CB-1 Zelnorm ® (tegaserod maleate) Benefit/Risk Philip Schoenfeld, MD, MSEd, MSc (Epi) Division of Gastroenterology University of Michigan School of Medicine

CB-2 Outline The Benefit/Risk Analysis for Constipation Therapies: An Evidence Based Medicine Approach –Based on RCT evidence, what is the efficacy of tegaserod & traditional therapies? –Based on clinical trial data, what is the safety of tegaserod & traditional therapies?

CB-3 Epidemiology of Constipation Chronic constipation (CC) is common 1-3 CC has a negative impact on quality of life 4,5 Many constipation patients are not satisfied with available treatments 4,6 1. Stewart WF, et al. Am J Gastroenterol. 1999;94: Pare P, et al. Am J Gastroenterol. 2001;96: Sandler RS, et al. Dig Dis Sci. 1987;32: Irvine EJ, et al. Am J Gastroenterol. 2002;97: Damon H, et al. Gastroenterol Clin Biol. 2004;28: Ferrazi S, et al. Can J Gastroenterol. 2002;16:

CB-4 Efficacy

CB-5 Commonly Used Treatments* for Constipation Stimulant Laxatives –Surface-Acting Agents Dioctyl Sodium Sulfosuccinate (e.g., Colace ® ) Dioctyl Calcium Sulfosuccinate (e.g., Surfak ® ) –Diphenylmethane derivatives: Bisacodyl (e.g., Dulcolax ® ) –Anthraquinones: Senna (e.g., Senokot ® ) Bulking Agents –Psyllium (e.g, Metamucil ® ) –Methylcellulose (e.g., Citrucel ® ) Osmotic Laxatives –Poorly absorbed disaccharides: Lactulose –PEG-3350 (e.g., Miralax ® ) –Poorly absorbed ions: Magnesium Hydroxide (e.g., Milk of Magnesia) *Partial list: all treatments are FDA-approved for constipation.

CB-6 Commonly Used Treatments* for Constipation “Randomized trials … have been carried out, albeit many of them, under deficient designs” 1 “Trials revealed little difference between laxatives, and modest improvement over placebo” 1 Lack of Objective Evidence of Efficacy of Laxatives in Chronic Constipation 2 1. Prizont R. Clinical Summary of Efficacy. FDA Briefing Document, Jones MP, Talley N, et al. Dig Dis Sci. 2002;47:

CB-7 Lack of Objective Evidence of Efficacy of Laxatives* in Chronic Constipation 1 Change in Stool Frequency/week (compared to baseline) –Trials ≤ 4 weeks duration Placebo: 1.0 (95% CI: -0.3 to 2.2) Laxatives: 1.9 (95% CI: 1.0 to 2.8) –Trials 5-12 weeks duration: Placebo: 1.5 (95% CI: 0.3 to 2.8) Laxatives: 1.0 (95% CI: 0.3 to 1.6) *Laxatives in meta-analysis include senna, psyllium, lactulose, docusate, surfak, bran, calcium polycarbophil. 1. Jones MP, Talley N, et al. Dig Dis Sci. 2002;47:

CB-8 The Treatment of Chronic Constipation in Adults: A Systematic Review 1 Change in Stool Frequency/week (compared to baseline) –Bulking Agents: 1.4 (95% CI: 0.6 to 2.2) –Laxatives: 1.5 (95% CI: 1.1 to 1.8) Study Conclusions –Fiber and laxatives modestly increase stool frequency –Unknown if these agents improve global satisfaction or general well-being *Laxatives in review include psyllium, lactulose, docusate, cisapride, magnesium hydroxide, etc. 1. Tramonte S, Brand M, Mulrow C, et al for the San Antonio Veterans Affairs Cochrane Center. J Gen Int Med. 1997;12:15-24.

CB-9 Efficacy of Commonly Used Treatments for Constipation RCT evidence indicates that psyllium, PEG-3350 (e.g., Miralax ® ), and lactulose increase stool frequency RCT evidence does not demonstrate increases in stool frequency for other treatments –Most of these RCTs suffer from “deficient designs” and do not meet Rome criteria 1 1. Van Zanten et al. Gut. 1999; 5:II69-II77 (Suppl II).

