A pill combining bupropion and naltrexone for weight loss (Contrave) won't receive the FDA's approval until its manufacturer, Orexigen, conducts a new clinical trial evaluating its cardiovascular risks, the company said.
In an unusual move, the agency went against the recommendation of its advisory committee on endocrine and metabolic drugs, which voted 13-7 in December in favor of approval.
The agency disagreed with the committee majority on whether the product's acknowledged cardiovascular risks outweighed its clinical benefit.
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Orexigen had submitted four placebo-controlled, one-year, phase III clinical trials in support of its application. The trials included 3,200 obese patients with at least one comorbid condition, including diabetes and depression.
In all four trials, patients on the naltrexone/bupropion combination lost more weight than those in the placebo group, and more than 30 percent lost at least 5 percent of their body weight, which is one standard by which the FDA judges efficacy of weight-loss drugs.
In a pooled analysis, naltrexone/bupropion patients lost an average of 4.2 percent more weight than the placebo group (ranging from 3.3-4.8 percent). That falls short of the other FDA standard that, after one year, the difference in mean weight loss between the active and control groups should be at least 5%.
But patients taking the combination pill -- especially those whose weight loss was less than 5 percent -- also showed increases in blood pressure. Blood pressure elevations and cardiovascular events were recorded as adverse events, but were not prespecified endpoints.
Orexigen said the FDA's complete response letter denying the approval 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 FDA's denial was the third for a weight-loss product in the past year. In 2010, the agency also rejected applications for phentermine/topiramate (Qnexa) and lorcaserin hydrochloride (Lorqess), although in those cases the Endocrine and Metabolic Drugs Advisory Committee had voted against their approval.
For Contrave, the panel majority indicated that, although the weight-loss benefit appeared smaller than for the other drugs, its adverse effects were less significant as well, tipping the balance in the product's favor.
Both bupropion (Wellbutrin) and naltrexone (Vivitrol) have been available individually for two decades, but the idea of combining them for weight loss is new enough that the Contrave studies have provided most of the evidence base.
Orexigen did not indicate whether it would conduct the new trial. "We plan to work closely with the agency to gain more information to determine the appropriate next steps regarding the Contrave application," the company said in a statement.