1. CE-1 Zelnorm ® (tegaserod maleate) Efficacy and Safety in Chronic Constipation Eslie Dennis, MD Senior Medical Director: Gastroenterology Clinical Development and Medical Affairs Novartis Pharmaceuticals Corporation Eslie Dennis, MD Senior Medical Director: Gastroenterology Clinical Development and Medical Affairs Novartis Pharmaceuticals Corporation C

2. CE-2 Outline  Rationale  Study objectives  Study design  Patient population  Efficacy –Primary –Secondary  Safety and tolerability –12-wk double-blind, placebo-controlled –13 months extension, double-blind, uncontrolled  Rationale  Study objectives  Study design  Patient population  Efficacy –Primary –Secondary  Safety and tolerability –12-wk double-blind, placebo-controlled –13 months extension, double-blind, uncontrolled C

3. CE-3 NH NH 2 OH SerotoninTegaserod C Rationale for Drug Design Similarity to Serotonin (5-HT)  An aminoguanidine indole, designed to act specifically at 5-HT 4 receptors in the GI tract NH N O

4. CE-4 Rationale for Zelnorm ® in Chronic Constipation Program #Nguyen A, et al. J Pharmacol Exp Ther. 1997;280:1270-1276. §Weber E, et al. Gastroenterology. 2004; 126(Suppl 2):A147-A148. ‡Novick J et al. Aliment Pharmacol Ther. 2002;16:1877-1888. #Nguyen A, et al. J Pharmacol Exp Ther. 1997;280:1270-1276. §Weber E, et al. Gastroenterology. 2004; 126(Suppl 2):A147-A148. ‡Novick J et al. Aliment Pharmacol Ther. 2002;16:1877-1888. In IBS-C clinical studies:  Increases stool frequency ‡  Improves stool consistency ‡  Improves straining ‡ In IBS-C clinical studies:  Increases stool frequency ‡  Improves stool consistency ‡  Improves straining ‡ C Mechanism of action:  Enhances gut motility #  Decreases transit time #  Increases chloride and water secretion § Mechanism of action:  Enhances gut motility #  Decreases transit time #  Increases chloride and water secretion §

5. CE-5 Phase III Chronic Constipation C

6. CE-6 Study Objectives Pivotal Studies E2301, E2302  To evaluate efficacy, tolerability, and safety of Zelnorm ® in patients with chronic constipation –2 mg and 6 mg BID vs placebo –12-wk treatment period  To evaluate efficacy, tolerability, and safety of Zelnorm ® in patients with chronic constipation –2 mg and 6 mg BID vs placebo –12-wk treatment period 19 CSRs E2301, E2302; Sections 2

7. CE-7 Study Designs C

8. CE-8 Study E2301 Study Design Study E2301 11 2.5 Clinical Overview F1-1 12-wk Treatment period Screening Zelnorm ® 2 mg BID Placebo Zelnorm 6 mg BID N = 1264 Europe, Australia, South Africa 2-wk Baseline No study drug

9. CE-9 Studies E2301, E2301E Study Design Studies E2301, E2301E 11 2.5 Clinical Overview F1-1 12-wk Treatment period Screening No study drug Zelnorm ® 2 mg BID Placebo Zelnorm 6 mg BID N = 1264 Europe, Australia, South Africa n = 842 Zelnorm 2 mg BID Zelnorm 6 mg BID 13-mo Extension period E2301E1 2-wk Baseline Zelnorm 6 mg BID

10. CE-10 Study E2302 Study Design Study E2302 11 2.5 Clinical Overview F1-1 12-wk Treatment period Screening Zelnorm ® 2 mg BID Placebo Zelnorm 6 mg BID N = 1348 North and South America 4-wk Withdrawal No study drug 2-wk Baseline No study drug

11. CE-11 CSBM Is the Basis for Patient Inclusion and Endpoints  BM: Bowel Movement  SBM: Spontaneous Bowel Movement –Spontaneous: non–laxative-induced stool; no laxative or enema in 24 hr preceding BM  CSBM: Complete Spontaneous Bowel Movement –Complete: BM that results in sensation of complete evacuation –Measure of quality and frequency  BM: Bowel Movement  SBM: Spontaneous Bowel Movement –Spontaneous: non–laxative-induced stool; no laxative or enema in 24 hr preceding BM  CSBM: Complete Spontaneous Bowel Movement –Complete: BM that results in sensation of complete evacuation –Measure of quality and frequency C Protocol CSR E2301, E2302, Sections 2, Pages 8 -9

