Fat Chance for Rimonabant

Tomorrow is a big day for Sanofi-Aventis’ fat-buster rimonabant. FDA’s Endocrine and Metabolic Drugs Advisory Committee will scrutinize whether the drug’s beneficial effects on weight, triglyceride levels and cholesterol outweigh its side-effects, most significantly depression and suicidal thoughts.

The odds don’t look good for Sanofi. The timing is terrible—this review comes amid huge political controversy over FDA’s role in assessing drug safety, inflamed most recently by the cardio-vascular concerns raised around another drug the endocrinologist experts know well: GlaxoSmithKline’s diabetes drug rosiglitazone (Avandia).

What’s more, Sanofi hasn’t been known for its smooth relations with FDA; nor, say analysts, was it fast to get endocrinologists on its side. The French group is said to have cosied up early on in its rimonabant campaign primarily to the cardiovascular experts it knew already through anti-platelet drug Plavix. (Don’t forget that rimonabant, an cannabinoid receptor antagonist, is one of these multi-faceted treatments that act on a number of pathways, making it both incredibly effective in addressing metabolic disease, says Sanofi, but also incredibly dangerous in terms of unknown or unwanted side-effects, say detractors.)

Small wonder, perhaps, that the FDA review document released yesterday has no qualms about washing rimonabant’s dirty linen in public. The document highlights a statistically significant increase in suicidal thoughts and behavior, a high drop-out rate in the rimonabant trials, in part due to depression side-effects, and reels off various neurological side-effects seen with greater frequency in patients taking rimonabant.

Now granted, the drug is already approved in Europe, as Acomplia, although Sanofi still faces marketing and reimbursement challenges (many European countries consider obesity treatments as life-style medications; a convenient excuse to avoid huge payouts). So won’t six-months’ worth of post-approval data from over 78,000 European patients help reassure the US gate-keeper?

Seems not. The FDA document lists over 2300 cases of adverse reactions in the UK and Germany, “frequent” reports of nervous system disorders “driven predominantly by dizziness”, and describes in detail a handful of individual cases including a man who attempted to strangle his daughter, and another who beat his wife while on rimonabant.

This degree of detail may very well be standard Advisory Committee meeting practice. The experts will know to consider these adverse events in the light of the thousands of patients using and potentially benefiting from the drug.

But rimonabant’s path to the US market has already been bumpy. Its sponsor’s ambition has been heavily clipped by US regulators: Sanofi submitted its NDA in May 2005 for three indications besides weight management (Type II diabetes, dislipidemia and metabolic syndrome), none of which were approved. Even for the obesity indication, FDA in February 2006 requested additional data—you guessed it, on adverse events. Even the Advisory Committee meeting was hurled at rimonabant at the last minute: back in 2006, it wasn't considered necessary. Not to mention the FDA's requested name-change: just to make life a little more challenging still for Sanofi, rimonabant will be known as Zimulti in the US.

If it gets there.