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Panel votes down rimonabant on safety concerns.

SILVER SPRING, MD. -- The Food and Drug Administrations Endocrinologic and Metabolic Drugs Advisory Committee voted unanimously against recommending approval of Sanofi-Aventis' weight-loss drug Zimulti (rimonabant).

Though panel members said they believed the drug effectively helped patients lose about 5% of body weight, they also said that there were too many questions about psychiatric and neurologic side effects. The advisory committee also expressed concerns about a high number of drop-outs in the company's four pivotal studies, and about whether Zimulti was safe for long-term use.

Sanofi said Zimulti would have to be taken daffy for a lifetime to combat what it called a chronic condition.

"There's much good about rimonabant," said obesity expert Dr. Jules Hirsch of the Rockefeller University in New York, a temporary member of the FDA panel. He lauded the drug's ability to help patients lose weight and to improve triglyceride, HDL cholesterol, and hemoglobin [A.sub.1c] levels. "But I wouldn't in any way suggest that it be approved at the present time for use," he added, citing safety concerns.

Sanofi repeatedly told the panel it would insist that Zimulti only be prescribed to patients who were prepared to comply with diet and exercise counseling, and who did not have a history of depression or epilepsy and were not currently receiving therapy for either of those conditions. The company also said it would ask physicians to administer a two-question depression screen to patients before prescribing Zimulti, and that it would monitor doctors" prescribing habits through regular surveys that would tell the company if depressed or epileptic patients were getting the drug.

Panelists were impressed but not swayed.

"This is a real quandary for me," said Dr. Wayne Goodman, chairman of psychiatry at the University of Florida, Gainesville. "There are very few effective treatments for obesity out there.... I don't want to deny this option." However, Dr. Goodman said he could not vote for approval became of concerns about higher rates of depression, anxiety, and suiddality among Zimulti patients.

Zimulti is approved in 37 countries, but is currently only marketed in 18, according to Sanofi. It is indicated as an adjunct to diet and exercise for obese patients (those with a body mass index greater than 30 kg/[m.sup.2]), or overweight patients (those with a BMI greater than 27 kg/[m.sup.2]) with associated risk factors such as type 2 diabetes.

Sanofi initially sought the same indication in the United States, along with using it in combination with metformin or a sulfonylurea to improve glycemic control and reduce, weight in type 2 diabetes. The company later dropped the diabetes indication.

The FDA is required to act on the Zimulti application by July 26.

Although it voted against recommending approval, the advisory committee said it was willing to reconsider the issue after Sanofi completes the 17,000-patient Comprehensive Rimonabant Evaluation Study of Cardiovascular Endpoints and Outcomes (CRESCENDO) in 2010; that study will have 5-year follow-up data on patients.

The agency generally follows its panel's advice.

Sanofi's pivotal data came from four international multicenter studies that were part of the Rimonabant in Obesity and Related Metabolic Disorders (RIO) trials: RIO-North America, which involved 3,040 obese or overweight patients without comorbidities who were randomized to drug (5 nag or 20 rag) or placebo for a year, followed by having half of each group randomized to placebo for another year; RIO-Europe, a 2-year study with 1,507 patients similar to those in RIO-North America; RIO-Lipids, a 1-year trial involving 1,033 obese patients with untreated dyslipidemia; and RIO-Diabetes, a 1-year trial involving 1,045 obese or overweight patients with type 2 diabetes who were taking either metformin or a sulfonylurea.

Patients had a mean BMI of 34-37 in those studies, and a mean age of 45-55. Overall, they lost 9-12 pounds, or about 5% of baseline weight, though there was a trend toward a plateauing and then weight increase at the 2-year mark. In RIO-Lipids, patients taking the 20-mg dose saw an increase in HDL cholesterol of about 8%, and a decrease in triglycerides of 12%.

Neither the panel nor the FDA questioned Zimulti's effectiveness; instead, safety was the big concern.

The FDA estimated that the relative risk for psychiatric adverse events in patients taking Zimulti in the four trials was 1.9, compared with placebo, and for neurologic adverse events the relative risk was 1.7. Four completed suicides have been reported for all of the company's completed and ongoing trials, said Dr. Amy G. Egan of the FDA's division of metabolic and endocrine products.

Because of the high drop-out rate seen in the trials--32%-49% in the first year, and 23%-58% in the 'second year the relative risk may be underestimated, she said.

Postmarketing data from the European Agency for the Evaluation of Medicinal Products (EMEA) shows that since rimonabant (marketed as Acomplia) was launched in Europe in 2006, there have been 384 adverse event reports, with 208, or 54%, classified as psychiatric, said Dr. Eric Colman, deputy director of the division of metabolic and endocrine drug products at the FDA. Those figures can be compared with the 117 psychiatric reports (21% Of the total 567 reports) for sibutramine since 1999, and 208 (8% of the total 2,734 reports) for orlistat since 1998, said Dr. Colman.

Zimulti appeared to double the risk of psychiatric adverse events, increased a variety of neurologic events, and increased nausea and vomiting, said Dr. Egan, adding that many of the risks "appear to be more pronounced in diabetics." And, she said, the FDA believes that given its pharmacologic properties, Zimulti's association with increased suicidality "is causal."

BY ALICIA AULT

Associate Editor, Practice Trends
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Title Annotation:NEWS FROM THE FDA
Author:Ault, Alicia
Publication:Family Practice News
Geographic Code:1USA
Date:Jul 1, 2007
Words:944
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