12. CE-12 Current Concepts: Chronic Constipation Lembo, Camilleri N Engl J Med 2003; 349:1360-8 “An epidemiologic study of constipation in the United States identified it as an inability to evacuate stool completely and spontaneously three or more times per week” ‡ ‡ Stewart et al. Am J Gastroenterol. 1999;94;3530-3540

13. CE-13 Main Inclusion Criteria Pivotal Studies E2301, E2302  Male or female, ≥ 18 yr of age  Chronic constipation # –Chronic: ≥ 6 months of constipation symptoms –Constipation: < 3 CSBM/wk and ≥ 1 of the following (≥ 25% of occurrences): Hard/very hard stools Sensation of incomplete evacuation Straining  Normal endoscopic/radiologic bowel evaluation within past 5 yr and after onset of symptoms –No alarm features  Male or female, ≥ 18 yr of age  Chronic constipation # –Chronic: ≥ 6 months of constipation symptoms –Constipation: < 3 CSBM/wk and ≥ 1 of the following (≥ 25% of occurrences): Hard/very hard stools Sensation of incomplete evacuation Straining  Normal endoscopic/radiologic bowel evaluation within past 5 yr and after onset of symptoms –No alarm features 19 CSRs E2301, E2302; Sections 3.3.2; 2.5 Clinical Overview, Section 4.3 CSBM = Complete spontaneous bowel movement. #Modified Rome II criteria.

14. CE-14 Main Exclusion Criteria Pivotal Studies E2301, E2302  Constipation due to: –Organic disease of the colon –Known mechanical outlet dysfunction –Bowel or gynecologic surgery –Metabolic disturbances –Neurologic disturbances  Concomitant medications  Fecal impaction requiring surgical or manual intervention  Significant medical disorder that could interfere with completion of study  Constipation due to: –Organic disease of the colon –Known mechanical outlet dysfunction –Bowel or gynecologic surgery –Metabolic disturbances –Neurologic disturbances  Concomitant medications  Fecal impaction requiring surgical or manual intervention  Significant medical disorder that could interfere with completion of study 19 CSRs E2301, E2302; Section 3.3.2

15. CE-15 Exclusion Criteria at Randomization Pivotal Studies E2301, E2302 Patients excluded if  During the 14-day baseline period –Constipation not confirmed by diary data –Loose or watery stools > 3 days –Laxatives > 2 days outside of guidelines –Noncompliant with completion of diary (< 11 days) Patients excluded if  During the 14-day baseline period –Constipation not confirmed by diary data –Loose or watery stools > 3 days –Laxatives > 2 days outside of guidelines –Noncompliant with completion of diary (< 11 days) C Protocol E2301, E2302; Sections 3.3.2

16. CE-16 Data Collected Pivotal Studies E2301, E2302  Daily per bowel movement –Straining –Stool frequency –Stool form –Complete/incomplete evacuation  Weekly –Satisfaction with bowel habits –Bothersomeness of Constipation Distension/bloating Abdominal discomfort/pain  Daily per bowel movement –Straining –Stool frequency –Stool form –Complete/incomplete evacuation  Weekly –Satisfaction with bowel habits –Bothersomeness of Constipation Distension/bloating Abdominal discomfort/pain C

17. CE-17 Patient Disposition

18. CE-18 Patient Disposition—ITT Population Pivotal Studies E2301, E2302—Pooled Patients, % Placebo n = 863 Zelnorm ® 2 mg BID n = 867 Zelnorm 6 mg BID n = 882 Completed81.584.283.1 Discontinued18.515.816.9 Reason for discontinuation Unsatisfactory therapeutic effect 7.24.43.7 Adverse event(s)3.73.25.3 Withdrew consent3.03.34.3 Other4.64.83.5 Summary of Clinical Efficacy T 3-8 C

19. CE-19 Results C

20. CE-20 Demographic Information Pivotal Studies E2301, E2302 CSR E2301, PTT 7.3-1, 7.6-5; CSR E2302, PTT 7.3-1, 7.6-5 E2301 N = 1264 E2302 N = 1348 Female86%90% Age (mean, yr)4647 Range, yr18 - 8618 - 88 ≥ 65 yr14%12% Postmenopausal # 43%48% Caucasians98%85% C #Female population (E2301, n = 1091; E2302, n = 1213).

