Conflicted FDA committee votes against recommending approval of weight-loss drug Qnexa

Fran Lowry

July 16, 2010

Gaithersburg , MD - The FDA Endocrinologic and Metabolic Drugs Advisory Committee has failed to endorse recommendation of a new obesity drug, a combination of phentermine and controlled-release topiramate (Qnexa, Vivus) because of fears about its safety.

The initial tally was nine against and seven in favor, but this later changed to 10 against, as one panel member admitted he had made a mistake due to unfamiliarity with the voting procedure.

All agreed that Qnexa was very effective in inducing weight loss, but even those panel members who voted to give Qnexa the benefit of the doubt struggled over a litany of adverse events seen with treatment, including depression; anxiety; sleep disorders; attention, memory, language, and other cognitive disorders; metabolic acidosis; increased heart rate; and teratogenicity.

Despite these serious adverse events, the panel felt that good drugs are needed to treat obesity. Some of the panel offered the FDA suggestions for registry and pharmacodynamic studies and longer follow-up out to five years.

"Clearly, we need more information about this medication, but the type of information we need, particularly with respect to teratogenicity, cannot be gained in a clinical-trial setting; it can be gained only when the drug is on the market and large numbers of individuals are exposed to it," said Dr Michael A Rogawski (University of California, Davis) in explaining his "yes" vote.

Others disagreed. Safety concerns should be dealt with before a drug is approved, not afterward, said Dr Katherine M Flegal (Centers for Disease Control and Prevention, Hyattsville, MD). Approving Qnexa before addressing them would be "a public-health experiment and a large gamble," she said.

Dr Abraham Thomas (Henry Ford Hospital, Detroit, MI) agreed, saying currently available obesity drugs leave much to be desired, with little effectiveness and lots of side effects.

"Qnexa is far superior to anything that's on the market," he said. "But our concerns are with safety. These have to be addressed, and I think it's best if these are addressed before approval."

As did other panel members, Thomas said obesity drugs need to be considered in terms of long-term use. "I think we have to get away from the concept of usage for the short term. Obesity is a chronic disease; I would never go to someone who has high blood pressure and say, 'Your blood pressure is normal; now we stop all your medications, see you in a year.' Yet, with obesity, we view it that way. So we have to look at the long-term safety of these medications so we can prevent weight regain."

Acting chair Dr Kenne th D Burman (Washington Hospital Center, Washington, DC) said he hoped that his "no" vote will prompt further discussion with the FDA to address the safety issues.

"We know that obesity is a major health problem, and all efforts to address this issue should be lauded," he said. "Qnexa does meet or exceed the agency's requirement for efficacy. On the other hand, the medication has serious potential adverse effects, including potential teratogenicity, increased suicidal ideation, cognitive issues, decreased bicarb, tachycardia, and possible renal stones. Some of these side effects are serious and could be life-threatening, and they have to be weighed against the potential of a relatively modest weight loss and its long-term health benefits."

Burman said that one year was not long enough to allow him to recommend approval with confidence. "This medication will be used for a much longer time frame in a much wider population, and it is difficult to extrapolate the potential adverse effects to this larger population."

Dr Lamont G Weide (University of Missouri, Kansas City) seconded Thomas. "It doesn't surprise me that among people who are treating people with obesity we are starting to call it a chronic disease. When you think that way, you look at the drugs differently, and you have to say, 'Tell me what's going to happen with my patients as I allow them to stay on the medication.' That's one of the things that bother me. If, with a year's trial, you have double the depression risk, and you have some cardiovascular questions, I would like to see it extended, so that we can find out whether or not these safety concerns are going to be a major issue."

Weide added that he was sick of having to take drugs off the market after they have been in use for a few years because of failing to identify problems. Earlier in the week, members of the same advisory panel grappled with the difficult decision of whether the safety profile of rosiglitazone warranted removing it from the market.

Drug withdrawal "really is some of what has given the FDA a bad reputation . . . in the public. We have a responsibility to protect the public at large. As much as I feel for the people who want this drug and want to lose weight, we have to protect the population at large, and we need longer-term data with the people who are really going to be using it out there, rather than a select group of patients in fairly good health."

One panel member who voted to recommend approval said he feared that the naysayers would be sending the wrong message to people who struggle with their weight.

"I voted 'yes.' I agree that the population at large needs to be protected from dangerous drugs; however, one-third of that population is already obese and there's a very large segment of the population who are headed that way," said D r Ed J Hendricks (Center for Weight Management, Sacramento, CA).

"Qnexa fills a gap our treatment spectrum," he continued. "The sponsor did an outstanding job of managing several very difficult clinical trials. The data show that the drug is reasonably safe in the target population, which is obese patients. We should approve it. If we say no, we will send a very bad message to our obese patients. This will further drive them away from seeking medical solutions to their weight problem, to all the various quackery things that are out there. I hope the FDA doesn't just go by the yes/no votes."

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