FDA advisory committee recommends approval of combination weight-loss drug

The FDA Endocrinologic and Metabolic Drugs Advisory Committee voted 13-7 for approval of the novel combination of bupropion plus naltrexone for the treatment of obesity and weight management.

Decisions were based on results of four phase 3 trials suggesting that the drug is associated with statistically significant and clinically meaningful weight loss, as compared with placebo. Safety data also indicate that, during the trials, adverse events occurred early in treatment, and were generally mild or moderate in severity and self-limited, according to briefing documents supplied by Orexigen. Researchers also noted that the treatment’s safety profile was similar to those of bupropion (Wellbutrin, GlaxoSmithKline) and naltrexone (Embeda, King Pharmaceuticals; Revia, Duramed; Vivitrol, Alkermes) alone.

While panel members commended Orexigen for providing quality evidence and adhering to the guidelines set forth by the FDA, some expressed concerns during the vote about the study results supporting the efficacy of bupropion plus naltrexone (Contrave, Orexigen) as well as a lack of long-term data. Further, they remained apprehensive because of data that link the treatment to increased risk for blood pressure.

“Despite the fact that the company has done an excellent job putting data together, I’m just not convinced that the benefits of this drug outweigh the cardiovascular risks,” Vera A. Bittner, MD, MSPH, professor of medicine and section head of preventive cardiology at the University of Alabama at Birmingham, said during the meeting.

Other members also pointed out that the withdrawal of sibutramine (Meridia, Abbott Laboratories) from the market made them wary of approving another drug that would eventually be pulled after more data become available.

Some panel members, however, noted that the decision to approve combination naltrexone plus bupropion was difficult but they felt the treatment is sorely needed.

“It’s not going to be a perfect drug for everyone, but it will give us one more treatment option,” patient representative Melanie Coffin, said.

More research needed

In a separate decision, the panel voted 11-8 to include a controlled clinical trial designed to thoroughly examine the effects of combination bupropion and naltrexone on major CV events as a post-approval requirement.

Members who voted for the post-approval requirement said the sponsor met the FDA’s criteria for efficacy, and although safety concerns regarding CV events persist, the risks did not appear overwhelmingly alarming. Additionally, they felt that adding a post-approval requirement may expedite initiation of controlled clinical trial and would perhaps help acquire more long-term data in larger cohorts.

“It would most likely be difficult to enroll the large scale populations needed for these studies if they were conducted pre-approval,” Coffin said.

Panel member Jacqueline S. Gardner, PhD, MPH, professor in the department of pharmacy at the University of Washington, also explained that the extensive research on the individual components, which have been available for the past 20 years, influenced her decision regarding safety.

“These compounds have been in wide use, and in fact have been evaluated repeatedly for different indications in recent years,” Gardner said.

Sanjay Kaul, MD, director of the fellowship training program in cardiovascular diseases at Cedars-Sinai Heart Institute, disagreed.

“I could have voted for a post-market approval study if the weight loss was more impressive,” he said. “Also, it is not exactly clear whether weight loss or modest weight loss may enhance life expectancy or exert impact on CV mortality or morbidity. Data on hand are insufficient, but there are sufficient clues [related to BP risks] to be concerned.”

Public, patient concerns

In light of the hearing, the Obesity Society and the Obesity Action Coalition asked the FDA to bear in mind the need for more tools to address the obesity epidemic when considering approval of combination bupropion and naltrexone.

“We are deeply concerned about the effect that the FDA’s recent decisions will have for ongoing and future research into desperately needed new obesity treatments,” Jennifer Lovejoy, PhD, president of the Obesity Society, said in a press release. “As the FDA’s advisors consider the application before them, we hope that the agency will assure a balanced process, taking into account the urgent medical need.”

President and CEO of the Obesity Action Coalition Joe Nadglowski agreed. “The number of those affected by obesity is growing at an incredibly rapid rate and the millions of Americans already affected by the disease are lacking the necessary medically approved treatment and long-term options so desperately needed.”

While the FDA is not required to follow the recommendations of the advisory committee, it usually does. – by Melissa Foster

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