Dec. 8, 2010 -- SILVER SPRING, Md. -- An FDA advisory committee has voted 13-7 that the modest weight-loss benefits of an investigational combination of naltrexone and bupropion -- marketed under the brand name Contrave -- outweigh the drug's blood pressure risk.
The bupropion-naltrexone combo is the last in a trio of new weight-loss drugs that went before FDA panels this year, striving to be the latest treatment in the dwindling field of medications to fight obesity. The previous two drugs, phentermine/topiramate (Qnexa) and lorcaserin hydrochloride (Lorqess) were both rejected by the FDA after they fared poorly at advisory committee meetings.
But Tuesday's advisory committee ended very differently than the previous two.
Bupropion/naltrexone appeared to offer fewer side effects than the previous two drugs, although it also doesn't appear to work as well at helping obese patients lose weight.
The FDA will make an approval decision by Jan. 31. The agency does not have to follow the advice of its advisory committees, but it often does.
Orexigen, the company that makes naltrexone/bupropion in partnership with Takeda, is seeking approval for treatment of obesity and weight management in patients with a body mass index of 30 or above, or 27 or above and with one or more risk factors, such as diabetes, dyslipidemia or hypertension.
Contrave combines an antidepressant and an anti-addiction drug, both of which have been used individually for 20 years -- naltrexone for opioid addiction and alcohol dependence and bupropion for depression and smoking cessation. However, little is known about combining the drugs for weight managment.
The Endocrine and Metabolic Drugs Advisory Committee reviewed results from Orexigen's four placebo-controlled, one-year, phase III clinical trials, which enrolled 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 (P<0.001), 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.
Contrave Yields modest Weight Loss, Research Shows
In a pooled analysis, naltrexone/bupropion patients lost an average of 4.2 percent more weight than the placebo group (ranging from 3.3 percent to 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 percent.
In one trial where patients taking naltrexone/bupropion were compared with those undergoing a lifestyle modification program, the difference between the groups was even smaller, suggesting that diet and exercise can achieve similar results as naltrexone/bupropion.
"As far as efficacy goes, I think they made it by the hair of their chinny chin chin," said Melanie Coffin, the panel's patient representative.
In the FDA's assessment of the drug released last week, reviewers expressed concerns over several side effects -- a potential increased risk for dizziness, nausea, seizures, and high blood pressure among patients taking naltrexone/bupropion.
However, the panel was mostly just concerned with one side effect: The drug's effect on blood pressure.
In the trials, patients taking naltrexone/bupropion were more likely to have an increase in blood pressure and heart rate than placebo patients, an effect that was most pronounced during the first eight weeks of treatment.
However, patients taking naltrexone/bupropion who lost at least 5 percent of their body weight achieved lower blood pressure and heart rate compared with those who lost less weight. But the most impressive improvements in blood pressure and weight loss were seen among patients taking placebo who achieved more than a 5 percent weight loss, suggesting diet and exercise is the best option for obese patients to lower their blood pressure.
Panelists were concerned that a drug that is supposed to reduce obesity -- and hopefully other comorbidities along with it -- actually raised blood pressure instead.
"This is my biggest concern," said Dr. Lamont Weide, chief of diabetes and endocrinology at Truman Medical Centers Diabetes Center in Kansas City, Mo. "That we are blunting all the good effects that we should see with weight loss."
Concerns Over Possible Risks of Contrave Linger
The FDA reviewers concluded there wasn't enough data on the cardiovascular risks of the drug. The panel seemed to agree, but voted 11-8, with two panelists abstaining, that the company could submit new data after approval to show that the drug doesn't present major heart risks.
The panel's one neurologist, Dr. Michael Rogawski, said he thought the panel downplayed the drug's seizure risk.
Two patients in the clinical trials experienced seizures after going on naltrexone/bupropion; no participants in the placebo group had seizures. About one in 1,000 patients who take the drug would be expected to have a seizure, the panelists said.
"They occur only in one out of 1,000, but still, the consequences of having a seizure could be catastrophic," said Rogawski, who ended up voting in favor of the drug.
There is currently just one anti-obesity drug on the market: Orlistat (Xenical, Alli), after Abbott, the maker of another drug sibutramine (Meridia) voluntarily agreed to remove it from the U.S. market in October because of increased risk of stroke and MI.
Several physicians and other healthcare professionals contacted by MedPage Today and ABC News were pleased with the panel's decision and said that doctors badly need a new drug to help patients battle obesity.
"It is nice to have a medication that can help those who are watching their diet and boosting activity lose the weight that thus far has been a slow process," said dietitian Connie Diekman, director of University Nutrition ?at Washington University in St Louis. "This is one more option in the tool chest to deal with the obesity issue."
"Finally!" said Dr. Robert F. Kushner, professor of Medicine at Northwestern University Feinberg School of Medicine. "I fully endorse the panel's vote. The key will be to educate physicians on how to best prescribe the medication -- identify patients who will benefit from the medication and to accompany it with lifestyle and behavioral recommendations."
Paul L. Doering, a pharmacy professor at the University of Florida, said he doesn't "doubt for a minute that this drug will be wildly successful, at least at first," adding, "Time will ultimately tell if it is a good drug or not. In the meantime, I'm going to let somebody else be the first to take it."