Efficacy and Safety

1. Efficacy and Safety Martin P. Lefkowitz, MD Director, Clinical Research

2. Overview of Clinical Results • Totality of data provides convincing evidence of efficacy for tegaserod 12 mg/d on global relief measure and secondary parameters of efficacy • Safe and well tolerated • Favorable benefit-to-risk profile in constipation-predominant IBS, a disorder with no proven therapeutic options

3. 1 Tegaserod Clinical Program in Constipation-Predominant IBS Study Dose, mg/d* N Location (% of patients) Phase II dose-ranging B251 1-24 547 US (54%), Europe (43%), Canada Phase III efficacy/safety B351 4, 12 799 US (97%), Canada B301 4, 12 881 Europe (90%), US, S Africa B307 4, 4-12 845 US (66%), Europe (32%), Canada Long-term safety B209 4-12 579 Europe (50%), US (41%), Canada *Divided into 2 daily doses.

4. Efficacy Presentation • Phase II • Phase III • Design and endpoints • Results • Summary

5. 1 Phase II Study Design (B251) 24 mg/d; n = 110 12 mg/d; n = 110 Baseline 4 mg/d; n = 108 1 mg/d; n = 107 Placebo; n = 113 Randomization Week –4 Week 0 Week 4 Week 8 Week 12

6. 1 Phase II Subject’s Global Assessment (SGA) of Overall GI Symptoms (B251)

7. 1 Phase III Design ConsiderationsOutcome Measures in IBS Trials (1) No consensus • No consensus on primary outcome measure • Assessment variable • Overall measure that integrates IBS symptoms • Specific symptom measure: abdominal discomfort/pain • Measurement • Ordinal and visual analog scales (VAS)

8. 1 Outcome Measures in IBS Trials (2) General consensus • Responder approach for primary efficacy variable • Frequency: at least weekly • Self-administered by patient

9. 1 B351 B301 B307 4 mg/d 4 mg/d 4 mg/d 12 mg/d 12 mg/d 4 mg/d 4 mg/d 12 mg/d Baseline Baseline Baseline Placebo Placebo Placebo 4 weeks 12 weeks 4 weeks 12 weeks 4 weeks 12 weeks Phase III Study Designs

10. 1 Inclusion Criteria • Males and females  18 years of age (B351:  12 years) • Colon evaluated within last 5 years • Rome criteria Continuous or recurrent discomfort/pain in lower abdomen in last 3 months Discomfort/pain • Relieved by BM (1 of 3) • Associated with change in frequency of BMs • Associated with change in consistency of stool  25% of the time • < 3 BMs/week (2 of 3) • Hard or lumpy stool • Straining

11. 1 Exclusion Criteria • Diarrhea associated with IBS  25% of the time • Other relevant GI conditions • Concurrent use of • Narcotics, motility agents • Laxative use except as rescue

12. 1 Randomization Criteria • Abdominal discomfort/pain • Mean baseline score  35 mm on 100-mm VAS • No upper limit cutoff for pain severity • Stool consistency • No specific mean score • Eligibility based on clinical history • Abdominal discomfort/pain • Constipation VAS = Visual analogue scale.

13. 1 Primary Efficacy VariableSGA of Relief (B351) Please consider how you felt this past week in regard to your IBS, in particular your overall well-being, and symptoms of abdominal discomfort, pain, and altered bowel habit. Compared to the way you usually felt before entering the study, how would you rate your relief symptoms during the past week: • Completely relieved • Considerably relieved • Somewhat relieved • Unchanged • Worse Response:  50% complete/considerable relief at study endpoint

14. 1 Primary Efficacy VariableSGA of Abdominal Discomfort/Pain (B351) “How much of a problem was your abdominal discomfort/pain over the last week?” Absent Very Mild Moderate Severe Very mild severe 100 mm Response:  40% reduction and at least 20-mm absolute reduction from baseline at study endpoint

15. 1 Statistical Methodology for Primary Efficacy Variables • Study endpoint: last 4 available weekly scores • Treatment comparisons by Mantel-Haenszel test stratified by center • A multiple comparison procedure was used to ensure the overall 2-sided type I error rate of  < .05

16. 1 Adjustment Rules Applied to primary efficacy variables at endpoint: • Patient defined as nonresponder if • No postrandomization SGA assessment • < 28 days treatment • Laxative intake > 5 days overall or any use in last 4 weeks of study

17. Secondary Efficacy Assessments Weekly: •SGA of bowel habit (VAS) Daily: •Intensity of abdominal discomfort/pain (6-point scale) •Intensity of bloating (6-point scale) •Number of bowel movements •Stool consistency (7-point scale) Intensity scale 0 = none 1 = very mild 2 = mild 3 = moderate 4 = severe 5 = very severe Stool consistency scale 1 = watery 2 = loose 3 = somewhat loose 4 = neither loose nor hard 5 = somewhat hard 6 = hard 7 = very hard

