ZELMAC (tegaserod)

1
ZELMAC (tegaserod)

• Presentation to
• GI Advisory Committee
• June 26, 2000

Raymond E. Joseph MD Medical Officer HFD-180
2
Zelmac Background

• Proposed Indication
• 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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Zelmac NDA Submission

• 2 Phase II-double-blind trials
• Study 251 (n547) 45 sites in North America and
  Europe dose-ranging with 4 dose levels of
  tegaserod or PL for 12 weeks
• Study 202 (n123) 16 sites in Europe and Canada
  dose-titration with 4 dose levels of tegaserod or
  PL for 20 weeks

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Summary of Phase II Studies

• Study 251
• 1mg/d PL 4mg/d most effective dose
• No dose response seen over the range of
• 4 to 24 mg/d
• Study 202
• Increased response rates observed during
• dose-titration from 4 to 12 mg/d
• Doses of 4 and 12 mg/d chosen for Phase III
  trials

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Phase III Trials -2521 PtsSimilarities
PL-controlled, double-blind, randomized, three
parallel groups with dose levels of 4, 12 mg vs
placebo with 4 week baseline and 12 -week
treatment period
Study 351 Study 301 Study 307
(Dose titration- 4 to 12 mg/d at 1
mo)
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Phase III Trials

• Study 351(n799)
• First of the three Phase III studies to be
  completed
• The protocol pre-specified analysis failed to
  demonstrate efficacy
• Subsequently
• a) the definition of responder in the SGA of
  relief was
• changed to incorporate somewhat relieved
  100 of
• the time
• b) the SGA of abd. discomfort/pain was changed to
  a
• secondary efficacy variable
• Post-hoc analyses incorporating the above changes
  demonstrated efficacy for the 12 mg/d dose level

• Led to protocol amendments for studies 301 and 307

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Responder Rates for SGA of Relief
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Efficacy Issues

• 1. Pain not adequately assessed as an efficacy
• endpoint
• 2. Overall difference between drug and PL group
  is 8
• 3. Efficacy in males not established
• 4. Potential affect of laxatives

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Abdominal Pain

• Pain is an essential component of IBS
• When analyzed as a component of SGA of relief
  along with well-being and altered bowel function
  was statistically significant for studies 351 and
  301
• However, when analyzed independently no
  statistical difference was seen in studies 301
  and 307

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Responder Rates for SGA of Abdominal
Discomfort/Pain
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Overall Efficacy 8-11

• Discussion Factors
• a) effect of gender in this study group
• b) effect of long-standing disease
• Are results clinically meaningful?

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Efficacy in Males

• Studies included 15 males
• Response to Zelmac in males was not different
  compared to placebo
• Lack of differentiation from placebo
• inadequate sample size
• may raise the question whether the disease is
  different in males

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Laxative Use

• 1. In the clinical trails, laxative use including
  bulking-agents was allowed
• 2. The use and timing of laxatives may influence
  the response of the SGA of relief
• 3. There was similar qualitative consumption
  between groups
• Quantitative differences not assessed may be
  affecting outcome in constipation study patients

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Efficacy Summary

• 1. Overall efficacy was shown in one of the
  pivotal studies (301) for both the 4 mg and 12 mg
  dose levels supportive study 351 showed
  efficacy for the 12 mg dose level only efficacy
  not replicated in 307
• 2. Efficacy in males not demonstrated
• 3. Laxative usage may have had an affect on
  efficacy

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Most Frequently Reported AEs in Phase III
In Phase II and long term results are similar