Federal health advisers unanimously rejected a weight-loss drug Wednesday after hearing testimony that it increases the risk of suicidal thoughts, even in patients without a history of depression. The manufacturer, Sanofi-Aventis SA, further failed to show the drug rimonabant is safe, the panel said.
The back-to-back, 14-0 votes by the expert panel made it unlikely the Food and Drug Administration will approve the drug. The agency usually follows its panel's advice, but it isn't required to do so.
"There is a reasonable suspicion we better learn some more and watch this affair more closely before we launch into massive use of this drug," said panelist Dr. Jules Hirsch, a senior physician at New York's Rockefeller University.
In studies, patients given the once-daily tablet reported twice as many psychiatric side effects, including depression, anxiety and sleep problems, than those who received sham treatment, Dr. Amy Egan, an FDA medical officer, told the advisers.
"The numbers of events are small, but in aggregate they are worrisome," Egan said.
Officials from Sanofi-Aventis suggested that patients be screened for depression before they are prescribed the drug. They also advised that patients visit their doctors five times during the first year of treatment to be reassessed to further curtail any potential problems.
"Who is the right patient to receive rimonabant? Not everybody," Sanofi-Aventis' Richard Gural told the panel of advisers earlier Wednesday. The drug is not appropriate for anyone with a history of depression or suicidal thoughts, or who has been diagnosed with depression or is taking antidepressant medication, he added.
The FDA is to make a final decision on the drug by July 27.
The company proposes selling the drug under the brand name Zimulti. Rimonabant already is sold in Europe as Acomplia.
The litany of mental problems associated with the drug clearly gave the panelists pause.
"I think this is a drug that needs further understanding with respect to what it does to people's psyche," said panelist Dr. Sid Gilman, a University of Michigan neurologist.
Even if the FDA does approve the first-in-its-class drug, the findings make it highly likely it would bear stern warnings. Company officials embraced the idea of such warnings, which could exclude FDA-approved use in some patients.
The company, FDA and panelists all agreed that Zimulti, along with diet and exercise, works to help shed weight. In yearlong studies, patients on the drug lost roughly 14 pounds. Those given dummy pills lost only about 4 pounds. However, patients regained weight when treatment was stopped after a year.
But the FDA and its outside advisers shared deep concerns that the drug's effect on the body could lead to an array of psychiatric symptoms, including anxiety, phobias, post-traumatic stress disorders and depression. No panelist felt the company had sufficiently characterized the drug's safety.
"What I am really troubled by is the lack of good safety data," said panel chairman Dr. Clifford Rosen, senior staff scientist at the Maine Center for Osteoporosis.
The company believes those increased cases were associated with depression or other disorders and weren't directly caused by its drug. Egan, however, said they were.
"We strongly believe that it is causal," Egan said. She noted 88 percent of those reporting psychiatric problems while on the drug had no prior history of depression.
Furthermore, patients in the studies were carefully screened and monitored, suggesting the problems would be more common should the drug enter broad use, Egan added.
The screenings proposed by the company won't keep the depressed and obese from Zimulti, warned Lynn McAfee, head of medical advocacy for the Council on Size & Weight Discrimination, a fat acceptance group.
"If this gets out to be a real big deal in the public, you can figure out how to answer those questions to get the drug," McAfee said. "It's not going to stop anyone." The potential market for the drug is huge, as obesity rates have exploded in the past two decades. Today, nearly one in three American adults age 20 or older is obese, according to government data.
Dr. Sidney Wolfe, of the advocacy group Public Citizen, said the obese are more likely to be depressed. Many of them likely would take Zimulti along with the antidepressants they already use — with unknown consequences, Wolfe told panelists.
Rimonabant blocks the same pleasure centers in the body activated when pot smokers get the munchies. Blocking the receptors leads to patients eating less and losing weight. Sanofi-Aventis also believes the drug decreases fat storage.
The FDA previously told the French company it would not approve the drug to help smokers quit.
Sanofi-Aventis has proposed selling 20-milligram Zimulti tablets to the obese and to those who are overweight and have type 2 diabetes, high blood pressure or other conditions that put them at risk of cardiovascular disease.
There currently are two FDA-approved prescription drugs for the long-term treatment of obesity: Meridia, an appetite suppressant, and Xenical, which limits the amount of fat the body can absorb. Sales of Alli, a lower-dose version of Xenical that won't require a prescription, start this week.
Heart problems led to the withdrawal of the diet drug fenfluramine in 1997. It had made up with phentermine the popular yet unapproved fen-phen combination treatment.