July 16, 2010 -- A U.S. Food and Drug Administration panel has voted by a narrow margin against recommending the new diet drug Qnexa, citing concerns about a lack of data on the drug's cardiovascular effects.
The FDA's Endocrinologic and Metabolic Drugs Advisory Committee voted 10-6 against recommending approval for the combination drug. The pill contains the amphetamine phentermine -- supposedly the safer of two active ingredients in the infamous diet pill Fen-phen, which was pulled from the market in 1997 because of its link to heart damage. Qnexa also contains the anticonvulsant topiramate.
An initial review found Qnexa to be safe and effective, with some participants in early clinical trials losing an average of 10 percent of their starting body weight.
"In terms of efficacy, it's far superior to anything on the market," said panel member Dr. Abraham Thomas, an endocrinologist at Henry Ford Hospital in Detroit.
The committee, however, was concerned about increased risk of psychiatric and cognitive issues uncovered in the company's trials, and said the there was a lack of data to rule out cardiovascular risks and the drug's potential to cause birth defects in women who become pregnant while taking it.
There were also concerns because 18 percent of participants taking a high dose withdrew from trials after experiencing mild side effects, such as tingling of the hands and feet, headache and constipation. About 40 percent of all participants either taking high or low doses of Qnexa did not complete the study for various reasons.
Dr. Sidney Wolfe, director of Public Citizen's Health Research Group, said he was pleased with the panel's decision.
"The two drugs that make up the combination of Qnexa are dangerous on their own," Wolfe said. "Topiramate is a drug that was studied several years ago to see if it worked for diabetics who are obese. It worked well for weight loss, but the side effects were so significant that it should not be used for weight loss."
Experts Debate Safety of New Diet Drug
As for phentermine, Wolfe said there are a number of adverse side effects associated with it, including increased pulse.
But Dr. Ken Fujioka, director of the Scripps Clinic Center for Weight Management in San Diego, said before Thursday's hearing that while phentermine was dangerous as part of the fen-phen combination, it is safe and effective on its own. Fujioka is on the advisory committee for Vivus, the company that makes Qnexa, and the advisory committees for companies that make two other proposed weight-loss drugs, Lorcascerin and Contrave.
Lorcaserin and Contrave go before the FDA for approval later this year. Although the panel voted against recommending Qnexa, the agency doesn't have to follow the panel's advice.
Qnexa Renewed Hopes for Safe and Effective Diet Drugs
Experts said they hoped that Qnexa and the other drugs would provide effective weight-loss without the dangerous side effects that doomed other drugs, such as Fen-phen, Meridia and Alli. Fen-phen was pulled from the market in 1997 after it was linked to heart valve thickening. Meridia was pulled from the European drug market in 2009, and the FDA recently warned consumers about Alli's link to severe liver damage.
After news of the new drugs came out, they questioned the safety of a combination pill that appears to show striking similarities to previously recalled drugs.
"Whether any drug will become another Fen-phen is hard to predict," said Dr. Gerard Mullin, associate professor of medicine at the Johns Hopkins School of Medicine. "Every time we see a drug recalled, none were predictable, but it seems that similar classes of drugs can have inherent problems."
It's also unclear to some experts whether topiramate actually works.
"The anticonvulsant in both Contrave and Qnexa is a new variation on the theme of tweaking brain pathways to adjust appetite, but does not appear to be more than a minor innovation to me, and one of questionable utility," said Dr. David L. Katz, associate professor adjunct in public health practice at the Yale School of Public Health.
Year-Long Studies on Qnexa, Lorcaserin, Contrave
"We did very detailed studies and found it wasn't the phentermine. It was fenfluramine that was linked to the heart issues," Katz said.
Fujioka said the trials for Qnexa, Lorcaserin and Contrave lasted about a year. The drugs were tested on about 4,500 patients each.
However, others believe there have not been enough studies done to show that these drugs are safe for most patients.
"Just because these compounds don't have the same chemical mix as Fen-phen doesn't mean they don't have a chemical mix that can cause long-term harm," said Joanne P. Ikeda, nutritionist emeritus and former co-director of the Center on Weight and Health at the University of California, Berkeley. "I think we should demand long-term (three- to five-year) safety studies for these drugs."
Keith Ayoob, director of the nutrition clinic at the Rose R. Kennedy Center at the Albert Einstein College of Medicine, agreed.
"The new drugs seem safe, but so did the Fen-phen combo," he said.
Many experts, including Ayoob, said it is safe to assume that there will be side effects with these drugs.
"It is difficult to believe the risk of memory loss and other neurological effects found with topimarate will provide adequate safe use," said Dr. George L. Blackburn, associate director of nutrition at Harvard Medical School.
Blackburn said if the drugs do end up on the market, they will target those who are obese and possibly morbidly obese.
"Studies have looked at the morbidly obese -- about 7 percent of our population falls into this category -- that's a group that has a huge need," said Fujioka.
Though risky, invasive procedures such as gastric bypass surgery clearly offer better results than taking diet pills. But many obese Americans may not qualify for surgery. And given the grim history of many diet pills that have come and gone, many experts said they don't think the answer to the obesity epidemic can be found in a pill.
"Weight loss drugs have a checkered history with regard to cardiovascular risks," said panelist Dr. Sanjay Kaul, a cardiologist at Cedar Sinai Medical Center in Los Angeles. "We don't have enough evidence here to evaluate cardiovascular risk other than increased heart rate."
Diet Drugs' Approval Hopes Murky
Eric Coleman, deputy director of the FDA division that oversees metabolic drugs, said he was surprised by the vote.
"I was a little surprised the vote went as it did, but you learn in an advisory committee that you never know which way it is going to go."
Coleman said it was clear a lot of panelists weren't strongly against the drug but just had "lingering concerns to make them vote no."
Meanwhile, several patients who were enrolled in Vivus' trial pleaded with the committee earlier in the day to approve the drug.
Erin Aycock, a young woman who took lost 50 pounds while taking phentermine/topiramate but gained back most of the weight when the trial was over, said the drug made losing weight easier than anything else she has tried.
"It's like instant willpower," Aycock said. "I have the ability for the first time in my life to say 'I don't even care if I eat that cookie.'
"I would do anything to be back on this drug."
As for Lorcaserin and Contrave, the other drugs set to go before the FDA, Wolfe said he's unsure about how they'll fare in front of the panel.
"The history of drugs for weight loss is littered with drugs that are dangerous," said Wolfe. "When a new drug comes to market, you know that it works, but you don't know about its side effects."
Fujioka said he hopes the FDA panel's meetings will provide guidance on drug safety issues and some insight about the future of other drugs.
"They'll give us an idea about how much safety will be required to get a drug approved," he said.
"What happens in this meeting affects the other drugs as well," he added.