Diet drug Contrave to get another shot at FDA approval

The makers of the proposed weight-loss drug Contrave said this week they have taken a key first step in showing that the medication does not boost the heart and stroke risks of those taking it, and they announced plans to return to the Food and Drug Administration to seek its approval in the coming weeks.

As early as June, Contrave -- an investigational drug that pairs the antidepressant and anti-smoking drug bupropion with the anti-addiction medication naltrexone -- could become the third weight-loss drug to be approved by the drug agency for the U.S. market in the space of two years.

In June and July of 2012, the FDA approved the marketing of Belviq and Qsymia. But Contrave, the first of the three to come before the agency for approval, was rebuffed by the FDA in February 2011. Its sponsor, LaJolla-based biotech firm Orexigen Therapeutics Inc., was told its application would be reconsidered if it sponsored a clinical trial that demonstrated that obese patients taking it did not have a significantly higher risk of suffering heart attack, stroke or cardiovascular death than those who did not take the drug.

This week, Orexigen announced it had reached the interim target laid out by the FDA. At 300 centers across the United States, it enrolled 9,000 obese patients at higher-than-usual risk of cardiovascular disease into the “Light study” and assigned them randomly into a group that took the medication and a comparison group that got a placebo pill. Four in 10 of those participants had Type-2 diabetes, and virtually all were taking medication for hypertension, high cholesterol or both.

After 87 cardiovascular “events” had taken place among subjects enrolled in the trial, the investigators set out to explore whether strokes, heart attacks or cardiovascular death among those taking Contrave were within the bounds laid out by the FDA as a preliminary target. They were, clearing the way for a resubmission as early as December and an FDA decision in June.

“It’s a big milestone for us,” said Orexigen President and CEO Mike Narachi in an interview Wednesday. Narachi added that Contrave is also under consideration by the European Drug Agency, and predicted the interim findings would bolster that application as well. He said that if the drug were approved, Orexigen and its partner, Takeda Pharmaceuticals, would launch a large and well-funded campaign to market the medication to physicians and patients.

“We know primary-care drugs don’t take off unless you invest heavily in them at the start,” Narachi said.

In four clinical trials of Contrave originally submitted to the FDA -- with a total of roughly 4,500 overweight and obese subjects -- the weight-loss differences between those taking Contrave and those taking a placebo for roughly a year were “of nominal statistical significance,” and FDA staff report said But the proposed diet drug did satisfy a backup measure of adequate effectiveness the FDA said it would consider: in all four trials, more than a third of subjects lost a total of at least 5% of body weight while taking Contrave. In one of the four, two-thirds lost more than 5% of their body weight, and on average, roughly half did in the other trials.

Narachi defended Contrave as a medication better than those statistics would suggest.

“You really have to look at how that person improved from baseline and how many people had a shot at a good result,” Narachi said. As many as half of obese patients may respond poorly to Contrave, but responders have shown solid weight-loss results, with a quarter of responders in a final round of trials losing an average of 43 pounds.

“Physicians, when you show them efficacy numbers, don’t care about mean weight loss. They want to know, ‘What kind of shot will my patient have of losing 20% or more of their body weight?’” Narachi said. Early conversations with primary-care physicians -- the doctors most likely to prescribe these medications, suggest they will be satisfied enough with the answer to those questions to write prescriptions, he added.

[Corrected at 6:29 p.m., Nov. 27: An earlier version of this post said Contrave could become the third diet drug to be FDA-approved in a year. It would be the third to be approved in two years.]