FDA Says “NO” to Rimonabant: Safety Not Demonstrated

In a blow to the drug maker and millions of overweight and obese Americans hoping for a new weight-loss medication, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee unanimously told Sanofi-Aventis to gather more detailed safety information about rimonabant over the long term, in larger patient numbers. All 14 members of the advisory committee agreed that rimonabant did not demonstrate the risk/benefit profile that would enable it to be approved for the indication sought: weight management in individuals with a body-mass index (BMI) of >30 kg/m2 or in individuals with a BMI of >27 kg/m2 when accompanied by at least one comorbid condition. Their concerns centered on a "clear" signal of increased risk of neurological and psychiatric side effects—seizures, depression, anxiety, insomnia, aggressiveness, and suicidal thoughts among patients randomized to rimonabant.

Indeed, new analyses of the randomized controlled trials of rimonabant suggest that "suicidality"—ranging from suicidal thoughts to successful suicides—was 30% higher among subjects taking rimonabant.

"We don’t have enough patients who are on this for a long enough period of time to know what’s going to happen down the road, and we have enough concerns," panel member Dr Paul D Woolf (Crozer-Chester Medical Center, Upland, PA) summarized.

Experts presenting data on behalf of the company recapped data from the RIO series of trials, showing that roughly one quarter of obese subjects randomized to rimonabant lost 10% of their body weight after one year, while half of subjects lost about 5% of their original body weight. These losses were significantly greater than those among placebo-treated patients. They also acknowledged some of the side effects of the drug but emphasized that the neurological and psychiatric effects were seen predominantly in people with a history of depressive or neurological disorders.

Members of the panel, while praising the sponsor’s attempts to come up with novel ways of managing use of the drug, suggested the degree of benefit was insufficient given the unknown risks.

The panel was universally discomfited by the lack of long-term data in large numbers of patients. In all, only 441 patients stayed on the dose of 20-mg rimonabant over two years; the dropout rate during the first year of the RIO studies ranged from 32% to 49%. The trials were designed to carry over last reported events to the end of the trial rather than follow the large number of patients who discontinued their trial drug, many for adverse events, a design feature that did not sit well with panel members. In fact, patients who required treatment for depression were automatically taken out of the trial yet were not followed to the trial’s conclusion. "I think the real implication here is that you’ve lost data on adverse effects and you’ve lost serious data on depression and anxiety," Dr Domenic A Ciraulo (Boston Medical Center, MA) suggested.

Several committee members acknowledged the clear need for a new weight-loss medication and suggested that certain subgroups might ultimately benefit from a selective CB1 endocannabinoid receptor antagonist such as rimonabant, but that the sponsor may not be chasing the right group.

Indeed, more data was the unanimous recommendation of panel members.

The FDA had issued an "approvable letter" to Sanofi-Aventis back in February of 2006, but the panel’s opinions Wednesday suggest that an antiobesity indication for rimonabant won’t be coming any time soon.

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