21. CE-21 Constipation Symptoms Prior to Start of Treatment E2301 (N = 1264)E2302 (N = 1348) Mean History Duration of symptoms, yr14.719.5 Hard/very hard stools73.9%77.0% Average SBM/wk, n1.4 Diary data (14-day baseline) CSBM/wk, n0.50.6 SBM/wk, n3.13.6 SBM with straining/wk, n2.63.1 Stool form2.62.9 C CRS E2301,E2302 PTTS 7.5-1, 7.6-5

22. CE-22 Constipation Symptoms Prior to Start of Treatment E2301 (N = 1264)E2302 (N = 1348) MeanMedianMeanMedian History Duration of symptoms, yr14.710.019.515.3 Hard/very hard stools73.9%90%77.0%90% Average SBM/wk, n 1.4 1 1 Diary data (14-day baseline) CSBM/wk, n0.500.60 SBM/wk, n3.12.53.62.9 SBM with straining/wk, n2.62.03.12.5 Stool form2.62.52.92.8 C CRS E2301,E2302 PTTS 7.5-1, 7.6-5

23. CE-23 Primary Efficacy Variable

24. CE-24 Primary Efficacy Variable Pivotal Studies E2301, E2302 Wk 1 - 4 Wk 5 - 8 Wk 9 - 12 2-wk drug-free baseline 12-wk treatment Responder –Increase of ≥ 1 CSBM/wk during the first 4 wk of treatment compared with baseline –≥ 7 days of treatment Responder –Increase of ≥ 1 CSBM/wk during the first 4 wk of treatment compared with baseline –≥ 7 days of treatment CSBM = Complete spontaneous bowel movement. 19 CSR E2301, F 3-1; E2302 pages 22-23

25. CE-25 Primary Efficacy Variable Pivotal Studies E2301, E2302 *P <.05, ***P <.0001 Responder = Increase of ≥ 1 CSBM/wk during Wk 1- 4 and ≥ 7 days of treatment. CSBM = Complete spontaneous bowel movement. C E2301 * *** CSRs E2301, E2302 PTT 9.1-1 n = 416 E2302 *** n = 450n = 447n = 451 n = 417n = 431

26. CE-26 Secondary Efficacy Variable: Increase of ≥ 1 CSBM/wk During Wk 1 - 12 Pivotal Studies E2301, E2302 Responder –Increase of ≥ 1 CSBM/wk during the entire 12-wk treatment period compared with baseline # Responder –Increase of ≥ 1 CSBM/wk during the entire 12-wk treatment period compared with baseline # 18 CSBM = Complete spontaneous bowel movement. # ≥ 7 days of treatment. Protocol E2301 Amendment 3, Sections 1, 2 Wk 1 - 4 Wk 5 - 8 Wk 9 - 12 2-wk drug-free baseline 12-wk treatment

27. CE-27 Secondary Efficacy Variable: Increase of ≥ 1 CSBM/wk During Wk 1- 12 Pivotal Studies E2301, E2302 ***P <.0001 Responder = Increase of ≥ 1 CSBM/wk during Wk 1 - 12 and ≥ 7 days of treatment. CSBM = Complete spontaneous bowel movement. C E2301E2302 *** CSRs E2301, E2302 PTT 9.1-5 n = 416n = 450n = 447n = 451n = 417n = 431

28. CE-28 Weekly Responder Rate Pivotal Studies E2301, E2302 CSR E2301, PTT 9.1-4; CSR E2302, PTT 9.1-4 E2301 N = 1264 E2302 N = 1348 48 P <.05, Zelnorm 2 mg BID vs placebo; P <.05, Zelnorm 6 mg BID vs placebo, Cochran-Mantel-Haenszel test. Responder = Increase of ≥ 1 CSBM/wk and ≥ 7 days of treatment. EOT = End of treatment; W = Withdrawal. PlaceboZelnorm® 2 mg BIDZelnorm 6 mg BID

