FDA issues CRL for obesity treatment due to concerns about cardiovascular safety

FDA has issued a complete response letter for Orexigen’s and Takeda’s Contrave (naltrexone HCl/bupropion HCl) extended-release tablets for the treatment of obesity, including weight loss and maintenance of weight loss.

FDA noted concern about the cardiovascular safety profile of naltrexone/bupropion when used long-term in a population of overweight and obese subjects. Specifically, the letter stated that “before your application can be approved, you must conduct a randomized, double-blind, placebo-controlled trial of sufficient size and duration to demonstrate that the risk of major adverse cardiovascular events in overweight and obese subjects treated with naltrexone/bupropion does not adversely affect the drug’s benefit-risk profile.”

FDA’s rejection of Contrave, its third rejection of an obesity drug in recent months, is a strong indicator of FDA’s current threshold for evaluation of risk versus benefit in products being developed in this therapeutic area, according to Formulary Clinical Editor David Calabrese, RPh, MHP.

“This recent FDA activity, while likely well-justified from a clinical perspective, is also likely to trigger significant recoil in pharmaceutical industry R&D investments within the obesity drug market moving forward,” said Calabrese, clinical officer, Med Metrics Health Partners, Worcester, Mass. “Consequently, this will compel our healthcare industry to further focus its attention on developing more unique, non-pharmaceutical programming alternatives to address our obesity epidemic.”

Back in December, an FDA advisory panel recommended approval of the drug, voting 13 to 7 that the diet pill’s benefits outweigh the risks.

“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 December 7 Advisory Committee meeting,” said Michael Narachi, president and CEO of Orexigen, in a company statement. “We plan to work closely with the Agency to gain more information to determine the appropriate next steps regarding the Contrave application.”

Contrave, an investigational combination therapy of naltrexone HCl and bupropion HCl, was studied for its ability to help people with obesity initiate and sustain weight loss of at least 5% of their starting body weight in 1 year. Contrave was submitted for FDA approval in March 2010. The original submission was based on multiple clinical trials that evaluated Contrave in more than 4,500 patients.