Unanimous "No" to Rimonabant: Safety Not Demonstrated, FDA Advisory Panel Says

Shelley Wood

June 13, 2007

June 13, 2007 ( updated June 14, 2007) Silver Spring, MD
- 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/m 2 or in individuals with a BMI of >27 kg/m 2
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. "If the drug were going to cause a 30% weight loss we'd all be jumping up and down and throwing our hands in the air and saying this is marvelous, and we wouldn't be overly worried about the safety concerns. But . . . this drug seems to have the same efficacy as the other two approved [weight-loss] drugs."

No way of managing unknown risks

Experts presenting data on behalf of the company recapped data from the RIO series of trials, previously reported by heart wire , 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. This risk, they argued, could be managed by making these conditions contraindications to getting the drug and by the creation of a novel "risk management plan" for physicians. They also stated their intention to refrain from marketing the drug directly to consumers for the first year, so that physicians could have a chance to better understand the drug before being pestered about it by patients who might not be ideal candidates.

But panelists and speakers punched holes in the sponsor's testimony and plans. During the open public-hearing session, Lynn McAfee, director of the Medical Advocacy Project of the Council on Size and Weight Discrimination, suggested that the sponsor had to be more realistic about the environment a new weight-loss drug would be entering. "People are desperate," she said. "People will take on an enormous amount of risk; it's amazing what people will do, and we have a system in which the unscrupulous can prey on us and cause us harm. . . . I will tell you right now that if this gets out in the public, people will figure out a way to get the drug; it's not laser brain surgery."

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.

"You're going to tell a 220-lb womanthat she has a one in four chance that she'll get down to 200 lbs if she sticks with the program? Well, that's not going to make anyone very happy," Dr Jules Hirsch (Rockefeller University, New York) pointed out. "On the other side, what are the dangers? At least everyone will agree that we have to learn a little more and watch this whole affair carefully before we lunge into massive use of the drug."

Long-term data needed

Others pointed out that the popularity of the drug would vastly amplify the signal of adverse events that were seen in the study. "I have made some rough calculations based upon the psychiatric and neurological adverse effects, recognizing that some might be kind of trivial," Dr Robert Kreisberg (University of South Alabama, Birmingham) stated. "The absolute increase in risk is such that the number you'd need to treat to harm is about six and the number you'd have to treat for a benefit of 5% weight loss is about four and for a 10% weight loss is about six. So it looks to me like the number needed to harm and number needed to treat are pretty much balanced."

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.

Dr Philip S Wang (National Institute of Mental Health, Bethesda, MD) pointed out that the apparent doubling of neurological and psychiatric side effects with rimonabant also occurred in people with no history of these types of problems. Better candidates might be those with "extreme obesity," with BMIs over 40, he suggested.

"There's some preferential efficacy in this group, and according to my back-of-the-envelope calculation, it looks like you actually have lower risks of these psychiatric events in that group. . . . But this is all going to take more data."

Starting from scratch?

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

Dr Katherine M Flegal (Centers for Disease Control and Prevention, Atlanta, GA) called the sponsor's evaluation of adverse effects "a post hoc collection of adverse events and symptoms that really have not been adequately investigated enough in detail and that weren't identified in advance."

Dr Sid Gilman (University of Michigan, Ann Arbor), likewise, questioned why the sponsor had not "drilled down" into reported side effects like "dizziness" or "tremors" and performed the sorts of tests and imaging studies that would have better characterized these events.

"In this case," said acting chair Dr Clifford Rosen (St Joseph Hospital, Bangor, ME), "it's the adverse events and not the serious adverse events that tell the story, and we don't have enough information. . . . I would go back and askthe question, Why weren't these more detailed at the beginning of these big trials, when we knew that this is a central nervous system acting agent that's going to have these kind of effects?"

Even the ongoing CRESCENDO trial may not provide the answers the FDA would need, several members suggested, since it was not appropriately designed to clarify the types of adverse events occurring in people taking the drug.

"I personally don't think there is much you can do with the trials that are already under way," Kreisberg said. "They are what they are, and they probably all suffer from this lack of specificity about definitions. So I think it's going to be hard to mine that information" in the existing data set, he concluded.

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.

The complete contents of Heart wire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.


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