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Long road to FDA approval of weight loss drug Contrave

by
Scope Correspondent

Diet and exercise continue to make little headway against the obesity epidemic, which according to the CDC now affects over one-third of American adults. The recent FDA approval of Contrave adds another weapon in the fight against America’s growing waistline.

Patients taking Contrave, a combination of the two existing anti-depression and anti-addiction drugs bupropion and naltrexone, lost 6.1% of their total body weight in one clinical trial. Patients receiving placebo lost only 1.4%. These outcomes place Contrave squarely in line with Qsymia and Belviq, the two weight loss drugs that the FDA approved in 2012.

Michael Cowley, who led the Contrave studies, says that bupropion and naltrexone’s anti-addictive properties and their effect on food cravings were not initially considered when they chose to combine the two into a fat loss drug. “That side of the equation became much clearer later on and is clearly an important part of it,” he says.

Their original reasons for selecting bupropion and naltrexone were twofold: first, developing and approving a drug that combines two existing drugs is more cost effective than developing an entirely new molecule; second, bupropion and naltrexone’s side-effect profiles both include moderate weight loss

Cowley’s team started out by examining bupropion and naltrexone’s combined ability to stimulate firing in the brain’s hypothalamic neurons that regulate appetite and energy expenditure. The experiments, published in the journal Obesity in 2009, showed in mice that treatment with both drugs increased the firing of these neurons and decreased food consumption. Human subjects also lost weight on the combined therapy.

Emmanuel Pothos, an expert on the connection between the brain’s reward circuitry and obesity at Tufts’ Sackler School of Medicine, says that for a long time obesity was thought to simply be a disorder of the switches that regulate hunger and satiety in response to the body’s energy needs. However, the rapid growth of the obesity epidemic suggests that more may be at play than a large proportion of the population simply consuming more calories than it burns. Pothos, who provided his expertise for Contrave’s labeling but was not financially compensated, explains that there is an ongoing shift to considering how the pleasure of eating might drive compulsions to overeat.

Basic studies presented at a 2007 meeting and funded by Orexigen, the company that developed Contrave, suggest a potential connection between Contrave’s weight loss properties and the reward associated with eating: they found that injecting naltrexone and bupropion directly into the area of the mouse brain that associates behaviors with their learned rewards (e.g., eating food with feeling pleasure) reduced food intake. Questionnaires administered to patients during the clinical trials also hinted that the treatment reduced patients’ food cravings, although the results from two of the trials were mixed.

How Contrave fits into the interplay between brain systems responsible for energy balance and for reward signaling remains to be clarified. “Even though the drug has been approved now, I think maybe more efforts towards the advanced type of understanding of the mechanism of action is warranted here,” Pothos says.

The FDA decided that more efforts towards confirming Contrave’s cardiovascular safety were also warranted and required that these studies be conducted prior to official approval. As a result, four years have elapsed since the FDA’s advisory committee first recommended that Contrave be approved. Dr. Frank Greenway of Pennington Biomedical Research, who helped to design the clinical trials, says that although the study is ongoing, the FDA’s satisfaction with the results to date contributed to the recent approval. “We know that much, but we don’t know the details,” he says. The investigators have not yet been unblinded to the treatment groups.

Jeffrey Mechanick, Immediate Past President of the American Association of Endocrinology, welcomes any additional help in the fight against obesity. “The FDA needs to change its policy so that it approves drugs a little better,” Mechanick says. “You look at anti-obesity drugs, and there are a lot that are in the pipeline but far fewer are making it out.”

He adds that Contrave is a drug that works, and adding it to the arsenal of existing pharmaceuticals provides more options for each patient to find the right weight loss therapy. “We need lots of variety, just like we have for hypertension and diabetes. Not all people are the same,” Mechanick says.

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