29. CE-29 Weekly Responder Rate Pivotal Studies E2301, E2302 CSR E2301, PTT 9.1-4; CSR E2302, PTT 9.1-4 E2301 N = 1264 E2302 N = 1348 48 P <.05 vs placebo, Cochran-Mantel-Haenszel test. Responder = Increase of ≥ 1 CSBM/wk and ≥ 7 days of treatment. EOT = End of treatment; W = Withdrawal. PlaceboZelnorm 6 mg BID

30. CE-30 Complete Spontaneous Bowel Movements Pivotal Studies E2301, E2302 E2301 N = 1264 E2302 N = 1348 48 P <.05, Zelnorm 2 mg BID vs placebo; P <.05, Zelnorm 6 mg BID vs placebo, van Elteren test. Mean data. CSBM = Complete spontaneous bowel movement; EOT = End of treatment; W = Withdrawal. PlaceboZelnorm® 2 mg BIDZelnorm 6 mg BID CSR E2301, E2302, PTTs 9.2-2

31. CE-31 Complete Spontaneous Bowel Movements Pivotal Studies E2301, E2302 E2301 N = 1264 E2302 N = 1348 48 PlaceboZelnorm ® 6 mg BID P <.05 vs placebo, van Elteren test. Mean data. CSBM = Complete spontaneous bowel movement; EOT = End of treatment; W = Withdrawal. CSR E2301, E2302, PTTs 9.2-2

32. CE-32 Further a priori Secondary Variables

33. CE-33 Satisfaction With Bowel Habits Wk 1 - 12 Pivotal Studies E2301, E2302 *P <.05; **P <.001 Responder = Mean decrease of ≥ 1 point on a 5-point scale compared with baseline, Wk 1 - 12. Scale 0 - 4, 0 = a very great deal satisfied, 4 = not at all satisfied. * * ** 48 n =416417431447450451 SCE T 3-18

34. CE-34 Stool Form Change From Baseline Pivotal Studies E2301, E2302 P <.05, Zelnorm 2 mg BID vs placebo; P <.05, Zelnorm 6 mg BID vs placebo. Mean data. EOT = End of treatment; W = Withdrawal. Scale 1- 7, 1 = hard, 7 = watery. CSRs E2301, E2302 PTTs 9.2-5 32 Placebo Zelnorm® 2 mg BID Zelnorm 6 mg BID E2301 N = 1264 E2302 N = 1348

35. CE-35 Straining Score of Spontaneous Bowel Movements—Change From Baseline Pivotal Studies E2301, E2302 P <.05, Zelnorm 2 mg BID vs placebo; P <.05, Zelnorm 6 mg BID vs placebo. Mean data. EOT = End of treatment; W = Withdrawal. Scale 0 - 2, 0 = no straining, 1 = acceptable straining, 2 = too much straining. CSRs E2301, E2302 PTTs 9.2-6IMPROVEMENT 32 Placebo Zelnorm® 2 mg BID Zelnorm 6 mg BID E2301 N = 1264 E2302 N = 1348

36. CE-36 Response Rates by Reduction of Bothersomeness - Wk 1 - 12 Pivotal Studies E2301, E2302 Patients, % Study E2301Study E2302 Placebo n = 416 Zelnorm ® 2 mg BID n = 417 Zelnorm 6 mg BID n = 431 Placebo n = 447 Zelnorm ® 2 mg BID n = 450 Zelnorm 6 mg BID n = 451 Constipation27.7 34.6* 40.9***25.7 35.1* 37.5** Abdominal Distension/ bloating 27.130.832.327.6 36.0* 35.4* Abdominal discomfort/pain 22.527.828.321.4 31.8** 30.5* *P <.05; **P <.001; ***P <.0001; Responder = Mean decrease of ≥ 1 point on a 5-point scale compared with baseline. Scale 0 to 4, where a lower score indicates less bother and greater satisfaction. Summary of Clinical Efficacy T 3-18 C

