Sanofi-Aventis intends to resubmit its NDA for Zimulti (rimonabant) pending clarification of FDA's questions regarding its obesity claim. The firm announced it was withdrawing the application June 29, roughly two weeks after the agency's Endocrinologic and Metabolic Drugs Advisory Committee unanimously voted against approval of the cannabinoid-1 receptor antagonist for weight loss.

During a same-day conference call discussing the decision, Senior VP-Scientific and Medical Affairs Marc Cluzel said it was "mainly due to our difficulty to understand some points raised by the advisory panel and written in the minutes of the advisory committee from the FDA such as the duration of treatment requested for chronic disease."

"We do not understand exactly some points in terms of the obesity indication and we want to have more time to discuss [those issues] with the FDA."

One of the concerns raised during the June 13 Endocrinologic and Metabolic Drugs Advisory Committee meeting was the duration of the four pivotal trials for the weight loss indication. Questions about the psychiatric and neurological profile of Zimulti ultimately led the panel to conclude that existing data do not sufficiently characterize rimonabant's safety (¹ Also see "Advisory Committee Unanimously Rejects Sanofi’s Zimulti" - Pink Sheet, 13 June, 2007.).

While Sanofi's NDA included a broad array of weight-related claims, FDA focused on the obesity claim, which was the only indication presented for the advisory committee review.

"Of course we are committed to providing Zimulti to the appropriate American patients because we are very confident [in its benefit]," Cluzel stated. "In order to do so, we [will] continue our clinical program, and we've quickly approached the FDA in order to determine together the most suitable label."

"We think that the [optimal treatment candidate] is the one that we described [at the] advisory committee, which is in fact not obese patients per se, but obese with morbid complications linked with obesity."

The firm seems to have decided to head FDA off at the pass by pulling the NDA now, before the agency can issue a "not approvable" letter; the weight loss indication had a late July user fee date.

Sanofi received an "approvable" for the indication requesting additional trials in 2006, but another NDA for smoking cessation was deemed "not approvable" (² Also see "Acomplia Is "Not Approvable" For Smoking Cessation, "Approvable" For Weight Loss" - Pink Sheet, 17 February, 2006.).

A complete response submitted by the firm included no new data and failed to address FDA's concerns regarding incidence of psychiatric and neurological adverse events with the drug (³ [A#14061031009]).

In addition to concerns over Zimulti's psychiatric and neurological profile, a possible increased risk in suicidality likely contributed to the committee's recommendation. A retrospective meta-analysis of clinical data conducted by Columbia University researchers 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 (⁴ Also see "Will Zimulti’s Outlook Be Affected By Suicidality Signal?" - Pink Sheet, 12 June, 2007.).

Cluzel maintained that FDA's odds ratio was incorrect; according to Sanofi, the ratio was 1.3.

Regardless of the outcome for the obesity NDA, Zimulti could still enter the market as a type 2 diabetes drug, although the company will not confirm plans to pursue that indication.

During the advisory committee, Sanofi presented results of a second Phase III trial in diabetes, SERENADE, which could potentially serve as a confirmatory trial supporting the Phase III Rimonabant In Obesity-Diabetes Trial, part of the original NDA package. SERENADE, which was conducted in 278 treatment-naive type 2 diabetes patients, was submitted to FDA in February. SERENADE data were first reported in late 2006 (⁵ Also see "Acomplia SERENADE Data Is Music To Sanofi’s Ears" - Pink Sheet, 5 December, 2006.).

The company has another ongoing trial, CRESCENDO, evaluating the risk of major cardiovascular events in abdominally obese patients with clustering risk factors. The study has thus far enrolled 8,000 patients.

Rimonabant is marketed as Acomplia in the EU, where it has been approved since June 2006 (⁶ Also see "Acomplia To Launch In July In Europe For Obesity Indication" - Pink Sheet, 21 June, 2006.).

- Brooke McManus (b.mcmanus@elsevier.com)

Sanofi Withdraws Zimulti NDA For Weight Loss

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