The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 20-2 to recommend approval of combination phentermine plus topiramate for the treatment of obesity, but also suggested that the FDA require a post-approval cardiovascular outcomes trial.

“Obesity exists in epidemic proportions in the United States, with serious morbidity and mortality consequences, and there is an urgent need for better pharmacological interventions,” committee member Elaine H. Morrato, DrPH, MPH, CPH, told the panel. “Qnexa demonstrated a meaningful efficacy benefit and that there are consequences to nontreatment of obesity. I believe that the FDA and the sponsor are starting to find the right balance between providing access to effective anti-obesity medications and associated risks.”

The same committee voted in July 2010 against recommending approval for phentermine plus topiramate (Qnexa, Vivus) because of safety concerns, including the drug’s teratogenicity and an elevation in heart rate and CV events associated with the drug.

“The sponsor has done a good job at demonstrating efficacy, and they need to step up to the plate and do the cardiovascular outcomes trial and do it fast,” committee member Sanjay Kaul, MD, said during the meeting. “There is opportunity for the sponsor to fully characterize the impact of the drug on heart rate and blood pressure.”

Two studies were conducted to determine efficacy of the combination drug, intended for use as an adjunct to lifestyle modifications for treatment of obesity. The first study, OB-302, was a 1-year, randomized, double blind, placebo-controlled study that included 1,267 obese adults. Participants on the drug lost 14.4% of their baseline body weight.

The second study, OB-303, was a 1-year, randomized, double blind study that included 2,487 overweight and obese adults. Participants who took the drug lost 12.4% of their baseline body weight.

To further evaluate the long-term safety and efficacy of the drug, a 1-year extension study to OB-303 was conducted. The study, OB-305, was also a double blind, placebo-controlled trial that included 676 of the participants on the OB-303 trial. In the study, there were small increases in heart rate among participants who took the drug, but the increase was only significant among those who took the top dose of the drug vs. the low dose or the middle dose. There was no connection between this increase in heart rate and major adverse coronary events in those participants who took the drug.

Regarding teratogenicity, the prevalence of major congenital malformations associated with topiramate exposure during pregnancy was analyzed in three studies. The studies found that although topiramate exposure during the first trimester of pregnancy had no effect on prevalence of major congenital malformations overall, there may be a twofold increase in the prevalence of oral clefts.

Vivus proposed a Risk Evaluation and Medication Strategy (REMS) consisting of a medication guide, a communication plan and Elements to Assure Safe Use (EASU) for health care provider training and pharmacy training.

Although the FDA is not required to follow the recommendations of the advisory committees, it usually does.

Source: Endocrine Today