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NDA 21-200 NDA 21-200

Gastrointestinal Advisory Committee Meeting

Gaithersburg, MarylandJune 26, 2000

Gastrointestinal Advisory Committee Meeting

Gaithersburg, MarylandJune 26, 2000

Zelmac™

(tegaserod)Zelmac™

(tegaserod)

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IntroductionIntroduction

Mathias Hukkelhoven, PhD

Vice PresidentHead, US Drug Regulatory Affairs

Novartis Pharmaceuticals Corporation

Mathias Hukkelhoven, PhD

Vice PresidentHead, US Drug Regulatory Affairs

Novartis Pharmaceuticals Corporation

Zelmac™

(tegaserod)Zelmac™

(tegaserod)

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Proposed IndicationProposed 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.

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 SyndromeIrritable 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

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 IBSSpectrum of IBS

Patients can have different bowel symptoms over timePatients can have different bowel symptoms over time

DiarrheaDiarrhea ConstipationConstipationAlternatingAlternating

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TegaserodPharmacologic Profile

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

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 BackgroundRegulatory 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)

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

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

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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AgendaAgenda

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

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