37. CE-37 Association of CSBM and Improvement of Symptoms (Wk 1 - 4) Pivotal Studies E2301, E2302—Pooled Median % change from baseline VariableResponderNon-responder P value Stool form of SBM41.612.5<.0001 Satisfaction with bowel habit–40.0–6.7<.0001 Constipation score–37.5–8.3<.0001 Straining score–37.6–9.4<.0001 Days with too much straining–50.0–25.0<.0001 Abdominal pain score–33.30<.0001 Bloating score–33.3–8.3<.0001 C No DV

38. CE-38 Additional Analyses

39. CE-39 Responder –≥ 3 CSBM/wk during the first 4 wk of treatment ‡ –No comparison with baseline Responder –≥ 3 CSBM/wk during the first 4 wk of treatment ‡ –No comparison with baseline CSBM = Complete spontaneous bowel movement. #FDA responder definition #1. ‡ ≥ 7 days of treatment. Protocol E2301 Amendment 3, Sections 1, 2 18 Wk 1 - 4 Wk 5 - 8 Wk 9 - 12 2-wk drug-free baseline 12-wk treatment ≥ 3 CSBM/wk Secondary Efficacy Variable: ≥ 3 CSBM/wk During Wk 1 - 4 # Pivotal Studies E2301, E2302

40. CE-40 Secondary Efficacy Variable: ≥ 3 CSBM/wk During Wk 1 - 4 # Pivotal Studies E2301, E2302 C ** * E2301E2302 *** *P <.05; **P <.001; ***P <.0001. #FDA responder definition #1. CSRs E2301, E2302 PTT 9.2-16 n = 412n = 444n = 442n = 449n = 410n = 428

41. CE-41 Secondary Efficacy Variable: ≥ 3 CSBM/wk During Wk 1 - 12 # Pivotal Studies E2301, E2302 *** ***P <.0001 #FDA responder definition #2. E2301E2302 C CSRs E2301, E2302 PTT 9.2-17

42. CE-42 Responders by Baseline Bowel Movements/Wk C

43. CE-43 Responders by Baseline Bowel Movements/wk Primary Efficacy Variable Pivotal Studies E2301, E2302—Pooled *P <.05; **P <.01; ***P <.0001 Responder = increase of ≥ 1 CSBM/wk, Wk 1 - 4, and ≥ 7 days of treatment. BM = Bowel movement; CSBM = Complete spontaneous bowel movement. n = 890 (34.4%)n = 1695 (65.6%) SCE PTT 9.1-1c *** ** *** 20

44. CE-44 0.1110 Overall < 65 yr ≥ 65 yr Male Female Caucasian Black No baseline laxatives Baseline laxatives Responders by Subgroup Primary Efficacy Variable Pivotal Studies E2301, E2302—Pooled Patients, n Zelnorm 6 mg BID Placebo 32 805 771 106 88 789 877 33 780 761 93 117 737 854 Odds ratio Zelnorm ® 6 mg BID versus placebo, Wk 1 - 4 Responder = Increase of ≥ 1 CSBM/wk; CSBM = Complete spontaneous bowel movement. 470 407 438 416 C SCE Ts 3.12-13.13-1, 3.14-1, 3.15-1, 3.16-1, 3.17-1, 3.24-1

45. CE-45 Patients With IBS-Like Features Pivotal Studies E2301, E2302—Pooled Addendum to SCE T 3-1, ED June 8, 2004 Patients, n (%) Criteria Placebo n = 863 Zelnorm ® 2 mg BID n = 867 Zelnorm 6 mg BID n = 882 a. History of diagnosis of IBS 21 (2)29 (3)39 (4) b.Abdominal discomfort/pain as main complaint 102 (12)108 (12)109 (12) c. Abdominal discomfort/ pain > 0 and diarrhea # 82 (10) 89 (10) 78 (9) d. Meets any of the above criteria 185 (21)201 (23)197 (22) #Patients with ≥ 25% of SBM loose or watery (stool form 6 or 7) or > 3 SBM/day for ≥ 25% of days. SBM = Spontaneous bowel movement. 54-1

