Soon after the Food and Drug Administration's Endocrinologic and Metabolic Drugs Advisory Committee voted unanimously against recommending approval of the weight-loss drug Zimulti, Sanofi-Aventis withdrew its new drug application, saying it needed time to discuss the panel's findings with the FDA.
The agency had been required to act on the Zimulti (rimonabant) application by July 26, and the likely result would have been a “nonapprovable” letter. The committee's recommendations are not binding, but the FDA generally follows its advice.
The panel members said at their June 13 meeting in Silver Spring, Md., that although they believed that the drug effectively helped patients lose about 5% of body weight, questions about psychiatric and neurologic side effects were too numerous. 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 daily 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 A1c 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 department 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 because of concerns about higher rates of depression, anxiety, and suicidality 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
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.
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.
In announcing its NDAwithdrawal, Sanofi did not say whether it would wait until those results are in. But the company did acknowledge that duration of treatment was a major concern of the panel. The reason for withdrawal was “our difficulty [in understanding] some points raised by the advisory panel and written in the minutes of the advisory committee from the FDA, such as the duration of treatment requested for a chronic disease like obesity,” said Marc Cluzel, Sanofi's senior vice president of scientific and medical affairs, in a June 29 conference call. “We thought that we have not enough time up to the [Prescription Drug User Fee Act] date to discuss this point with the FDA.”
The company will continue with its clinical program in rimonabant and will “quickly approach the FDAin order to determine together the most suitable label for Zimulti and the activities to be performed in order to resubmit,” he said.
The 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 mg or 20 mg) 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.