NDA 21-200

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NDA 21-200
Zelmac (tegaserod)

• Gastrointestinal Advisory Committee Meeting
• Gaithersburg, MarylandJune 26, 2000

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Introduction
Zelmac (tegaserod)

• Mathias Hukkelhoven, PhD
• Vice PresidentHead, US Drug Regulatory Affairs
• Novartis Pharmaceuticals Corporation

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Proposed Indication

• Zelmac (tegaserod) is indicated for the
  treatment of irritable bowel syndrome (IBS) in
  patients who identify abdominal pain/ discomfort
  and constipation as their predominant symptoms.

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Irritable Bowel Syndrome

• Symptoms
• Abdominal pain or discomfort
• Bloating
• Altered bowel function
• Frequency of bowel movements
• Stool consistency
• Chronic or recurrent course
• Severity ranging from mild to severe/intractable
• Symptoms due to disturbances in GI motility and
  enhanced visceral sensitivity
• Highly prevalent and associated with significant
  disability and healthcare costs

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Spectrum of IBS

• Patients can have different bowel symptoms over
  time

Diarrhea
Constipation
Alternating
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TegaserodPharmacologic Profile

• Potent and selective 5-HT4 receptor partial
  agonist
• Modulates normal and impaired motility throughout
  the gastrointestinal tract
• Modulates intestinal chloride/water secretion
• Inhibits visceral sensation upon colorectal
  distension
• Lacks cardiovascular, renal, respiratory, CNS,
  and endocrine effects

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Regulatory Background

• No clinical guidelines or medical consensus
  regarding appropriate outcome measures in IBS
• Novartis conferred with medical experts and had
  several interactions with FDA regarding outcome
  measures for the 3 tegaserod phase III studies
• Specific consultation with GI Division following
  analysis of first phase III study (B351) and
  prior to the unblinding and analysis of the
  remaining 2 phase III studies (B301 and B307)

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TegaserodClinical Profile

• Totality of data derived from 4,000 subjects of
  whom 3,000 IBS patients were enrolled in clinical
  studies, support the following clinical profile
• Tegaserod 12 mg/d (6 mg BID) is effective in
  relieving abdominal pain or discomfort, bloating,
  and constipation in patients who identify
  abdominal pain or discomfort and constipation as
  their predominant symptoms
• Tegaserod is safe and well tolerated

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Agenda

• Irritable Bowel Syndrome . . . . . . . . . .
  Arnold Wald, MD
• 5-HT4 Receptor Activation . . . . . . Michael
  Camilleri, MD
• Efficacy and Safety of Tegaserod . . . . . . . .
  . . . . . . . . . Martin Lefkowitz, MD
• Preclinical Findings . . . . . . . . . . . . .
  Philip Bentley, PhD
• Review of Data on Ovarian Cysts . . . . . . . .
  . . . . . . . . . . . . . . Bruce Carr, MD
• Closing Remarks . . . . . . . . . . . . . . .
  . Sidney Cohen, MD