46. CE-46 Responders Without IBS-Like Features Primary Efficacy Variable Pivotal Studies E2301, E2302—Pooled *P <.05; ***P <.0001 Responder = increase of ≥ 1 CSBM/wk, Wk 1 - 4, and ≥ 7 days of treatment. CSBM = Complete spontaneous bowel movement. Addendum to Summary of Clinical Efficacy T 3-3 C PlaceboZelnorm® 2 mg BIDZelnorm 6 mg BID CC patients without IBS-like features n = 666 n = 651 n = 675 0 10 20 30 40 50 Patients, % *** 26 40 44

47. CE-47 Efficacy Summary  Efficacy demonstrated in patients who were chronically constipated –Early onset of relief –Sustained –No rebound  Efficacy demonstrated for the treatment of the multiple symptoms of chronic constipation  Zelnorm ® 6 mg BID consistently more efficacious than Zelnorm 2 mg BID  Efficacy demonstrated in patients who were chronically constipated –Early onset of relief –Sustained –No rebound  Efficacy demonstrated for the treatment of the multiple symptoms of chronic constipation  Zelnorm ® 6 mg BID consistently more efficacious than Zelnorm 2 mg BID C

48. CE-48 Zelnorm ® (tegaserod maleate) Safety in Chronic Constipation C

49. CE-49 Overview  12-wk safety profile –Exposure –Adverse events profile –Serious adverse events –Laboratory evaluations  Long-term safety profile (16 months)  12-wk safety profile –Exposure –Adverse events profile –Serious adverse events –Laboratory evaluations  Long-term safety profile (16 months) C

50. CE-50 Overall Exposure Pivotal Studies E2301, E2302—Pooled Summary of Clinical Safety PTT 2.1-1 14 Placebo n = 861 Zelnorm ® 2 mg BID n = 861 Zelnorm 6 mg BID n = 881 Mean duration, days ± SD 79 ± 2381 ± 2180 ± 23 ≥ 77 days, n712738740 ≥ 85 days, n603604585

51. CE-51 Most Frequent Adverse Events Pivotal Studies E2301, E2302—Pooled Clinical Overview T5-2 C

52. CE-52 Most Frequent Adverse Events # Leading to Discontinuation Pivotal Studies E2301, E2302—Pooled SCS Table 4-12 18 Patients, % Placebo n = 861 Zelnorm ® 2 mg BID n = 861 Zelnorm 6 mg BID n = 881 Any AE3.73.45.7 Abdominal pain NOS0.61.00.8 Diarrhea NOS0.20.30.9 Abdominal distension0.2 0.6 Nausea0.60.3 Headache NOS0.2 0.3 NOS = Not otherwise specified. #≥ 5 patients treated with Zelnorm ® any dose.

53. CE-53 Diarrhea Evaluation Pivotal Studies E2301, E2302—Pooled Placebo n = 861 Zelnorm® 2 mg BID n = 861 Zelnorm 6 mg BID n = 881 Patients with diarrhea, n (%)26 (3.0)36 (4.2)58 (6.6) Diarrhea episodes per patient 1 episode, n (% of patients with diarrhea) 22 (84.6)29 (80.6)48 (82.8) Duration of first episode, days (median) 2.0 2.5 Stool characteristics, first day of diarrhea (median) Bowel movements3.02.03.0 Stool form score # 5.76.06.3 SCS Table 8-1 C E2301&E2301 Diarrhea data.xls #Bristol stool form scale.

54. CE-54 Diarrhea Management Pivotal Studies E2301, E2302—Pooled Patients, n Placebo n = 861 Zelnorm ® 2 mg BID n = 861 Zelnorm 6 mg BID n = 881 Diarrhea, n (%)26 (3.0)36 (4.2)58 (6.6) No action taken192430 Concomitant medication taken 3 5 6 Dose adjusted/interrupted 3 621 Dose permanently discontinued 2 3 8 Each AE occurrence counted. C SCS T8-1 and SCS PTT 4.28-1

55. CE-55 Diarrhea—No Clinically Significant Consequences Pivotal Studies E2301, E2302  No clinically significant consequences of diarrhea  None required IV hydration or electrolyte replacement  No clinically significant consequences of diarrhea  None required IV hydration or electrolyte replacement C

