Vivus' Qnexa Gets "Complete Response" Letter From FDA

FDA wants more data on risk of birth defects, cardiovascular effects, but doesn't ask for new clinical trials - at least for now.

Now that Arena Pharmaceuticals, Inc. has received word from FDA on its obesity treatment lorcaserin, the focus has shifted to Vivus, Inc. and its diet pill Qnexa (phentermine/topiramate).

FDA issued a" complete response" letter for Qnexa on Oct. 28. The letter asked "a comprehensive assessment of topiramate's and phentermine/topiramate's teratogenic potential," including a plan to evaluate and mitigate the risks of birth defects in women of child bearing age. It also asked for the company to provide evidence that the elevated heart rate associated with Qnexa does not increase the risk for serious cardiovascular issues.

Beyond that, FDA requested that the company continue its discussion with the agency concerning its Risk Evaluation and Mitigation Strategy. It didn't demand new clinical trials, but it could ask for further studies later on, if its concerns are not alleviated.

Vivus said in a press release that it plans to respond to the letter within six weeks. "As part of the written response, the company plans to compile analyses integrating existing nonclinical and clinical data to provide a comprehensive assessment of the teratogenic potential of topiramate. In addition, Vivus plans to provide several new analyses to demonstrate Qnexa "does not increase the risk for major cardiovascular events, which would include data from our OB-305 and OB-204 studies."

The letter and its contents were not a surprise to most investors, who had been expecting a negative outcome since the Endocrinologic and Metabolic Drugs Advisory Committee in mid-July voted 10 to 6 against approval of the drug. The panel focused primarily on three safety concerns: cardiovascular risks, teratogenicity and suicidal thoughts.

Since the advisory committee meeting, Vivus has released the data from a two-year study called Sequel, which is a follow-up trial to an earlier study named Conquer. Sequel included 675 patients who completed the first 56 weeks of Conquer as well as another 52 weeks. FDA asked for the submission of this data in the complete response.

Sequel showed that patients taking the highest dose of Qnexa achieved and maintained weight loss of 11.4%, or about 26 pounds, throughout the two years, while placebo patients achieved about 2.5% weight loss. Beyond that, the trial showed patients without diabetes were 76% less likely to develop the disease while taking the highest does of Qnexa. Patients also saw improvements in weight-related co-morbidities like hypertension. The trial was not submitted as part of the original new drug application for Qnexa, but will be resubmitted as per the letter's request.

The AC concerns revolved around Qnexa's components - phentermine and topiramate, both of which have been on the market separately in generic form for other indications. Phentermine, an appetite suppressant, is the non-lethal half of Wyeth's Fen-Phen combination obesity drug, while topiramate is the generic form of Johnson & Johnson's anti-seizure medication Topimax.

The advisory committee that reviewed Qnexa was concerned that safety issues for phentermine and topiramate would also be characteristics of Qnexa, even though it is a controlled release formulation, and given in much lower doses than for the earlier indications. Phentermine raises the heart rate in patients, yet patients taking Qnexa in clinical trials experienced only a modest increase in heart rate and did not have any cardiovascular adverse events. Meanwhile, topiramate has been proven to cause birth defects and suicidal thoughts, but Qnexa again exhibited no evidence of these issues during studies. Women who became pregnant during the clinical trials did not have problem pregnancies or babies with birth defects.

The difference in safety profile may be related to dosing or administration, but ultimately, the panel was most concerned about the lack of sufficient data to allay these fears, calling for trials that followed patients for a longer period of time. "When you listen to the no votes you get the sense that they just had a little bit of hesitancy," Eric Colman, deputy director of the Division of Metabolism and Endocrinology Products, commented to reporters after the meeting, adding that he "was a little surprised that the vote went as it did."

Panel members "weren't strongly against the drug, but they had some lingering concerns that were enough to make them lead toward voting no," Colman added ( (Also see "Qnexa May Get Staged Launch After No Vote From Advisory Panel" - Pink Sheet, 19 Jul, 2010.) ).

On the other hand, Vivus seemed to avoid the worst case scenario, in which would have FDA might have required the company to do a lengthy, costly cardiovascular outcomes study prior to approval. Vivus would not be able to afford this responsibility, and investors almost certainly would have backed away. Trials like these could become the norm; FDA has more stringent safety concerns after Abbott Laboratories Meridia (sibutramine) had to be pulled form the market due to cardiovascular concerns that cropped up in an outcomes study of 10,000 patients after the drugs approval. (Also see "Will A CV Warning On Meridia Alter FDA Views On Obesity Drugs?" - Pink Sheet, 23 Nov, 2009.).

-Lisa LaMotta ([email protected])