What's Ahead for Rimonabant?

AFood and Drug Administration (FDA) advisory committee recently deemed rimonabant (Acomplia, Sanofi-Aventis) unfit to hit the U.S. market for the indication of weight management in people with a body mass index (BMI) of ≥30 kg/m², or with a BMI of ≥27 kg/m² and at least one comorbid condition.

Sanofi-Aventis subsequently withdrew its U.S. application to market the drug, which some had hoped would be an obesity-fighting breakthrough.

The FDA committee rebuffed rimonabant because of uncertainty that the drug's benefits outweigh, or at least counterbalance, its potential risks. At a June 13 hearing, the 14 committee members expressed concern about an increased risk of neurological and psychiatric side-effects among some patients taking the drug. These side-effects include depression, anxiety, insomnia, aggressiveness, suicidal thoughts, dizziness, and seizures.

Committee members were troubled particularly by certain findings of the Rimonabant In Obesity (RIO) trials involving >1,110 people on rimonabant for a year:

1. Suicidal thoughts and behavior—including completed suicides—were 30% higher among participants taking rimonabant.

2. Among rimonabant-takers with a baseline history of depression, 32% experienced a psychiatric event while on the drug; 17% of those without a depression history experienced such an event.^1,2

On the benefits side, a quarter of those on rimonabant lost 10% of their body weight and half lost 5% of their body weight after 1 year.^1,2 But that weight-loss curve is no better than the typical results achieved with weight-loss drugs such as sibutramine (Meridia, Abbott) and orlistat (Xenical, Roche), Jules Hirsch, MD, physician-in-chief of Rockefeller University Hospital in New York City, said at the hearing.

Moreover, the data to date suggest the psychiatric risks may exceed the weight-loss benefits, said committee member Domenic A. Ciraulo, MD, professor and chairman of the Division of Psychiatry at Boston University School of Medicine. Ciraulo also noted problems with high dropout in the RIO trials.

“The reports of psychiatric adverse effects are just too high, especially given the attrition,” he said.

The committee paid little attention, however, to the blood glucose and cardiovascular (CV) benefits seen with rimonabant in diabetes patients—benefits that have led to speculation that Sanofi-Aventis might resubmit its rimonabant application for a specific diabetes or CV risk indication.

PAST FINDINGS

The largest study showing rimonabant benefits in type 2 diabetes is the international RIO-Diabetes trial, involving 1,045 patients at 159 centers. In the study, type 2 diabetes patients took 5 mg or 20 mg of rimonabant, or placebo, as well as metformin (Glucophage, Bristol-Myers Squibb) or a sulfonylurea, for a year.

Results for the 20-mg dose, but not the 5-mg dose, were significant: The rimonabant participants lost 5.3 kg (11.68 lb), compared with 2.3 kg (5.07 lb) for placebo, and the rimonabant group reduced its glycated hemoglobin (A1C) levels an average of 0.7% lower than the placebo group's levels; almost half of rimonabant participants achieved A1Cs under 6.5%.²

The rimonabant group also showed increases in HDL cholesterol and reductions in triglyceride levels and systolic blood pressure.

“Rimonabant had a nice effect on cardiovascular risk factors, in addition to the weight loss,” says RIO-Diabetes researcher Priscilla Hollander, MD, medical director for the Ruth Collins Diabetes Center of Baylor University Medical Center in Dallas. “With their cardiovascular disease risk, diabetes patients could really benefit from a drug like this.”

Hollander acknowledges, however, that 4–5% of the 20 mg patients developed depression, compared with 1.2% in the placebo group, and “people with diabetes are already more prone to depression than the general population.”

Similar findings emerged from the Study Evaluating Rimonabant Efficacy in Drug-Naïve Diabetic Patients (SERENADE), a smaller trial involving 278 type 2 diabetes patients at 56 centers. In that trial, patients receiving a 20-mg rimonabant dose for 6 months lowered their A1Cs by 0.8%, on average, compared with an average 0.3% reduction for placebo.³

SERENADE patients showed a CV benefit profile similar to that of RIO-Diabetes patients and slightly higher weight-loss benefits (DOC News, February 2007, page 9).

NEXT STEPS

The SERENADE trial, however, also revealed the psychiatric and neurological effects found in other rimonabant studies.

“This is clearly not a drug for those with a history of depression,” says SERENADE investigator Julio Rosenstock, MD, clinical professor of medicine at University of Texas Southwestern Medical School in Dallas. “But this study did find other attractive results for patients otherwise naïve to diabetes therapies. What's needed now is further research on the drug's sustained efficacy and safety.”

And that's exactly what the FDA advisory committee asked for at the June hearing: more research to assess rimonabant's weight-loss, CV, psychiatric, and neurological effects over several years. Such studies are under way at multiple international sites. Meanwhile, the drug remains available in Europe, but with a stepped-up warning on its potential side-effects.

Even if rimonabant never gains FDA approval for the U.S. market, several other drugs in the same class, the central cannabinoid (CB1) receptor antagonists, are being developed, notes Rosenstock. The drugs act on adipose tissue, the gastrointestinal tract, muscles, peripheral systems, the pancreas, and brain circuits involved in appetite, metabolism, and energy regulation, he says.

But pharmaceutical market analyst Shaojing Tong isn't ready to give up on rimonabant yet. He predicts that, if Sanofi-Aventis produces stronger outcomes data on rimonabant's weight-loss and CV benefits, the company will resubmit its U.S. application in 2010.

“You can bank on them trying to get better beneficial results,” says Tong, of New York City-based Mehta Partners. But, he adds, the indication may be different—either for patients with diabetes or, more generally, with high CV risk. ▪