The New York Times
June 14, 2007
By STEPHANIE SAUL
A drug once viewed as a possible magic bullet against obesity was rejected yesterday by a federal advisory panel because of worries that it causes neurological and psychiatric problems and increases the risk of suicide.
Although the drug, rimonabant, is already marketed in 37 countries, it is now unlikely that the Food and Drug Administration will approve its sale in the United States without additional safety data.
The advisory panel voted unanimously, 14 to 0, against recommending the drug, saying there was inadequate evidence of its safety. The F.D.A. is not required to follow the advice of such panels, but it typically does.
The panel’s vote was a blow to Sanofi-Aventis, the French company that makes the drug, which is sold in many countries under the brand name Acomplia. As the advisory committee finished voting, the company’s stock, which trades in this country as American depositary receipts, closed at $43.07, down $1.31 or 2.95 percent. It fell another $1.02 in after-hours trading.
Sanofi had expressed hope that the drug would be a $3 billion seller, with much of that market in the United States, a country with a growing obesity problem.
In a statement issued after the panel’s vote, the company said it would continue to work with the F.D.A. to address the panel’s concerns, which included worries about a high dropout rate in clinical studies of the drug, evidence of a doubling of psychiatric events and questions about whether the drug induced seizures.
Dr. Jules Hirsch, an advisory committee member who is a research physician at Rockefeller University, summed up the sentiments of the other panelists. “I couldn’t in any way suggest that it be approved at the present time for use.”
The drug, which the company had planned to call Zimulti in the United States, works on the brain’s endocannabinoid system. The system was discovered through research into marijuana, which works on brain receptors to give users the “munchies.”
By suppressing those receptors, Zimulti curbs hunger. Clinical studies revealed that patients taking it lost about 5 percent of their weight.
But the same brain system also modulates depression, phobias, anxiety and post-traumatic stress disorder. Testimony before the panel yesterday in Silver Spring, Md., suggested that tampering with the endocannabinoid system also increased such psychiatric symptoms, including suicidal thoughts.
“The potential market for this drug and the continued uncertainty about its risks, both known and unknown, lead to our concern about the use of this drug in the general population,” an F.D.A. staff medical reviewer, Dr. Amy G. Egan, told the panel.
The committee’s vote that there was not enough safety data to approve the drug came after Dr. Egan’s presentation, which indicated that the drug doubled a patient’s risk of problems like anxiety, depression, aggression and psychosis.
The committee also heard about data showing an increase in suicidal thinking among users of the drug, including four patients who did commit suicide while taking it: three during clinical studies and one in Europe after the drug was approved last year.
In a presentation to the panel, representatives of Sanofi recommended a special screening of prospective patients to measure their risk for psychiatric symptoms.
The company also argued that the drug should be evaluated in light of a growing need for drugs to treat obesity, citing benefits in glucose, HDL cholesterol, tryglycerides and inflammatory markers in patients taking the drug.
Currently only two drugs are approved to assist patients with weight loss. One of them, Meridia, by Abbott Laboratories, has been linked to high blood pressure. The other, Xenical by Roche, causes diarrhea and gas.
Yesterday’s vote came on the same day that Xenical became available without a doctor’s prescription under the brand name Alli. The drug is being marketed by GlaxoSmithKline, which purchased over-the-counter rights to the drug from Roche and won F.D.A. approval this year to sell the product directly to consumers.
Dr. Hirsch of Rockefeller University said Zimulti’s effects on weight were similar to those of other drugs already marketed — a 5 percent loss followed by a regain of weight.
“The problem I see with this whole thing is that the number of people who are going to lose weight is very small,” Dr. Hirsch said. “You’re telling a 220-pound woman that she has a one in four chance of getting down to 200 pounds if she sticks with the program. That’s not going to make anyone very happy.”
Sanofi-Aventis had first petitioned the F.D.A. in 2005 to approve the drug, counting on it to help replace the sales lost through the patent expiration this year of its sleep medication Ambien as well as the anticipated 2011 patent expiration of another big seller, Plavix, an anticlotting agent.
In a statement yesterday after the panel’s vote, the company said it would work with the F.D.A. to address concerns about the drug.
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