Advisers on the FDA's Endocrinologic and Metabolic Drug Advisory Committee voted 13-7, that the benefits of the fixed-dose combination obesity drug Contrave (a combination of naltrexone and bupropion, Orexigen Therapeutics) outweigh its risk. 

Eleven of the panel members voted that a controlled clinical trial evaluating the safety and efficacy of Contrave should be performed as a post-approval requirement to study adverse cardiac events. Eight advising members voted that the trial should be conducted pre-approval of the drug, while one advisor abstained.

During the full-day meeting, reviewers assessed the drug’s safety and efficacy after the Office of Surveillance and Epidemiology (OSE) requested further review.

Rejecting weight-loss drugs has been a popular theme with the FDA this year after the results of the SCOUT trial showed that Abbott Laboratories' sibutramine (Meridia) had the potential to increase the risk of MI and stroke in patients with previous cardiovascular disease. Abbott voluntarily removed the drug from the shelves. And again last month, the FDA rejected Vivus' weight-loss drug Qnexa (phentermine/topiramate) in the current form.

Orexigen is hoping the FDA will approve Contrave's new drug application. The drug is indicated to treat obesity in patients who have a body mass index that is equal to or greater than 30 kg/m2 or greater than or equal to 27 kg/m2 if the patient had one or more risk factors including diabetes, dyslipidemia or hypertension.

Questions of the drug’s safety arose after it was found that the obesity drug may raise blood pressure in patients, even while facilitating weight loss. Four placebo-controlled one-year clinical trials assessed the drug’s effectiveness in over 3,200 overweight and obese patients who were administered the drug—1,500 patients were administered placebo.

Study endpoints evaluated the mean weight change from baseline to endpoint in patients who achieved more than 5 percent reduction in body weight.

The sponsor is looking to gain approval for the drug to be administered in two twice-daily 8/90 tablets—32 mg of naltrexone and 360 mg bupropion. Orexigen also is looking to gain approval for a lower dose—two 4/90 tablets taken twice daily— for patients unable to tolerate the 32 mg of naltrexone and 360 mg of bupropion.

The researchers have so far found that changes in fasting HDL cholesterol levels were consistent across the four trials and patients administered NB [combination naltrexone/bupropion] 16 mg and 32 mg saw greater increases in HDL levels as compared with patients administered placebo.

In the pooled data, the researchers reported that the difference in mean weight loss between NB32 and placebo-treated groups was 4.2 percent.

In 2007 the FDA Committee issues draft guidance—Developing Products for Weight Management—that outlined when a weight loss drug is considered effective. “However, these weight loss results [for Contrave] do not meet the first criteria set out in the 2007 draft guidance,” the briefing materials stated.

The 2007 guidance outlined that weight-loss drugs must:

• Have a difference in mean weight loss between the active-product and placebo-treated groups of at least 5 percent and the difference is statistically significant; or
• The proportion of subjects who lose greater than or equal to 5 percent of baseline body weight in the active-product group is at least 35 percent, is approximately double the proportion in the placebo-treated group, and the difference between groups is statistically significant.

During the meeting, reviewers evaluated five areas of safety: blood pressure and pulse, cardiovascular events, seizures, psychiatric-related adverse events and neurological/cognitive adverse events.

“Shifts to high potentially clinically significant DBP [diastolic blood pressure] values where three to four times more frequent in the total NB group as compared to placebo in the first 12 weeks of the study,” according to the FDA. “NB [Contrave] attenuates or eliminates the blood pressure and pulse reductions that are normally seen with weight loss. It is not known how these vital sign changes in the overweight and obese population would impact cardiovascular risk over the long term," according to the FDA briefing documents.

"Obesity is a long-term problem, it is not a short-term problem" and what needs to be considered is that patients are taking these drugs long-term, said Lamont G. Weide, MD, PhD, a professor of medicine at the University of Missouri, Kansas City and a member of the FDA panel at the Dec. 7 meeting. "It is our responsibility to protect them and ask what are the long-term implications of taking these medications and what are the risks.”