FDA's Endocrinologic and Metabolic Drugs Advisory Committee will discuss whether Sanofi-Aventis' Zimulti causes an increase in suicidality at a June 13 meeting to evaluate the product's NDA.

Clinical data showing an increase in depressive disorders in Zimulti (rimonabant) treatment groups prompted FDA, in conjunction with Columbia University, to conduct retrospective meta-analyses of suicidality. The study, which is similar to the analysis that identified an association between antidepressants and suicidality, found an increase in suicidality that was statistically significant, with an overall odds ratio of 2.0, according to FDA briefing documents for the meeting.

In the four Phase III clinical trials supporting approval of Zimulti for weight loss, 26 percent of patients receiving rimonabant 20 mg experienced a psychiatric adverse event compared to 14 percent for placebo. The meta-analysis of rimonabant clinical data shows 46 cases of suicidality for patients receiving rimonabant 20 mg and 20 cases for placebo. There have been two suicides in the entire rimonabant clinical program, which consists of eight Phase III studies for various indications.

In addition, Sanofi has reported 15 instances of suicidal ideation adverse events for rimonabant, which is marketed in the EU as Acomplia .

The meeting will address the psychiatric and neurological profiles of rimonabant, after a complete response submitted by the firm failed to resolve the FDA's safety concerns.

An NDA for a weight-loss indication for rimonabant received an "approvable" letter in 2006; FDA cited concerns about increased incidence of psychiatric and neurological adverse events, including suicidality and seizures. Sanofi subsequently filed a complete response that did not provide new clinical data (¹ [A#14061031009]).

"Following review of the NDA resubmission, we remained concerned about rimonabant's adverse event profile, specifically adverse psychiatric reactions," FDA states.

FDA has asked the advisory committee to discuss whether available data sufficiently characterize Zimulti's safety profile - specifically whether rimonabant increases the incidence of suicidality, psychiatric events other than suicidality, seizures, and neurological events other than seizures.

Following a three-month extension, Zimulti has a late July user fee date for the weight-loss indication.

- Brian Marson (b.marson@elsevier.com)

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