FDA denies approval of weight-loss drug

Issue: February 2011

The FDA has issued a complete response letter regarding the new drug application for combination naltrexone plus bupropion extended-release tablets for the treatment of obesity. Due to concerns about the safety profile of the drug when used long-term in overweight and obese people, the FDA has required the manufacturers to conduct a randomized, double blind, placebo-controlled trial before the new drug application can be approved.

The drug (Contrave, Orexigen Therapeutics and Takeda Pharmaceutical Company Limited) was studied for its ability to help obese people initiate and sustain weight loss of at least 5% of their starting body weight in 1 year, according to a press release.

The companies submitted the drug for US regulatory approval in March 2010. The original submission was based on multiple clinical trials, dubbed the Contrave Obesity Research (COR) program, which evaluated the combination therapy in more than 4,500 patients.

"We are surprised and extremely disappointed with the Agency's request in light of the extensive discussion and resulting vote on this topic at the Dec. 7 Advisory Committee meeting," Michael Narachi, president and CEO of Orexigen, said in a company press release. "We plan to work closely with the agency to gain more information to determine the appropriate next steps regarding the Contrave application."

Recommendation for approval

In December 2010, the FDA Endocrinologic and Metabolic Drugs Advisory Committee voted 13-7 for approval of combination naltrexone plus bupropion for treatment of obesity and weight management, although the panel remained reluctant in its overall vote.

While committee 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 the drug as well as a lack of long-term data. Further, they remained apprehensive because of data linking the treatment to increased risk for elevated blood pressure. Some members pointed out that the withdrawal of sibutramine (Meridia, Abbott Laboratories) from the market made them wary of approving another weight-loss drug that could potentially be pulled after more data become available. Others, however, noted that the decision to approve combination naltrexone plus bupropion was difficult, but felt that the treatment is sorely needed for the obese.

In a separate decision, the FDA advisory committee voted 11-8 during the same meeting to include a controlled clinical trial designed to thoroughly examine the effects of the treatment on major CV events as a post-approval requirement.

Study results

All phase 3 trials in the COR program were 56-week, randomized, double blind, placebo-controlled trials. Participants were randomly assigned to receive twice-daily placebo or varying doses of naltrexone plus bupropion with a 4-week titration period. The trials also incorporated a typical diet and exercise regimen. The co-primary endpoints were the proportion of participants achieving at least 5% weight loss and percent change in body weight vs. placebo.

In trials, participants assigned to high-dose or low-dose naltrexone plus bupropion lost significantly more weight than those assigned to placebo. Data also revealed a greater weight loss of 5% or more and 10% or more as well as improvements in BP, appetite and food cravings

Key secondary endpoints met across the entire COR phase 3 program included significant improvements in CV and metabolic risk factors, such as HDL, triglycerides, visceral fat and waist circumference.

The drug was generally well tolerated. Nausea was the leading adverse event resulting in discontinuation; however, nausea was mild to moderate, transient and manageable for the majority of patients. Other adverse events included headache, constipation, vomiting, dry mouth, cholecystitis, seizure, palpitations, paresthesia and vertigo.

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