FDA Declines Approval for Contrave Diet Drug; Asks for CVD Outcomes Studies

Shelley Wood

February 01, 2011

February 1, 2011 (Silver Spring, Maryland) — The FDA has declined to approve the diet drug Contrave, instead asking its manufacturer, Orexigen Therapeutics, to conduct a study "of sufficient size and duration" examining the potential heart risks of the drug, a combination of naltrexone and bupropion HCL.

Last December, a majority of members of the US Food and Drug Administration (FDA)'s Endocrinologic and Metabolic Drugs Advisory Committee gave a thumbs-up to Contrave, something they had not done for two other diet drugs they'd reviewed earlier in the year.

Early Tuesday morning, the company issued a statement noting that the FDA had issued a "complete-response" letter for the Contrave new drug application yesterday, the deadline for the Prescription Drug User Fee Act action date. In it, the statement reads, "TheFDA 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.' "

The Orexigen statement goes on to quote president and CEO Michael Narachisaying that the company was "surprised and extremely disappointed with the agency's request" but that it plans "to work closely with the agency to gain more information to determine the appropriate next steps regarding the Contrave application."

Lorcaserin (Arena Pharmaceuticals) and phentermine/controlled-release topiramate (proposed name: Qnexa, Vivus) were the other two proposed diet drugs not recommended for approval by the FDA advisory committees reviewing the evidence for both drugs last year, and the FDA subsequently rejected their marketing applications, asking for more data. Yet another diet drug, sibutramine (Meridia, Abbott Laboratories), was yanked from the market earlier in the year due to concerns about its cardiovascular safety.

Had Contrave been given the green light, as many predicted following the advisory committee's deliberations, it would have been the first new diet drug on the US market in the past decade.

Speaking with heartwire , Dr Sanjay Kaul (Cedars Sinai, Los Angeles, CA), one of the seven FDA panelists who voted against approval back in December, said the FDA, which more often than not follows its advisors' recommendations, made "the right decision" and not a very surprising one.

"I went on record saying that the 13 to 7 vote is going to create a buzz that is not going to accurately reflect the tepid enthusiasm for this drug. Even the individuals who voted for the drug were not very enthusiastic for it."

In fact, Kaul points out, ambivalence and mixed feelings were a hallmark of the Contrave panel discussions: three panel members who voted to recommend approval also voted for preapproval studies, while two who voted for postapproval studies also voted against approval.

The bottom line for Kaul was the fact that the modest weight loss achieved with Contrave was unlikely to translate into tangible morbidity/mortality benefits to offset any risks. "You can never establish safety in preapproval assessment, so there is always some degree of risk that you are willing to trade off, providing the benefit is large enough. And in my opinion, the benefit [with Contrave] was very modest," Kaul said.

Not everyone agrees. Contacted by heartwire , Joe Nadglowski, president and CEO of the Obesity Action Coalition, a lobby group for both patients and industry, observed, "Unfortunately, we weren't particularly surprised by the decision, given the FDA's track record of setting nearly impossible standards for obesity medications and their continuing to ignore the very real ongoing risks of untreated obesity. . . . We still believe strongly that we need new pharmaceutical agents to treat obesity and that the medications that have recently been presented hopefully can be part of safe and effective treatment programs in the hands of skilled clinicians with experience treating obesity sometime in the near future."

Kaul, however, says the FDA's decision was the right one.

"There were some panelists who said that requiring a [safety] trial before approval would kill the development of the drug or send a chilling message to the pharmaceutical industry--I think those should hardly be the criteria for approval. The FDA should make decisions based on objective, dispassionate, and rigorous evaluation of the scientific evidence and should be driven by the core mission of protecting the public health, and in my opinion, the FDA has delivered on that."

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