Suicide Associated With Sanofi-Aventis’ Acomplia, U.K. Agency Says

One suicide and 48 suicidal ideation cases reported following treatment with Acomplia between June 2006 and May 9.

With adverse psychiatric events, including suicide, being linked to Sanofi-Aventis' weight loss agent Acomplia (rimonabant) in the U.K., approval of the cannabinoid-1 receptor antagonist by U.S. regulators appears even less likely, particularly given FDA's cautious approach to suicide risk.

Safety concerns could also impact upcoming drugs in the class, such as Merck's taranabant, also in development for obesity.

From the start, Sanofi has been dogged by data linking rimonabant with depression. It is the reason the drug has failed to gain support from U.S. regulators thus far. But now an analysis by the U.K.' s Medicines and Healthcare Products Regulatory Agency citing reports of depression, suicide and suicidality in the U.K. -where it is marketed - is adding to Acomplia's woes.

Between the time it was approved in Europe in June 2006 and May 9, Acomplia is linked to 974 spontaneous psychiatric reports and one suicide, according to an MHRA Drug Analysis Print for Acomplia. Of the 974 reports, 149 were for depression and 48 for suicidal ideation. In addition, there were two suicide attempts, according to the Drug Analysis Print.

"Depressive reactions continue to be a source of concern," the agency said in separate Drug Safety Update. MHRA estimates such reactions may occur in up to 10 percent of patients treated with rimonabant.

MHRA notes symptoms of depression may occur in patients with no obvious risk factors, aside from obesity itself. "Evidence suggests that many patients who develop such reactions will do so within two weeks of starting treatment."

Sanofi said there were more than 100,000 prescriptions written for Acomplia in the U.K. in 2007 alone.

In the EU, Acomplia was approved despite evidence associating it with psychiatric events including depression and anxiety (¹ (Also see "Acomplia To Launch In July In Europe For Obesity Indication" - Pink Sheet, 21 Jun, 2006.)).

However, in the U.S., Sanofi withdrew its application for rimonabant for obesity after an FDA advisory committee unanimously rejected approval given the psychiatric and neurological profile of the drug. The company continues to evaluate rimonabant in clinical trials and aims to file for type 2 diabetes in 2009.

Suicidality is becoming an increasingly hot button issue at FDA. The agency recently issued a MedWatch alert on suicide risk for Merck's Singulair (montelukast).

In January, the agency suggested a link between antiepileptics and suicide would likely lead to broad labeling changes for the class (² (Also see "FDA Issues Suicidality Alert On Antiepileptics" - Pink Sheet, 31 Jan, 2008.)).

Following on that January Medwatch alert, antiepileptic drug manufacturers, including GlaxoSmithKline, Pfizer and UCB, met with FDA officials to discuss the addition of warnings on labels June 2, according to the Wall Street Journal. The expected outcome of that meeting is that the agency will indeed require the warnings.

Pfizer's Chantix (varenicline) has also come under the microscope recently, with FDA strengthening the warnings on neuropsychiatric events, following postmarketing reports.

It is no surprise FDA is taking a cautious approach, given it is getting increased attention from the media and Congress over its method of approving drugs.

The European Medicines Agency took steps, following the approval of Acomplia, to heighten awareness of potential psychiatric events associated with the drug; last year, the agency recommended adjusting labeling language contraindicating Acomplia in patients taking antidepressants.

In March, the U.K.' s National Institute for Clinical Excellence proposed coverage of Acomplia as an adjunct to diet and exercise but recommended that treatment should only continue past six months if the patient has lost at least 5 percent body weight and should not persist past two years without a formal clinical assessment (³ (Also see "UK’s NICE Proposes Coverage For Troubled Sanofi Obesity Drug Rimonabant" - Pink Sheet, 26 Mar, 2008.)).

The Acomplia label recommends a once-daily dose of 20 mg as an adjunct to diet and exercise in obese patients.

Merck, which is developing taranabant for obesity, recently said it would focus on developing the drug at a lower 2 mg dose after adverse psychiatric events were seen with 4 mg and 6 mg doses in a Phase III study (⁴ (Also see "Merck To Focus Taranabant Development On Lower Dose" - Pink Sheet, 31 Mar, 2008.)).

-Brooke McManus ([email protected])