FDA Panel Supports New Diet Pill After Rejecting Two Others

Dec. 9, 2010— -- Only one of three weight-loss pills that have come before the U.S. Food and Drug Administration this year has a hope of gaining the regulatory agency's approval, at a time when obesity is driving dual epidemics of heart disease and diabetes.

The medication, Contrave, passed a major hurdle on Tuesday when the FDA's Endocrine and Metabolic Drugs Advisory Committee voted 13-7 for approval. That leaves it to the agency to determine, most likely by the end of January, whether Contrave can be sold in the United States. The sustained-release formulation, designed to curb food cravings, combines two medications with long track records: the antidepressant bupropion (Wellbutrin, also sold as Zyban for smoking cessation), and naltrexone, prescribed for narcotic addiction and alcoholism.

Before Tuesday's hearing, Contrave had mixed support. It notably failed to meet one of the FDA's key benchmarks for determining weight-loss drug success. At minimum, a drug should lead to 5 percent more weight loss than a placebo. Study patients who took Contrave lost just 4.2 percent more weight than those given a dummy pill. However, the drug met another standard, with 30 percent of patients getting it losing at least 5 percent of their body weight.

During a day of testimony, the panel weighed the drug's modest weight-loss benefits against potential cardiac side effects, including elevated blood pressure that was most evident among diabetic study participants.

Heart risks were among side effects that led the FDA in October to kill Arena Pharmaceuticals' lorcaserin hydrochloride (Lorquess). The agency couldn't rule out cardiac effects when reviewing and ultimately rejecting Vivus Inc.'s Qnexa, a combination of the amphetamine phentermine and the anti-seizure drug topiramate that same month. Also in October, the FDA pulled Abbott Pharmaceuticals' sibutramine (Meridia) off the market because of increased heart attack and stroke risks. Meridia boosted blood pressure, heart rate and incidence of palpitations.

That leaves orlistat (Xenical) as the sole FDA-approved diet drug for sale in this country, although on May 26, 2010, the FDA said its label must spell out its potential to cause rare but severe liver damage.

Weighing Excess Drug Risk Against Obesity Risks and Surgical Risks

The central dilemma in consideration of weight loss drugs comes down to determining how any excess risks they carry compare with the perils of sustained obesity or the risks associated with weight-loss surgery -- the only treatment currently found to be effective in the long run.

The current dearth of options has made the FDA "desperate to approve a weight-reduction drug, desperate for a magic bullet," said Dr. Sidney Wolfe, director of Public Citizen's Health Research Group in Washington, D.C. "One way of looking at it is the FDA's desperation to put another weight reduction drug on the market is increased because of these other two."

Wolfe said he would lead "a major effort to stop this drug from being approved." If approved, Contrave would be the first new obesity drug in more than a decade.

Wolfe contends that bupropion's known risks make Contrave dangerous. In an interview Wednesday, he said he hoped the FDA would learn a lesson from 1996, when it approved Meridia over objections raised by its advisory committee, only to take the drug off the market this year.

"The very reasons why Meridia should not have been approved are identical to this," Wolfe said.

"People may well -- with the help of the company promoting it -- flock to this drug," Wolfe said. "For the FDA to put their blessing on that is unacceptable."

In testimony submitted to the panel, Wolfe and a colleague noted that increased blood pressure and heart rate caused 21 patients to withdraw from the Contrave clinical trials and that one of the FDA's own reviewers described as "concerning" the fatal heart attack of a study subject whose blood pressure rose despite significant weight loss. Wolfe also noted seizures among two study patients who took Contrave, but none among those receiving placebos.

Before voting to let the drug move ahead, the advisory panel voted 11-8 that if Contrave ultimately wins approval, its manufacturer must conduct an additional study of its cardiovascular effects.

Response to Tuesday's vote was mixed, based upon comments from nutritionists and physicians who deal with the medical consequences of obesity. Some called the panel's action reasonable given the oversized costs and health burdens of obesity. Contrave, developed by Orexigen Therapeutics of La Jolla, Calif., would be used by men and women with a body mass index of at least 30, or 27 if they also have an additional risk factor like diabetes, high cholesterol or high triglycerides.

With Options Running Out, Some Support New Diet Pills

"Perhaps FDA is getting the message that obese Americans need something short of major surgery to help them lose weight," said Carla Wolper, a dietitian with the St. Luke's Hospital Obesity Research Center in New York and an assistant professor of psychiatry in the Center for Eating Disorders Research at Columbia University Medical Center. "Surgical risks are far higher than those of appetite suppressants, but FDA approved obesity surgery." Dr. Ken Fujioka, director of nutrition and metabolic research and director of the Center for Weight Management at the Scripps Clinic in San Diego, Calif., was even more emphatic, calling the panel's endorsement "fantastic and badly needed. We were running out of options to treat weight with medications."

Connie Diekman, director of university nutrition at Washington University in St. Louis, described Contrave as "one more option in the tool chest to deal with the obesity issue," and said that the weight loss it helps achieve might help with overall blood pressure reduction.

At the same time, Dr. Rubert F. Kushner, clinical director of the Northwestern Comprehensive Center on Obesity in Chicago, said the key to proper use of the drug would be educating physicians "on how best to prescribe the medication -- identify patients who will benefit from the medication and accompany it with lifestyle behavioral recommendations."

Dr. Charles M. Clark Jr., an internationally renowned diabetes expert at the Indiana University School of Medicine, endorsed the concept of targeting appetite control medically: "We must look for innovative treatments acting on different parts of the complex mechanisms that control appetite such as the combination contained in Contrave."

But many experts expressed reservations about the limited amount of data available to the FDA from four trials involving more than 4,500 obese people with at least one complicating condition, such as diabetes or depression.

"My enthusiasm is mixed based on the published efficacy of the combination and the clear concerns reflected in the advisory committee vote," said David J. Kroll, a professor of pharmaceutical sciences at North Carolina Central University.

Dr. Peter A. McCullough, a cardiologist serving as chief academic and scientific officer at St. John Providence Health System in Novi, Mich., said bupropion and naltrexone are "reasonably safe" individually, but together "pose a complicated issue" of potential drug interactions in obese patients taking other commonly used medications.

Diet Landscape Littered With Failed Drugs

The diet drug landscape is littered with failure. In 1997, the FDA pulled the diet drug combination of phentermine and fenfluramine (Fen-phen) and a related drug dexfenfluramine (Redux) from the market because some patients developed leaky heart valves. The medical and pharmaceutical communities suffered another blow when reports of depression and suicide became the undoing of once-promising rimonabant (called Zimulti in the United States and Acomplia in Europe), which blocks appetite-stimulating cannabinoid receptors in the brain. In June 2007, its French manufacturer, Sanofi-Aventis, withdrew its FDA application.

In light of obesity's enormous toll on heart health, Dr. Carl J. Lavie, medical director of cardiac rehabilitation and prevention at the Ochsner Clinic Foundation and Hospital in New Orleans, said more effective therapies are needed. He said he thought the FDA panel "so far is leaning to the drug producing more benefit than harm. Time will tell whether the 13 or the 7 were correct."