As the dust settled after the two-day Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) meeting ended with a 17-6 vote in favor of requiring large cardiovascular outcomes trials (CVOTs) for all obesity drugs, regardless of cardiovascular risk or signal, analysts began scrambling to gauge whether the recommendations will affect the upcoming FDA decisions for Vivus Inc.'s Qnexa and Arena Pharmaceuticals Inc.'s Lorqess (lorcaserin). (See BioWorld Today, March 30, 2012.)

The agency is not obligated to follow the panel's advice, though it often has in the past, especially when safety issues arise.

In 2008, for instance, the FDA issued guidance calling for cardiovascular assessments in mid-stage and late-stage testing of diabetes candidates based on panel recommendations. (See BioWorld Today, July 3, 2008, and Dec. 18, 2008.)

A similar guidance is expected to emerge based on EMDAC's recommendations for obesity drugs.

The question is, will the drugs already under review be sent back with pre-approval CVOT requirements, a move that could level the playing field for a third weight-loss drug contender, Orexigen Therapeutics Inc.'s Contrave (naltrexone HC1/bupropion HC1), which is getting ready to start a CVOT to address issues raised in last year's complete response letter? (See BioWorld Today, Feb. 2, 2011, and Sept. 22, 2011.)

Divining the answer from the two-day EMDAC panel is impossible, since panel members discussed obesity drugs in general, hardly even mentioning the top three candidates by name. But for Mountain View, Calif.-based Vivus' Qnexa (phentermine/topiramate), most analysts continue to see a good chance for approval by the April 17 PDUFA date.

For one, Qnexa earned a surprisingly positive 20-2 vote at its advisory panel meeting last month, with panel members actually commenting on its superior efficacy compared to lorcaserin and Contrave. And, while the drug has shown a modest cardiovascular safety signal – including a heart rate elevation of one to two beats per minute – its major adverse cardiovascular effects (MACE) data have been compared to those of Victoza (liraglutide, Novo Nordisk A/S), a GLP-1 diabetes drug that was approved without the need for a pre-approval cardiovascular study.

In fact, Victoza's approval could bode well for Qnexa in another way. J.P. Morgan analyst Cory Kasimov called the diabetes drug a "reasonable proxy for obesity drugs currently under review," since its submission and approval came amid the changing guidelines for diabetes drugs. (See BioWorld Today, Jan. 27, 2010.)

Another point in Vivus' favor is that the company has compiled MACE analyses from its clinical trials. Though perhaps not the most robust data, most analysts said they believe those results should satisfy the FDA ahead of approval, with a postmarketing CVOT study obviously required.

At its meeting last week, EMDAC voted in favor of companies using a two-prong approach to assess cardiovascular risk, with one study before approval and one study to be conducted on a postmarketing basis.

Several analysts also noted that an FDA spokeswoman was quoted on the record, stating that the EMDAC vote is "unlikely to impact existing applications," which Rodman & Renshaw analyst Michael King said he believes "reduces one of the few remaining risks to approval."

In addition to being considered the most efficacious of the three late-stage obesity drugs, Qnexa also has been shown to lower blood pressure. Plus, there's the fact that the FDA has been under increasing pressure to approve a weight-loss drug to help counter the obesity epidemic. Given all those factors, "we took the overall tenor of the panel to be positive for Vivus," noted Cowen & Co. analyst Simos Simeonidis in a research report.

Shares of Vivus (NASDAQ:VVUS) gained $1.08 to close Friday at $22.36.

For San Diego-based Arena, however, analysts are less optimistic.

"We view the panel vote as an incremental negative for Arena," wrote Jim Birchenough, of BMO Capital Markets, citing the lack of data demonstrating an advantage of the drug over competing products. Plus, there's the fact that lorcaserin has had no obvious cardiovascular risk signals crop up on clinical studies – its safety issue has focused mainly on a potential cancer signal – which might mean Arena's studies won't have sufficient pre-approval MACE event data to satisfy the FDA.

Lorcaserin, which is partnered with Eisai Inc., of Woodcliff Lake, N.J., is set to be reviewed at a May 10 EMDAC panel. Its PDUFA date is June 27.

Shares of Arena (NASDAQ:ARNA) closed at $3.08 Friday, up 4 cents.

Ironically, shares of Orexigen were hardest hit following the EMDAC vote, though its obesity candidate Contrave, partnered with Japanese pharma Takeda Pharmaceutical Co. Ltd., likely will be the least affected. Orexigen already has been asked to conduct a pre-approval CVOT study, and the firm raised $90 million late last year to help fund the trial, expected to cost between $100 million and $120 million and launch in the second quarter. (See BioWorld Today, Dec. 16, 2011.)

"Having already been flagged as a drug with a [cardiovascular] signal, Contrave is on a path that today's panel would set," wrote J.P. Morgan's Kasimov, adding that Orexigen's upcoming study has been through a special protocol assessment with the FDA.

Still, the delay would put Contrave at least one and a half to two years behind if Qnexa wins approval this month.

On the plus side, however, Orexigen could finally move forward with its earlier-stage obesity candidate Empatic, which combines bupropion and zonisamide. Development of that drug has been on hold while the cardiovascular requirements were in limbo, but now the firm can move forward in designing Phase III trials.

Overall, the risk-reward picture for Orexigen is attractive, said analyst Joshua Schimmer, of Leerink Swann, who said the Contrave CVOT study is "highly likely to succeed, the obesity market is bigger than investors believe and shares do not reflect the value of Empatic."

Orexigen's stock (NASDAQ:OREX) fell 44 cents, or 9.7 percent, to close Friday at $4.10.

Following the EMDAC vote, there are still some outstanding issues the FDA will have to address, such as a clear definition for a cardiovascular signal and what may pose a theoretical cardiovascular risk for obesity drugs.

During the public comment period, Preston Klassen, senior vice president and head of global development at San Diego-based Orexigen, said clear standards for obesity drug approval were badly needed, and the current uncertainty in the space was making it difficult for drug developers to attract sufficient investment, despite the unmet need.