The Food and Drug Administration has informed the manufacturer of the weight-loss medicine combination naltrexone/bupropion that it cannot approve the drug without a new large-scale trial to establish its cardiovascular safety.
On Feb. 1, the California firm Orexigen Therapeutics, which developed naltrexone/bupropion (Contrave) along with Takeda Pharmaceutical of Japan, announced that it had received a letter from the agency saying that the drug would not be approved in advance of "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."
In a Feb. 1 conference call with stock analysts, Orexigen chief executive Michael A. Narachi called the agency’s decision a surprise and "a big setback" after the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 13-7 in December that the benefits of the drug, comprising two already-approved agents, outweighed its risks. Contrave, if approved, would have been the first new prescription antiobesity drug in the United States in a decade.
In December, the FDA advisory committee had cited concerns about elevated heart rates and systolic and diastolic blood pressure among the more than 4,000 obese patients, most of them women, who took part in phase III clinical trials. Mr. Narachi said that the FDA’s move stemmed not from any new analysis or data on cardiovascular events submitted since December but rather the same "small but consistent increase in blood pressure and heart rate" discussed at that meeting.
In studies submitted to the FDA by the manufacturer, after 56 weeks, those on the proposed dose (32 mg of naltrexone plus 360 mg bupropion per day, taken in two divided doses) lost 5%-8% of their baseline body weight, compared with a loss of 1%-2% in those on placebo. The proportion of those who lost at least 5% of their baseline body weight ranged from 45% to 56% of those on the proposed dose, compared with 16%-43% of those on placebo.
However, a quarter of people treated with naltrexone/bupropion had significant increases in systolic blood pressure of at least 10% over baseline, compared with less than a fifth of those in the control arms, and increases of diastolic blood pressure of at least 5 mm/Hg over baseline in 37% of those on the combination, compared with 29% of those on placebo. Regarding heart rate, 26% of patients in the treatment arms had increases in heart rate of at least 10 beats per minute over baseline, compared with 19% of those on placebo.
The panelists at the December FDA meeting who agreed that the potential benefits outweighed the potential risks said that the drug combination had met one of two criteria set by the FDA for being an effective weight-loss agent, and cited the extensive clinical experience with the two drugs and the company’s commitment to conduct a postmarketing long-term safety and efficacy study, which would also evaluate the risk for major cardiac events.
Mr. Narachi said on Feb. 1 that until the company begins talks with the agency, it cannot predict what the cardiovascular safety trial design might look like or whether the company would even proceed with such a trial, as cardiovascular safety trials require large numbers of patients and can last 4-5 years. "We’ll be doing what’s in the best interest of our shareholders," he said.
Contrave, containing the antidepressant bupropion and the drug- and alcohol-addiction treatment naltrexone, is one of two medications developed by Orexigen for obesity; the other, called Empatic, has completed phase IIb trials. Empatic is also a combination of two already-approved mediations, the anticonvulsant zonisamide and bupropion.
Internal Medicine News Digital Network reporter Elizabeth Mechcatie contributed to this story.