56. CE-56 Serious Adverse Events Pivotal Studies E2301, E2302—Pooled Patients, n (%) Placebo n = 861 Zelnorm ® 2 mg BID n = 861 Zelnorm 6 mg BID n = 881 SAEs # 14 (1.6)11 (1.3)12 (1.4) Discontinuations due to SAEs 3 (0.3) 4 (0.5) 3 (0.3) Deaths ‡ 0 1 (0.1)0 Clinical Overview T5-3; SCS P13 #Excluding deaths. ‡Patient 2521-9: 85-yr-old male with mesothelioma; died 67 days after last dose of Zelnorm 2 mg. C

57. CE-57 Laboratory Evaluations Pivotal Studies E2301, E2302  Low frequency of notable abnormalities –Hematology –Chemistry –Liver function –Renal function  Similar between Zelnorm ® and placebo  Low frequency of notable abnormalities –Hematology –Chemistry –Liver function –Renal function  Similar between Zelnorm ® and placebo C Summary of Clinical Safety T 6-1

58. CE-58 Abdominal and Pelvic Surgeries Pivotal Studies E2301, E2302—Pooled Placebo n = 861 Zelnorm ® 2 mg BID n = 861 Zelnorm 6 mg BID n = 881 All abdominal and pelvic surgeries, n (%) 8 (0.9)3 (0.3)6 (0.7) Cholecystectomies, n001 Other, n835 C Clinical overview T 5-4, p 23

59. CE-59 Long-term Safety Studies E2301, E2301E1 (Long-term Safety Population)  842 patients entered the extension trial  Exposure –518 patients (61.7%) exposed to Zelnorm ® ≥ 12 months  Discontinuation –46% of patients discontinued 19% Unsatisfactory therapeutic response 11% Withdrew consent 10% Other (lost to follow-up, administrative reasons, etc.) 6% AE  842 patients entered the extension trial  Exposure –518 patients (61.7%) exposed to Zelnorm ® ≥ 12 months  Discontinuation –46% of patients discontinued 19% Unsatisfactory therapeutic response 11% Withdrew consent 10% Other (lost to follow-up, administrative reasons, etc.) 6% AE C CSR E2301E1 T 7-1, 8-1

60. CE-60 Adverse Events ≥ 5% Study E2301E1 (Long-term Safety Population) Patients, % Placebo - Zelnorm ® 6 mg BID n = 274 Zelnorm 2 mg BID - 2 mg BID n = 283 Zelnorm 6 mg BID - 6 mg BID n = 283 Headache16.124.021.2 Abdominal pain NOS10.914.811.3 Diarrhea NOS10.68.19.9 Nasopharyngitis6.99.511.0 Nausea4.412.49.2 Influenza5.86.710.2 Back pain5.16.07.1 Abdominal distension4.05.77.8 Abdominal pain upper4.46.46.7 Constipation4.04.66.4 Dyspepsia3.37.43.9 Flatulence5.83.94.9 Sinusitis NOS2.25.74.9 C Summary of Clinical Safety T 4-5

61. CE-61 Conclusions—Safety  Incidence of AEs on Zelnorm ® similar to placebo –Except diarrhea  Low discontinuation rate due to AEs  Long-term safety similar to pivotal studies  Zelnorm is safe and well tolerated in patients with chronic constipation  Incidence of AEs on Zelnorm ® similar to placebo –Except diarrhea  Low discontinuation rate due to AEs  Long-term safety similar to pivotal studies  Zelnorm is safe and well tolerated in patients with chronic constipation C

62. CE-62 Final Conclusions Chronic Constipation  Zelnorm ® is effective in the treatment of multiple symptoms of chronic constipation –6 mg BID consistently more efficacious than 2 mg BID  Zelnorm improves –Satisfaction with bowel habits –Straining –Stool form –Stool frequency  Zelnorm has a favorable safety profile  Zelnorm ® is effective in the treatment of multiple symptoms of chronic constipation –6 mg BID consistently more efficacious than 2 mg BID  Zelnorm improves –Satisfaction with bowel habits –Straining –Stool form –Stool frequency  Zelnorm has a favorable safety profile C

63. CE-63 Proposed Indication Zelnorm ® (tegaserod maleate) is indicated for the treatment of patients with chronic constipation and relief of associated symptoms of straining, hard or lumpy stools, and infrequent defecation. C Proposed Package Insert, 1 Oct 2003, p 8