18. 1 Patient Disposition Patients, n (%) B351 B301 B307 Enrolled 1,093 1,122 1,163 Discontinued 292 (27) 240 (21) 313 (27)during baseline Randomized 799 881 845 Completed 633 (79) 751 (85) 680 (80) Discontinued during 166 (21) 130 (15) 165 (20)double-blind period

19. 1 Demographics Variable (mean) B351 B301 B307 Age, years 43 46 45 Gender, % female 87 83 84 Race, % Caucasian 88 98 91 Weight, kg 71 68 70 Smoking, % 21 26 22 Duration of IBS, years 14 13 14 Use of bulking agents, % 18 11 17 Fiber score, g 9 11 9

20. 1 Baseline Characteristics Variable (mean) B351 B301 B307 Abdominal discomfort/pain 63 60 61VAS score, mm Bowel habit VAS score, mm 64 60 62 Days with significant 87 84 86abdominal discomfort/pain, % Days with significant bloating, % 88 83 86 Number of bowel movements/week 5.7 5.4 6.2 Days without bowel movements, % 46 44 41 Days with hard stools, % 31 28 29 Stool consistency score 4.7 4.7 4.6

21. Efficacy ResultsPresentation Overview • Efficacy results of study B351 • Modification of primary efficacy variable for studies B301 and B307 • Efficacy results of study B301 • Efficacy results of study B307 • Summary

22. 1 SGA Data Presentation Weekly response Endpoint: Last 4 available SGA values Adjustment rules* Response, % Monthly response 1 2 3 4 5 6 7 8 9 10 11 12 Week *No SGAs, < 28 d treatment, laxative use.

23. 1 Primary Efficacy Variables at Endpoint (B351) P = .05 .27 P = .19 .08

24. 1 Placebo 4 mg/d 12 mg/d Complete or Considerable Relief by Week (B351) * † * * † * * † *P < .05 versus placebo. †P < .01 versus placebo.

25. 9 Placebo 4 mg/d 12 mg/d SGA of Abdominal Discomfort/Pain by Week (B351) * *P < .05 versus placebo. Response:  40% reduction and at least 20-mm absolute reduction from baseline on 100-mm VAS.

26. Placebo 4 mg/d 12 mg/d SGA of Bowel Habit (B351) Weekly * * † * *P < .05 versus placebo. †P < .01 versus placebo. Response:  40% reduction and at least 20-mm absolute reduction from baseline on 100-mm VAS.

27. Placebo 4 mg/d 12 mg/d Daily Diary: Abdominal Discomfort/Pain (B351) Pain score * Improvement * † † * † * * * * *P < .05 versus placebo; †P < .01 versus placebo (change from baseline). Significant: at least mild;  2 on a 6-point scale.

28. Placebo 4 mg/d 12 mg/d Daily Diary: Bloating (B351) Bloating score † Improvement * * † † * * * * * * * *P < .05 versus placebo; †P < .01 versus placebo (change from baseline). Significant: at least mild;  2 on a 6-point scale.

29. 1 Placebo 4 mg/d 12 mg/d Number of Bowel Movements and Stool Consistency by Week (B351) Bowel movements Stool consistency † † † † † † † † † † † * † † * * † † * * † * † † † † † † * † † * † * † † † * † † † † † † * † * † *P < .05 versus placebo; †P< .01 versus placebo (change from baseline).

30. 1 Summary (B351) • No statistically significant differences in primary efficacy variables • Low placebo response rates: • SGA of relief 22% • SGA of abdominal discomfort/pain 19% • Significant treatment differences observed in daily diary variables • Consistent pattern of improvement for tegaserod across primary and secondary variables

31. B351 Original SGA of relief Complete or considerable relief at least 50% of the time at study endpoint B301/B307 SGA of relief Complete or considerable relief at least 50% of the time at study endpoint OR At least somewhat (complete, considerable, or somewhat) relief for 100% of the time at study endpoint 1 Modification of Primary Efficacy Variables

32. 1 Associations Between SGA of Relief and Other Efficacy Variables (B351) Efficacy variable % change from baseline Responder Nonresponder VAS score: SGA abd discomfort/pain –48 –6 Days with significant pain –35 9 Daily pain score –40 –0.2 Days with significant bloating –32 3 Daily bloating score –38 –2 VAS score: SGA bowel habit –47 –6 Days with no bowel movement –44 –15 Days with hard or very hard stool –66 –23 All comparisons significant (P < .001) Response:  50% complete/considerable or 100% at least somewhat relief.

