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Side Effects of Diet Pill Still Concern Regulators
http://www.nytimes.com/2012/02/18/health/fda-still-wary-of-diet-pills-side-effects.html

By ANDREW POLLACK
Published: February 17, 2012

The Food and Drug Administration continues to have concerns that a weight-loss drug it is reviewing for the second time can cause birth defects and heart problems, documents released by the agency on Friday show.

The drug, called Qnexa, was rejected by the agency in 2010, largely because of those risks. A committee of outside advisers to the F.D.A. will meet on Wednesday to consider again whether the drug, developed by Vivus, should be approved.

Some obesity specialists and patient advocates say there is a strong need for new obesity drugs to help bridge a treatment gap between diet and exercise, which do not work for many people, and the more radical option of bariatric surgery. But the F.D.A. has been cautious, in part because with two-thirds of American adults overweight or obese, such drugs might be used for a long time by millions of people.

Qnexa is a combination of two existing drugs: the stimulant phentermine and the epilepsy and migraine drug topiramate, also known by the brand name Topamax. Some doctors say they believe the component drugs are an effective tool to combat obesity and prescribe the two component drugs to patients off label, which is legal.

One question the advisory committee will be asked to consider is whether Vivus, before the drug’s approval, should be required to conduct a large new clinical trial to assess whether the drug increases the risk of heart attack. Such a trial could delay approval by years, and Vivus has proposed doing the study after approval.

The latest studies show that use of topiramate during pregnancy increases the risk of oral clefts, such as cleft lip, by a factor of two to five, according to the F.D.A. staff review released Friday.

That is a concern, the reviewers said, because “the major consumers of weight-loss drugs are women of childbearing potential,” leading to “the potential for large numbers of pregnancy exposures.”

Vivus shares rose 81 cents, or 7.25 percent, on Friday before closing at $11.99, as investors and analysts offered differing interpretations of the documents.

Cory Kasimov of J. P. Morgan said in a note to clients that the documents contained “no big surprises,” and left him “incrementally more positive” about the outcome of Wednesday’s meeting.

But Simos Simeonidis of Cowen & Company said that the documents were “negative” for Vivus. He said he expected the new cardiovascular trial would be required before approval.

The ability of Qnexa to help people lose weight was not seriously questioned by the F.D.A. reviewers, although they did note that in the second year of one clinical trial, patients taking the drug regained roughly 10 to 20 percent of the weight they had lost in the first year.

The agency appears to be increasingly concerned about assessing the tangible benefits of weight loss in terms of improving health and quality of life. Dr. Janet Woodcock, the F.D.A.’s top drug reviewer, mentioned this emerging view in a talk at an investor conference on Thursday.

Vivus, which is based in Mountain View, Calif., argues that in addition to losing weight, users of Qnexa in the clinical trials had improvements in blood sugar, blood pressure, cholesterol and some other health measures, compared with those who got the placebo.

The rate of heart attacks, strokes and death from cardiovascular causes was lower in those who received Qnexa than in those who took the placebo, though the difference was not statistically significant.

“The ability of Qnexa to produce durable weight loss can be expected to contribute significantly toward ameliorating some of the consequences of obesity and weight-related comorbidities,” Vivus said in its own briefing document, which was also posted on the F.D.A. Web site.

However, the F.D.A. reviewers were not persuaded.

“Over all, the long-term clinical impact of the observed modest improvements in comorbidity outcomes is uncertain, particularly in a population with higher risk of CV adverse events,” they wrote, referring to cardiovascular events such as heart attacks.

The main cardiovascular concern is that Qnexa increases heart rate. Still, the reviewers did say that the effect of the drug in lowering blood pressure was “somewhat reassuring.”

To deal with the issue of birth defects, Vivus had proposed using the drug’s label and other steps to ensure that women of childbearing potential would not use the drug.

But the F.D.A. rejected that suggestion as overly broad, according to the documents. It said that for some women of childbearing age, the benefits of Qnexa might outweigh the risk of birth defects.

In addition, women who could not get Qnexa might instead have their doctors prescribe the two components separately, the documents said.

Instead, the agency and Vivus are discussing ways of keeping pregnant women from using the drug.

That, however, could be difficult. In the clinical trials, women had to use rigorous contraception and undergo frequent pregnancy testing. Yet there were still 34 pregnancies. In the 19 of those pregnancies carried to term, there were no known major birth defects.