like areas

12. Study 001 in FAP patients Patient Characteristics-1

13. Study 001 in FAP patients Patient Characteristics-2

14. Study 001 in FAP Patients Methodology 1 o efficacy endpoint –Polyp count is based on tattoo or marked areas assessed at 6 mos by one investigator –Committee review of videotapes (qualitative global assessment) 2 o efficacy endpoint –mean of one high- and one low-density plaque-like areas in the duodenum assessed at 6 mos

15. Efficacy Results of Study 001: Applicant’s Dataset

16. FDA Verification of the primary efficacy data Rectal polyps were counted from still color photos taken at baseline and 6 mos Blinded to patient treatment assignments 28 patients with varied responses from the St. Mark’s Hospital site reviewed FDA’s counts for patients on the Celebrex 400 mg arm are very similar to the Applicant’s

17. Primary Efficacy Verification FDA vs. Applicant

18. Safety Results of Study 001

19. Safety Profile in Arthritis Patients Exposure –OA: N=4200 up to 3 months –RA: N=2100 up to 6 months ADRs: –Incidence of GI ulceration detected by endoscopy: 3.4-7.6% (vs 2-2.3% in placebo)

20. Exploratory analysis of Study 001 Question: What proportion of patients had at least a 25%  or 25%  in colorectal polyp counts in focal area(s)?

21. Exploratory analysis of Study 001

22. Question: Does a decrease in rectal polyps in the tattoo area predict for an improvement in the entire rectum?

23. Rectal Video Assessment-1 Rectal video: N=74 3 reviewer consensus in 72 patients 4 reviewer consensus in 52 patients

24. Rectal Video assessment-2

25. Rectal Video assessment-3

26. Rectal Video assessment vs. Rectal polyp count change (%) in one tattoo area

27. Among 22 patients who had >=25% decrease in rectal polyp count in one area, only 6 patients (27%) had an overall improvement of the entire rectum by video assessment

28. Conclusions-1 Study 001 enrolled a heterogeneous patient population Mean % change in colorectal polyp count is -28% in the 400 mg group (p=0.003 when compared to placebo group) –More patients in the 400 mg group had >=25% decrease in colorectal polyp count in focal area(s) when compared to placebo group –More patients in the 400 mg group had a “better” rating of rectal video by 4 committee members

29. Conclusions-2: Celebrex at 400 mg BID was well tolerated for 6 months but safety data for this dose beyond 6 months is not available at the present time. % change in rectal polyps in one area does not appear to predict for changes in the entire rectum when the entire rectum is assessed by videotapes by 5 viewers. The durability of Celebrex effects on colorectal polyps cannot be assessed due to the short treatment duration of 6 months.

30. Unresolved Issue-1 Question: Is reduction in polyps in FAP patients a surrogate likely to predict clinical benefit in these patients?

31. Unresolved Issue-2 Clinical benefits in FAP: –Reduction in rectal cancer –Reduction in duodenal cancer –Reduction in other FAP-related cancers –Preservation of rectal stump without increasing risk for rectal cancer –Delay of prophylactic colectomy without increasing the risk for colorectal cancer

32. Points to Consider –Without a complete regression of all colorectal polyps, reduction in polyps may not result in a decrease in colorectal cancer incidence in FAP patients The entire GI mucosa is at risk for developing cancer due to the germline APC mutation Cancer may arise from the remaining polyps or non-polypoid areas

33. Points to Consider –The clinical significance of a partial reduction in colorectal polyps in FAP patients is difficult to assess from Study 001 –If ODAC recommends accelerated approval, Celebrex treatment should be considered only as an adjunct to the usual care of FAP patients (e.g., surgery, endoscopy)