Diet drug Contrave kicks up a tempest amid uncertainty about heart attack and stroke effects

Researchers have a gentle warning for patients on the receiving end of 765,000 prescriptions for the weight-loss drug Contrave: The cardiovascular safety of this treatment "remains uncertain," they write in a newly published study.

As for claims by the drug's maker that it dramatically drives down heart attacks, strokes and deaths? Those, says the lead author of the new study, are premature at best.

When the Food and Drug Administration gave its blessing to Contrave in September 2014, that approval came with some fine print -- a small but significant caveat to patients and physicians. The approval was based on the preliminary results of a clinical trial designed to rule out the possibility that taking Contrave significantly boosted a patient's risk of suffering a heart attack or stroke, or death.

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The early returns -- the first quarter of the trial's planned run -- looked good. So the FDA gave Orexigen, then the drug's sole sponsor, the go-ahead to begin marketing the diet drug. But the clinical trial was to continue apace: Researchers and subjects enrolled in the trial would remain "blind" to whether they were taking Contrave or a placebo, and the first look at the safety data (the numbers that the FDA had relied on) would remain in the vault until the drug's safety profile became clearer with time.

The FDA's intent was clear: The clinical trial -- called the LIGHT Trial -- had to continue. Obese patients deserved a timely shot at weight loss with a medication that appeared to be safe. But an ominous turn in the safety data could still prompt the agency to reverse its decision on Contrave.

Today, Contrave -- a combination of the antidepressant drug bupropion (known commercially as Wellbutrin) and the anti-addiction medication naltrexone -- is the most prescribed of four weight-loss drugs approved by the FDA in recent years. But the LIGHT Trial was abandoned after the makers of Contrave flouted the terms of their agreement with the FDA and the researchers conducting the clinical trial and made the preliminary safety findings public.

On Tuesday, the results of the LIGHT Trial, at roughly the planned halfway mark, were published in the Journal of the American Medical Assn.

These results are considerably more muted than those that emerged at the one-quarter mark. The new findings establish that taking Contrave will not double the risk of stroke, heart attack or death in those taking it. But the trial's stunted findings are insufficient to satisfy the safety standard set for Contrave by the FDA: that cardiovascular "events" or death must not increase by more than 40% in patients taking it.

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The newly published findings also fall far short of claims for Contrave made by the company last March: that it promises to be a powerful reducer of heart attack and stroke risk.

The trial's early results -- good results -- were touted to Orexigen's business partners and potential investors. In a filing to the Securities and Exchange Commission, Orexigen -- a La Jolla-based company -- touted the preliminary findings in support of its patent claim on Contrave, crowing that in addition to inducing weight loss, the drug had "a positive effect on [cardiovascular] outcome" that appeared to be independent of patients' weight loss.

The company's claim -- that taking Contrave appeared to drive down an obese person's risk of heart attack, stroke or death by 41% -- would position Contrave as a spectacularly effective cardiovascular drug. But it was based on a clinical trial only 25% complete -- a trial now so tainted by disclosure that it could not be completed.

Last March, facing the prospect that study subjects on placebo would bolt to the active drug, the LIGHT Trial's investigators at the Cleveland Clinic pulled the plug.

"It's very bad behavior," said Dr. Steven Nissen, who led the LIGHT Trial and was joined by his co-investigators in demanding its termination.

"We had a dilemma," Nissen said in an interview. "We didn't know what the data would show, but we strongly suspected it would not hold up" to the early returns, he said. "We had years to go to complete the trial and in the meantime, physicians were prescribing and patients were taking the drug with the belief that it could bring about this amazing reduction" in heart attacks, stroke and death.

A new trial aimed at probing Contrave's safety profile is now underway, but will take years to complete, said Nissen. "Until that's done, we cannot make any conclusions," about the medication's long-term safety, he added.

That has not slowed down Orexigen or its new partner, Takeda Pharmaceuticals, in marketing Contrave. Since Contrave's introduction to the U.S. market in October 2014, Takeda sales reps have briefed 100,000 healthcare providers in nearly 1.1 million product discussions. Some 55,000 practitioners have written more than 765,000 prescriptions of Contrave, Michael Narachi, CEO of Orexigen, told investors in February.

"With this strong early effort, Contrave has quickly been established as the most prescribed branded obesity medication since June 2015." The company is now focused on direct-to-consumer marketing aimed at the obese and "improving profitability per prescription of Contrave," he added.

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