1. 1 ZELMAC (tegaserod) Presentation to GI Advisory Committee June 26, 2000 Raymond E. Joseph MD Medical Officer HFD-180

2. 2 Zelmac Background Proposed Indication: Indicated for the treatment of irritable bowel syndrome (IBS) in patients who identify abdominal pain/discomfort and constipation as their predominant symptoms

3. 3 Zelmac NDA Submission 2 Phase II-double-blind trials: Study 251: (n=547) 45 sites in North America and Europe; dose-ranging with 4 dose levels of tegaserod or PL for 12 weeks Study 202: (n=123) 16 sites in Europe and Canada; dose-titration with 4 dose levels of tegaserod or PL for 20 weeks

4. 4 Summary of Phase II Studies Study 251 1mg/d =PL; 4mg/d most effective dose No dose response seen over the range of 4 to 24 mg/d Study 202 Increased response rates observed during dose-titration from 4 to 12 mg/d k Doses of 4 and 12 mg/d chosen for Phase III trials

5. 5 Phase III Trials -2521 Pts Similarities PL-controlled, double-blind, randomized, three parallel groups with dose levels of 4, 12 mg vs placebo with 4 week baseline and 12 -week treatment period Study 351 Study 301 Study 307 (Dose titration- 4 to 12 mg/d at 1 mo)

6. 6 Phase III Trials Study 351(n=799) First of the three Phase III studies to be completed The protocol pre-specified analysis failed to demonstrate efficacy Subsequently a) the definition of responder in the SGA of relief was changed to incorporate “somewhat” relieved 100% of the time b) the SGA of abd. discomfort/pain was changed to a secondary efficacy variable Post-hoc analyses incorporating the above changes demonstrated efficacy for the 12 mg/d dose level kLed to protocol amendments for studies 301 and 307

7. 7 Responder Rates for SGA of Relief

8. 8 Efficacy Issues 1. Pain not adequately assessed as an efficacy endpoint 2. Overall difference between drug and PL group is 8% 3. Efficacy in males not established 4. Potential affect of laxatives

9. 9 Abdominal Pain Pain is an essential component of IBS When analyzed as a component of SGA of relief along with well-being and altered bowel function was statistically significant for studies 351 and 301 However, when analyzed independently no statistical difference was seen in studies 301 and 307

10. 10 Responder Rates for SGA of Abdominal Discomfort/Pain

11. 11 Overall Efficacy 8-11 % Discussion Factors: a) effect of gender in this study group b) effect of long-standing disease Are results clinically meaningful?

12. 12 Efficacy in Males Studies included 15% males Response to Zelmac in males was not different compared to placebo Lack of differentiation from placebo –inadequate sample size –may raise the question whether the disease is different in males

13. 13 Laxative Use 1. In the clinical trails, laxative use including bulking- agents was allowed 2. The use and timing of laxatives may influence the response of the SGA of relief 3. There was similar qualitative consumption between groups k Quantitative differences not assessed may be affecting outcome in constipation study patients

14. 14 Efficacy Summary 1. Overall efficacy was shown in one of the pivotal studies (301) for both the 4 mg and 12 mg dose levels ; supportive study 351 showed efficacy for the 12 mg dose level only; efficacy not replicated in 307 2. Efficacy in males not demonstrated 3. Laxative usage may have had an affect on efficacy

15. 15 Most Frequently Reported AEs in Phase III In Phase II and long term results are similar

16. 16 Most Frequently AEs Led to Discontinuation in Phase II & III

17. 17 Duration of Exposure Pooled L-T Studies

18. 18 Safety in General n =1679 Approx. 72% phase III pts experienced one AE Only diarrhea was statistically significantly different from PL 11.7% vs 5.4% (p <0.0001) AEs only marginally greater in tegaserod groups vs placebo SAEs incidence-tegaserod (1.8%) = PL profiles were similar

19. 19 Safety (Cont.) One death- in study 301-Patient with 14y Hx of depression; committed suicide on day 36 of drug 5 SAEs in tegaserod pts-possibly related to test medication –abdominal pain [n=2] –gastritis [n=1] –SVT [n=1] –hypoglycemia [n=1]

20. 20 Safety Issues 1. Diarrhea (> 3 BMs/d, loose, watery with a sense of urgency) 2. Syncope tegaserod (n=8) vs PL (n=1) p=(NS) 3.”Ovarian Cysts”

21. 21 Diarrhea Incidence: 11.7% tegaserod vs 5.4% PL p value <0.0001 In alternators (18-36% at baseline) 21% Discontinuation secondary to diarrhea was 2.1% in tegaserod vs 0.6% in PL p value = 0.002 50% occurred during the first week; contributing factors? In long-term study 209, 14.6% experienced diarrhea leading to discontinuation in 3.5 %

22. 22 Possible Ovarian Cysts

23. 23 Pts Undergoing Surgery All 5 cases on 12 mg/d dose of drug –3 in study 209 ( ie. long- term) –1 in study 307 –1 in study 351 None from placebo groups

24. 24 Case No. 1 (12 mg) 50y WF 10y Hx. of ovarian cyst no abdominal pain Elective surgery performed on day 334 of drug Surgery: benign tumor; no cyst k Not associated with test med.

25. 25 Case No. 2 (12 mg) 45y WF with past Hx. of hysterectomy experienced abdominal pain; went to OR on day 261 of drug Surgery: –bilateral salpingo-oophorectomy –post-op diagnosis: adhesions –there is no mention of a cyst

26. 26 Case No. 3 (12 mg) 37y BF with past Hx. of hysterectomy abdominal pain on day 100 of drug CT scan: 2.7 cm right ovarian cyst Surgery: due to continue pain (performed 5 weeks later) right salpingo-oophorectomy, lysis of adhesions, appendectomy Pathology: 1cm peritubal cyst, adhesions, normal appendix

27. 27 Case No. 4 (12 mg) 35y F presented with unknown Hx Surgery: day 306 of drug Pathology: multiple ovarian cysts, including 3.5cm partially luteinized follicle cyst and adenomyosis of the uterus

28. 28 Case No. 5 (12mg) 13y WF with past Hx. of bilateral ovarian cysts Presented on day 87 of drug with right-sided abdominal pain Surgery: laparoscopic resection of a right ovarian cyst (4 to 5cm) and appendectomy. Ovarian cyst seen at surgery-lysed and drained Pathology: early appendicitis

29. 29 Surgery Summary Relationship between drug and ovarian cysts is unknown 3 of the 5 had previous pelvic surgery –Adhesion were seen in 2 –One had early appendicitis Pharmacologic effects - lower abdomen and pelvis

30. 30 Ovarian Cysts In Ongoing Studies One case- (Tx. group=blinded) 43y F with Hx. of tubal ligation with reversal Diagnosed with ovarian cyst via sonogram on day 23 of drug Discontinued from the trial due to nausea and flatulence

31. 31 Safety Summary AEs occurring more frequently in the tegaserod group Syncope p=(NS) Diarrhea p< 0.0001 Ovarian cyst - the significance of which is unclear at present Relationship of Zelmac to risk of abdominal pathology leading to surgery unknown