33. 1 Associations Between SGA of Relief and Other Efficacy Variables (B351) Efficacy variable Complete Considerable Somewhat Unchanged Worse% change from baseline (n = 48) (n = 164) (n = 222) (n = 256) (n = 61) VAS score: SGA abd –79 –50 –23 –5 8discomfort/pain Days with significant pain–73 –40 –7 18 3 Daily pain score–72 –44 –16 4 8 Days with significant –61 –37 –7 6 3 bloating Daily bloating score–64 –41 –16 1 7 VAS score: SGA bowel –75 –50 –23 –3 6 habit Days with no bowel –62 –46 –28 –10 –16 movement Days with hard or –71 –70 –50 –19 3 very hard stool Last study week

34. B351 Original SGA of relief Complete or considerable relief at least 50% of the time at study endpoint B301/B307 SGA of relief Complete or considerable relief at least 50% of the time at study endpoint OR At least somewhat (complete, considerable, or somewhat) relief for 100% of the time at study endpoint 1 SGA of abdominal discomfort/pain  40% reduction and at least 20-mm absolute reduction from baseline Secondary efficacy variable Modification of Primary Efficacy Variables for Studies B301/B307

35. 1 Efficacy Results SGA of Relief (B351) P = .05 .27 P = .16 .004 Original SGA of relief SGA of relief (retrospective analysis)

36. Study B301Efficacy Results

37. 1 Study Design (B351 and B301) 4 mg/d Baseline 12 mg/d Placebo Randomization Week –4 Week 0 Week 4 Week 8 Week 12

38. 1 SGA of Relief at Endpoint (B301) P = .018* .033* *Statistically significant. Response:  50% complete/considerable or 100% at least somewhat relief.

39. 1 B351 (retrospective analysis) P = .157 .004* P = .251 .006* Placebo 4 mg/d 12 mg/d SGA of Relief at Endpoint B301 P = .018* .033* P = .007* .003* *Statistically significant. Response:  50% complete/considerable or 100% at least somewhat relief.

40. 1 B351 (retrospective analysis) † † † † † * † Placebo 4 mg/d 12 mg/d Monthly SGA of Relief B301 *P < .05 versus placebo; †P < 0.01 versus placebo. Response:  50% complete/considerable or 100% at least somewhat relief.

41. 1 B351 † * † † † * * † Placebo 4 mg/d 12 mg/d At Least Somewhat Relief by Week B301 † † * † * * * † † † † † † † † † † * † † *P< .05 versus placebo. †P< .01 versus placebo.

42. Placebo 4 mg/d 12 mg/d * * * * * SGA of Abdominal Discomfort/Pain (B301) Weekly * *P < .05 versus placebo. Response:  40% reduction and at least 20-mm absolute reduction from baseline on 100-mm VAS.

43. Placebo 4 mg/d 12 mg/d * * * * * * † * * * * * * SGA of Bowel Habit (B301) Weekly *P< .05 versus placebo. †P< .01 versus placebo. Response:  40% reduction and at least 20-mm absolute reduction from baseline on 100-mm VAS.

44. Placebo 4 mg/d 12 mg/d Daily Diary: Abdominal Discomfort/Pain (B301) Pain score Improvement * † † † † † † † † † * * † † † † * * * * *P < .05 versus placebo; †P< .01 versus placebo (change from baseline). Significant: at least mild;  2 on a 6-point scale.

45. Placebo 4 mg/d 12 mg/d Daily Diary: Bloating (B301) Bloating score Improvement * * * † † † † * * † * * † * † * *P < .05 versus placebo; †P< .01 versus placebo (change from baseline). Significant: at least mild;  2 on a 6-point scale.

46. 1 Placebo 4 mg/d 12 mg/d Number of Bowel Movements and Stool Consistency by Week (B301) Bowel movements Stool consistency † † † † † † † † † † * † * † * † † † † † † † * † † † † † † † † * † † † † † † † † † † † † † † † *P < .05 versus placebo; †P< .01 versus placebo (change from baseline).

47. Summary Study B301 • Clear evidence of efficacy • Significant treatment differences for SGA of relief • Consistent positive findings on secondary efficacy variables

48. Study B307Efficacy Results

49. 1 Study Design (B307) 4 mg/d Nonresponder: 12 mg/d (65%) Baseline 4 mg/d Responder: 4 mg/d (35%) Placebo Randomization Week –4 Week 0 Week 4 Week 8 Week 12

50. 1 SGA of Relief (B307) Endpoint Monthly * † *P < .05 versus placebo; †P < .01 versus placebo. Response:  50% complete/considerable or 100% at least somewhat relief.