Vivus Inc. scored a near knockout in its second bout before the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) with its weight-loss contender Qnexa.

The committee voted 20 to 2 to support FDA approval for Qnexa (phentermine/topiramate) as a treatment of obesity in individuals with a body mass index greater than 30 kg/m2 or greater than 27 kg/m2 with weight-related co-morbidities.

However, it was a "much harder decision than the vote shows," said panel member Janet Cragan, of the National Center on Birth Defects and Developmental Disabilities.

Jessica Henderson, professor of community health education at Western Oregon University, agreed, saying that before she voted, she took a poll within herself. The results of her internal poll were 3 to 2 in support of the obesity drug. The two no votes, she said, were because of the teratogenic risks and inconclusive data about cardiovascular risk.

Those concerns tripped up Qnexa in its first bout with EMDAC. That time, the committee voted 10 to 6 against approval. The FDA followed through a few months later with a complete response letter that cited the birth defect and unknown cardiovascular risk. The agency raised the issues again in its briefing documents for Wednesday's meeting. (See BioWorld Today, July 16, 2010, Nov. 1, 2010, and Feb. 21, 2012.)

One of the things that tipped the scale for Qnexa this time around is that phentermine and topiramate are already approved separately for other indications. Given Qnexa's efficacy in weight loss, panel members feared the two could be used off-label without a risk evaluation and mitigation strategy (REMS) or appropriate labeling.

That's not to say the committee was comfortable with Qnexa's risks. The members overwhelmingly voiced the need for a large, postapproval cardiovascular outcomes trial. Vivus described a tentative design for a four-and-a-half-year Phase IV trial enrolling 11,000 patients to demonstrate both safety and superiority.

But with reminders of several diet drugs having to be withdrawn from the market because of postmarket safety problems, panel member Sanjay Kaul, director of the Fellowship Training Program in Cardiovascular Diseases at Cedars-Sinai Heart Institute, recommended the trial enroll more high-risk patients for a shorter period of time.

Another issue was the need and scope of a REMS to reduce the risk of birth defects associated with topiramate, which is on the market in higher doses as a treatment for epilepsy and migraine.

Speaking during the public comment period, Joe Nadglowski, president and CEO of the Obesity Action Coalition, asked whether there was a bias against obesity drugs at the FDA given that topiramate is not required to have a REMS for the other indications.

Another inequity is that Qnexa, if approved, would be a Category X, which means the risks of the drug clearly outweigh the benefits for pregnant women. However, Topomax (topiramate) was only recently bumped to a Category D, meaning that the benefits could outweigh the risks.

The difference for some panel members is that, if approved, Qnexa could be prescribed to millions of patients – a much larger population than Topomax treats.

The REMS Vivus proposed would include a medication guide, enhanced communication plan and two elements to assure safe use: provider training and controlled distribution through certified mail order pharmacies.

The panel debated the merits of the mail order distribution, citing delivery problems, with some hoping the REMS could become less restrictive over time.

Vivus, of Mountain View, Calif., came out swinging at the EMDAC meeting, countering the FDA's concerns with the fact that obesity itself carries high cardiovascular and teratogenic risks. "Today we have an opportunity – some would say we have an obligation – to change how we manage obesity," said Vivus presenter Arya Sharma, chairman of obesity research and management at the University of Alberta.

Several members of the public supported Vivus in urging the FDA to start treating obesity like the chronic condition it is. Kelly Close, a diabetes patient and editor of DiaTribe, said the cost of obesity in the U.S. is $270 billion a year, making it "the biggest public health problem of our time."

While at least 700 cancer drugs and 150 cardiovascular drugs are in clinical trials, Close said only 50 obesity drugs are in development – five of which are in Phase III. Those five include Qnexa, Arena Pharmaceuticals Inc.'s Lorqess (lorcaserin) and Orexigen Therapeutics Inc.'s Contrave (naltrexone HC1/bupropion HC1), all of which came before EMDAC in 2010.

Qnexa, which has an April 17, 2012, PDUFA date, demonstrated the most efficacy of the three drugs, panel members said Wednesday. Whether those sentiments will trip up the other two drugs remains to be seen. Lorqess has a June 27, 2012, PDUFA date. And the FDA required Orexigen to do a pre-approval cardiovascular outcomes trial, which is slated to begin in the next quarter. (See BioWorld Today, Dec. 16, 2011, and Jan. 12, 2012.)

Shares of Vivus (NASDAQ:VVUS) closed at $10.55 Tuesday ahead of the EMDAC meeting. Trading was held Wednesday.