F.D.A. Rejects Qnexa, a Third Weight-Loss Drug

By Andrew Pollack

OCT 29, 2010

The Food and Drug Administration rejected another new diet pill on Thursday, the latest setback in the quest to develop treatments for overweight Americans amid the nation’s obesity epidemic.

The rejected drug, called Qnexa, is the third weight loss medicine to run into trouble this month because of concerns about safety. Last week, the F.D.A. declined to approve another new drug, lorcaserin, because it caused tumors in rats. And earlier in the month it forced the withdrawal of Meridia from the market after 13 years, citing the risk of heart attacks and strokes for certain patients.

“It looks pretty bleak out there for anyone trying to get a drug approval for weight loss,” said Dr. Ken Fujioka, director of the center for weight management at the Scripps Clinic in San Diego.

Vivus, the developer of Qnexa, said late Thursday in a statement on its Web site that the F.D.A. had requested that the company provide a thorough evaluation of the drug’s potential for causing birth defects and heart problems.

The company, based in Mountain View, Calif., said it was confident it could provide this information to the F.D.A. in about six weeks. If the F.D.A. were to be satisfied, the drug could win approval sometime next year.

There has been no new prescription diet pill approved since Roche’s Xenical in 1999. Xenical is now the only drug approved for long-term use in managing weight.

“It’s tough to be a doctor and try to do something about the biggest problem in the U.S.,” said Dr. Fujioka, who is a consultant to some drug companies, including Vivus.

Some drug companies shied away from the diet market, after part of the popular fen-phen diet combination was removed from the market in 1997 because it damaged heart valves. The debacle resulted in huge legal settlements.

The F.D.A.’s decision on Qnexa was not unexpected, given that an advisory committee to the agency had voted 10 to 6 against approval in July.

But it is nonetheless disappointing to some specialists because Qnexa produced about twice as much weight loss as other diet pills. In clinical trials, patients on the highest dose of Qnexa lost an average of 10.6 percent of their weight after one year, compared with 1.7 percent for those taking a placebo.

Qnexa is a combination of two existing drugs – phentermine, a stimulant that is approved for short-term use as a weight loss drug, and topiramate, an epilepsy and migraine drug sold by Johnson & Johnson under the name Topamax.

An F.D.A. advisory committee in December will consider another diet drug, called Contrave, developed by Orexigen Therapeutics. But if that one also is not approved, some experts say it would discourage already wary pharmaceutical companies from working on drugs for obesity.

“It’s going to put the brakes on all obesity drug development for a decade,” said Dr. W. Timothy Garvey, chairman of the department of nutrition sciences at the University of Alabama at Birmingham, who was an investigator in the clinical trials of Qnexa.

Morgan Downey, an advocate for obese people who also consults for pharmaceutical companies, said the F.D.A. appeared to believe that a very effective drug would be used so much that unanticipated side effects would show up, while less effective drugs were not worth any risk.

“The F.D.A. has gotten itself into a real knot,” said Mr. Downey, who describes himself as obese and edits the Downey Obesity Report Web site. “They can’t approve a very effective drug and they can’t approve a modest drug.”

The F.D.A. does not comment or publicly release its reasons for turning down a drug.

Dr. John Jenkins, director of the agency’s office of new drugs, told reporters this month that the agency was “committed to working toward approval” of new obesity drugs, “so long as they are safe and effective for the population for which they are intended.”

Diana Zuckerman, president of the National Research Center for Women and Families, said the diet drugs that have made it to market are not very effective, so the F.D.A. should pay close attention to safety. “The vast majority of people taking them don’t stay on them long enough to get any health benefit,” she said.

About a third of Americans are obese and another third merely overweight. Obesity contributes to many other health problems like diabetes, heart disease and cancer.

So an effective diet pill could help cut medical costs over all and should, at least in theory, become a blockbuster.

“This is the biggest field, bigger than statins potentially,” Jack Lief, chief executive of Arena Pharmaceuticals, the developer of lorcaserin, said a year ago, referring to the popular cholesterol-lowering drugs like Lipitor.

Yet no diet pill has ever become a true blockbuster. COmbined sales of all prescription obesity drugs in the United States have been falling over the last few years and totaled only $154 million in 2009, according to IMS Health, a health care information company.

That is mainly because they generally produce a weight loss of only 5 percent or so. The body has so many mechanisms to maintain weight that any one drug is not likely to have much effect, scientists say.

A study published in the journal Obesity in January that used insurance records found that fewer than 1 percent of adults used obesity pills despite the considerable number of obese people. And only 11 to 18 percent of the users stayed with the drugs for longer than three months, a far greater dropout rate than for statins.

“With a statin, patients rely on their doctor to tell them whether they should be taking it or not,” said John A. Tucker, a pharmaceutical industry consultant in San Diego. “With an obesity drug, they can judge for themselves,” and many are disappointed in the weight loss they achieve.

The difficulties, and safety setbacks, have already soured many pharmaceutical companies on obesity drugs. When two drugs used in the fen-phen diet pill combination were withdrawn from the market in 1997 for damaging heart valves, their manufacturer Wyeth, now part of Pfizer, was left with more than $20 billion in liability.

Three years ago, the F.D.A, citing the risk of suicidal thoughts and depression, declined to approve rimonabant from Sanofi-Aventis. Merck and Pfizer then abandoned development of drugs that worked in the same way.

Dr. Fujioka said another reason obesity drugs were not more popular is that many physicians “have a bias against obese patients and don’t want to give them the easy way out.”

Unlike advocates for patients with, for example, AIDS or cancer, those who are obese may be more reluctant to pressure an agency like the F.D.A., because overweight people often view their condition as a sign of a lack of willpower.

“Most people feel it is their personal responsibility, so they are uncomfortable to go out and make a claim on society for additional help,” Mr. Downey said.

Dr. Caroline Apovian, director of the center for nutrition and weight management at Boston University Medical Center, who has consulted for drug companies, said, “We’ve shown over and over again that it’s very difficult for anyone to lose weight and keep it off through diet and exercise alone.” When that approach is successful, she said, it often requires intensive coaching, which is impractical for medical offices to provide on a large scale.

Despite the setbacks, there are still diet drugs under development. The next generation will probably not be pills but rather injections of synthetic versions of hormones the body already uses to control weight.

Bariatric surgery, which can reduce weight far more than pills, is now restricted for use in severely obese people because of risks and costs. In December, an F.D.A. advisory committee will consider a proposal from Allergan to lower the weight threshold for use of its Lap-Band gastric banding system.

There are also devices in development that do not require invasive surgery. Still, no surgical approach is likely to be as practical for a huge population as drugs.

“We have over 50 antihypertensive agents on the market,” Dr. Apovian said. “We have lots of drugs on the market for diabetes. With the epidemic of obesity, how is it possible that we have only two drugs on the market?”