CB-10 The Clinical Trial Data Are Adequate for the CC Population Likely to be Treated With Tegaserod Modified6. < 3 CSBM/wk (Required)6. < 3 BM/wk Not used5. —5. Manually assisted defecation § Not used4. —4. Sensation of obstruction/blockage § similar to Rome II3. Sensation of incomplete evacuation § Similar to Rome II2. Lumpy or hard stools § Similar to Rome II1. Straining § ≥ 6 mo history and baseline symptoms of 6 and ≥ 1 of 1,2 or 3 ≥ 12 wk in the last 12 mo with ≥ 2 of: Comparison Novartis criteria for chronic constipation Rome II criteria for functional constipation (1) #Loose stools are not present, and there are insufficient criteria for IBS. These criteria may not apply when the patient is taking laxatives. § > 25% of defecations. BM = Bowel movement; CSBM = Complete spontaneous bowel movement. 1. Thompson WG, et al. Gut 1999; 45 (Suppl II): II43-II47 Addendum to SCE T

CB-11 78% of RCT Patients Had Chronic Constipation Up to 22% of patients may have had IBS-C –“Responder rates for the non-IBS-like patients were similar to the overall rates” 1 Some patients with slow transit constipation may have been enrolled –Treatment recommendations for normal transit & slow transit constipation are quite similar 2 1. Mele J. Statistical Review & Evaluation. FDA Briefing Document. July 14, 2004, p American Gastroenterological Association Medical Position Statement on Constipation. Gastroenterology. 2000;119:

CB-12 Appropriateness of a Primary Efficacy Endpoint of ≥ 1 CSBM/wk (Compared to Baseline) Vs % of CC Patients Achieving ≥ 3 CSBM/wk ROME II Consensus Document 1 –Multiple symptoms are present in functional constipation and IBS –Multiple endpoints may be used to assess efficacy in these disorders Global improvement in satisfaction may be the most appropriate endpoint 1,2 1. Whitehead WE, Corazziari E, Prizont R, et al. Gut. 1999;45:II78-II Van Zanten et al. Gut. 1999;45:II69-II77 (Suppl II).

CB-13 Global Satisfaction With Bowel Habits *p < 0.05 for both analyses Responder: mean decrease ≥ 1 point on 5-point likert scale, compared with baseline on week * *

CB-14 Appropriateness of Efficacy Endpoints A priori secondary endpoints demonstrate significant improvement for tegaserod 6 mg bid vs placebo: –Average number of spontaneous BM/wk /wk vs /wk Tegaserod has demonstrated significant improvement vs placebo for proportion of patients with ≥ 3 CSBM/week: p < 0.05 for all analyses TegaserodPlacebo Weeks %13% Weeks – 25%13 – 14%

CB-15 Conclusions: Efficacy RCT data of tegaserod efficacy is robust and precise –The study population reflects patients with chronic constipation –The a priori primary and secondary endpoints are reflect the multiple symptoms of chronic constipation RCT data demonstrate that tegaserod produces significant and clinically important improvement in the multiple symptoms of chronic constipation

CB-16 Safety

CB-17 Commonly Used Treatments for Constipation: Safety The Treatment of Chronic Constipation in Adults 1 –“Few studies used standardized techniques for assessing adverse effects” –For laxatives vs placebo, no significant differences in adverse events were identified Conclusion: “Although there is no evidence that laxatives are unduly harmful, data are very limited and short-term” *Laxatives in review include psyllium, lactulose, docusate, cisapride, magnesium hydroxide, etc. Tramonte S, Brand M, Mulrow C, et al for the San Antonio Veterans Affairs Cochrane Center. J Gen Int Med. 1997;12:15-24.

CB-18 *Reported Adverse Effects of Laxatives 1 Bulking Agents –Acute esophageal obstruction (with or without esophageal disease) –Fecal impaction and large bowel obstruction –Anaphylaxis Osmotic Agents –Magnesium-based agents: hypermagnesemia –Phospate-based agents: hyperphosphatemia –Lactulose: hypernatremia Stimulant Laxatives –Anthraquinones: electrolyte imbalances, abdominal pain, allergic reaction, and potential hepatotoxicity. *Partial list: all treatments are FDA-approved for constipation. 1. Xing JH, Soffer E. Adverse Effects of Laxatives. Dis Colon Rectum. 2001;44:

CB-19 The clinical trials & post-marketing surveillance data provide adequate evidence of safety Over 2600 patients enrolled in two placebo-controlled RCTs of patients with chronic constipation –1742 tegaserod-using pts vs 861 placebo-using pts Clinical trial data on over 11,640 tegaserod-treated pts –3456 patient-years of tegaserod use in clinical trials Clinical trial safety data for tegaserod is more robust and precise than for any other constipation treatment

CB-20 RCT Data about Frequency of Serious Adverse Events in Constipation Patients Serious adverse events leading to discontinuation was 0.3% in both groups. n = 1742n = 861

