Zelnorm

1
Zelnorm(tegaserod maleate)Advisory Committee
PresentationGastrointestinal Drugs

• July 14, 2004

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IntroductionJohn Cutt, PhD

• Objectives of the Presentation
• Proposed indication
• Review Zelnorm Phase III clinical trial
  information
• Review postmarketing safety data

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Introduction (continued)John Cutt, PhD

• Activity of tegaserod in GI tract
• Clinical development program for chronic
  constipation
• Zelnorm experience in clinical studies
• Worldwide experience With Zelnorm
• Conclusions
• Agenda, speakers, and consultants

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Unmet NeedCharlene Prather, MD

• Division of Gastroenterology and Hepatology
• St. Louis University School of Medicine
• External Presenter

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Efficacy and Safety in Chronic Constipation
Eslie Dennis, MD Novartis Senior Medical
Director, Gastroenterology

• Background
• TegaserodMechanism of action
• Rationale for use of Zelnorm in the treatment of
  chronic constipation
• Phase III chronic constipation studies
• Pivotal Studies E2301, 2302
• Study Objectives

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Efficacy and Safety in Chronic Constipation(conti
nued) Eslie Dennis, MD, Senior Medical Director

• Studies E2301, E2301E, E2302
• Study design
• Inclusion and exclusion criteria
• Patient disposition
• Demographic information and constipation symptoms
  prior to treatment

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Efficacy and Safety in Chronic Constipation(conti
nued) Eslie Dennis, MD, Senior Medical Director

• Results
• Primary efficacy variable, responder increase
  of gt 1 CSBM, Wk 1-4
• Secondary efficacy variable, responder increase
  of gt 1 CSBM, Wk 1-12
• Weekly responder rate and complete spontaneous
  bowel movements
• Further a priori secondary variables
• Satisfaction with bowel habits, stool form,
  straining

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Efficacy and Safety in Chronic Constipation(conti
nued) Eslie Dennis, MD, Senior Medical Director

• Additional analyses
• Responder 3 CSBM/wk during wk 1 4
• Responder 3 CSBM/wk during wk 1 - 12
• Primary efficacy variable
• Responders by baseline bowel movements per wk
• Responders by subgroup
• Patients without IBS-like features
• Efficacy in chronic constipationsummary

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Efficacy and Safety in Chronic Constipation(conti
nued) Eslie Dennis, MD, Senior Medical Director

• Safety in Chronic Constipation12-wk safety
  profile
• Exposure
• Most frequent adverse events
• Most frequent leading to discontinuation
• Diarrhea
• Evaluation and management
• No clinically significant consequences
• Serious adverse events
• Laboratory evaluations
• Summary of ECG abnormalities and QTc intervals
• Abdominal and pelvic surgeries

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Efficacy and Safety in Chronic Constipation(conti
nued) Eslie Dennis, MD, Senior Medical Director

• Long-term safety profile (16 months)
• Studies E2301, E2301E1
• Adverse events gt5
• Conclusions
• Proposed Indication

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Safety Overview (continued) Bo Joelsson Head GI
Clinical Research and Development

• Safety data CC sNDA versus IBS-C NDA
• Summary of patients treated in clinical trials
  and postmarketing
• Serious adverse events in overall clinical
  experience

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Safety Overview (continued) Bo Joelsson Head GI
Clinical Research and Development

• Special Safety Topics
• Experience in Clinical Trials and Postmarketing
• Diarrhea
• Serious consequences
• Rectal bleeding
• Ischemic colitis
• Cholecystectomies
• Biliary tract disorders
• Ovarian disease

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Safety Overview (continued) Bo Joelsson,
Novartis, Head GI Clinical Research and
Development

• Safety profile of Zelnorm? supports the use in
  patients with chronic constipation
• Overall safety conclusions

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Benefit/Risk Philip Schoenfeld, MD, MSEd, MSc
(Epi)

• Assistant Professor of Medicine
• University of Michigan School of Medicine
• External presenter