CB-21 Diarrhea: Adverse Events *Clinical trial data on % of patients with diarrhea adverse event or discontinuation due to diarrhea comes from studies E2301 and E2302. **Clinical trial data on clinically significant consequences of diarrhea comes from the entire completed clinical trial database. CSC = Clinically significant consequences of diarrhea

CB-22 Background on Ischemic Colitis: Alosetron Data *17 cases (0.16%) of ischemic colitis among 10,805 alosetron-treated patients in clinical trials –Alosetron: 5.9 cases per 1000 patient-years –Placebo: 1.1 cases per 1000 patient-years Briefing Document on Lotronex (alosetron HCL) for the FDA Joint GI Drugs Advisory Committee and Drug Safety and Risk Management Sub-Committee. April 23, 2002.

CB-23 Reported Rate of Ischemic Colitis from Clinical Trial Data of PEG-3350 PEG-3350 (MiraLax ® ) NDA-Clinical Trial Data 1 –3 cases per 1000 patient-years 1.Gallo-Torres H. NDA Division of Gastrointestinal and Coagulation Drug Products Medical Officer’s Review. MiraLax ®. Aug 26, case of ischemic colitis/~300 patient- years CDER/CBER Pharmacovigilance Working Group. Concept Paper: Risk Assessment of Observational Data. FDA Center for Drug Research and Evaluation. March 3, Lines : FDA recognizes the value of comparisons of reporting rates across… different product classes prescribed for the same indication.

CB-24 Ischemic Colitis: Controlled Clinical Trial Data Zero cases among 11,640 tegaserod-treated patients –Zero cases over 3456 patient-years of exposure One probable IC case among 4267 placebo-treated patients –One probable IC case over 780 patient-years of exposure Chronic constipation RCT Data: 0 cases of ischemic colitis among 1742 tegaserod-using patients (e.g., ~ 430 patient-years)

CB-25 Maximum Rate (95% CI) of Ischemic Colitis Based on Clinical Trial Data Clinical Trial Patient PopulationMaximal IC Rate ~7000 Tegaserod patients (Preliminary analysis) 1 in ~ ,640 Tegaserod patients1 in Placebo patients1 in 867

CB-26 US Post-Marketing Surveillance Data Over 2 million prescriptions of tegaserod Over 233,000 patient-years of tegaserod use 26 reported cases of possible IC cases in US ~12 cases/100,000 patient-years in US

CB-27 Ischemic Colitis Is More Common in IBS C Non-IBSIBS Medi-Cal #1 ( ) United Health Care #2 ( ) (IBS > 1 year) 3 CORI, ASGE ‡ ( ) #Per 100,000 patient-yr. ‡Per 100,000 colonoscopies. 1. Singh et al. Gastroenterology 2004;126:A349;A41 2. Cole et al. American Journal of Gastro. 2004; Brinker A et al. Clinical Pharmacology and Therapeutics, 2003 vol 73, p 33 Abstract.

CB-28 Ischemic Colitis Is More Common in IBS C Non-IBSIBS Medi-Cal #1 ( ) United Health Care #2 ( ) (IBS > 1 year) 3 CORI, ASGE ‡ ( ) Post-marketing surveillance of tegaserod-using patients 12 #Per 100,000 patient-yr. ‡Per 100,000 colonoscopies. 1. Singh et al. Gastroenterology 2004;126:A349;A41 2. Cole et al. American Journal of Gastro. 2004; Brinker A et al. Clinical Pharmacology and Therapeutics, 2003 vol 73, p 33 Abstract.

CB-29 Conclusions: Safety More robust & precise clinical trial safety data for tegaserod than for other constipation therapies Safety data demonstrates a low rate of serious consequences of diarrhea Evidence does not support an association between tegaserod and ischemic colitis

CB-30 Global Benefit/Risk Assessment of Tegaserod Robust efficacy data from two largest RCTs of CC patients Significant improvement in multiple symptoms of constipation: –Global satisfaction –CSBM-SBM Robust safety data from clinical trials: –1742 CC patients –Over 11,000 patients (total) Diarrhea: –5.4% vs 3% in CC patients –D/C due to diarrhea: 0.6% –CSC of diarrhea: 0.04% Evidence does not support an association with ischemic colitis BenefitsRisks

CB-31 Global Benefit/Risk Assessment of Tegaserod This analysis demonstrates a favorable risk- benefit profile for tegaserod in the management of chronic constipation The risk-benefit analysis for tegaserod compares favorably with risk-benefit analyses of traditional therapies of constipation