Washington Editor

WASHINGTON – While the FDA determined that Vivus Inc.'s obesity pill Qnexa (phentermine/topiramate) met the agency's 2007 criteria for efficacy in weight loss, regulators said teratogenicity, along with metabolic acidosis and adverse psychiatric, cognitive and cardiovascular events were concerns of "particular interest" with the drug.

Nonetheless, the safety issues raised by the FDA, which came in briefing documents released Tuesday ahead of Thursday's meeting of the agency's Endocrinologic and Metabolic Drugs Advisory Committee, were on the most part expected.

Investors reacted by driving shares of the Mountain View, Calif.-based biotech (NASDAQ:VVUS) up 16.8 percent, or $1.79, to close at $12.44. Other potential competitors in the obesity drug space also gained on investors' confidence.

Shares of Arena Pharmaceuticals Inc. (NASDAQ:ARNA), which is developing lorcaserin as an obesity therapy, closed at $4.20, a gain of 41 cents, or 10.8 percent, while shares of Orexigen Therapeutics Inc. (NASDAQ:OREX), which also is investigating Contrave (naltrexone SR/bupropion SR) for weight loss, climbed 20.2 percent, or 84 cents, to close at $5.

The FDA's advisers will examine lorcaserin's data at a meeting in September, while Contrave is set to go before the advisory panel in December.

Although JP Morgan analyst Cory Kasimov said there appeared to be no unexpected "smoking gun" uncovered by the FDA's ongoing review of Qnexa, most analysts said they were worried about regulators' concerns over metabolic acidosis, a condition in which the body produces too much acid or the kidneys are unable to adequately remove acid from the body.

Even though there were no reports of severe metabolic acidosis in Qnexa's Phase III trials, the FDA said "real-world use" of the drug in susceptible patients, such as those with severe diarrhea, chronic kidney disease or patients who have abused laxatives, "could be expected to give rise to acute metabolic acidosis with clinical sequelae, including cardiac dysfunction and ventricular arrhythmias, in severe cases."

Regulators said that mild, sustained metabolic acidosis increases the probability of developing nephrolithiasis, or kidney stones, and adversely affects bone structure and function. FDA reviewers noted that in Qnexa's one-year clinical trials, there were 22 reported cases of kidney stones in the treatment group, compared with five patients who got a placebo.

The pregnancy category the FDA assigns to Qnexa also could impact its sales if the drug gains U.S. approval.

There were 34 pregnancies during Qnexa's development program, despite the recommendation of two forms of birth control. Regulators said 19 of the 34 pregnancies were carried to term, with no birth defects observed.

But drug reviewers said that because pregnancies would likely occur once Qnexa is on the market, even with appropriate pregnancy prevention recommendations and risk mitigation strategies, the drug should be designated as a "pregnancy category X," given its risk-benefit profile. They also called for a pregnancy exposure registry under a postmarketing commitment.

There are five pregnancy categories used in current drug labeling: A, B, C, D and X.

A pregnancy category X applies to drugs with positive teratogenic effects in animal and human studies or postmarketing experience, and which offer no potential benefit when taken during pregnancy.

Ortho-McNeil-Janssen Pharmaceuticals Inc.'s migraine drug Topamax, whose active ingredient topiramate is one of the two ingredients in Qnexa, currently is labeled with the pregnancy category C designation, which applies to drugs with positive teratogenic effects in animals, no adequate human studies, but with potential benefits to warrant the drug's use in pregnancy.

Drug reviewers noted that Qnexa's other ingredient, phentermine, does not have animal data, and limited human data have shown no increase in congenital malformations.

The FDA reviewers also raised concerns about psychiatric risks with Qnexa.

Regulators pointed out that there were four to seven times as many study participants on the high-dose vs. placebo who discontinued the study due to adverse events related to anxiety, sleep or depression.

While there were no suicidal attempts, suicidal behaviors or instances of serious suicidal ideation, the summary measure of suicidality occurred at a slightly higher frequency in the high-dose Qnexa group compared with those who got a placebo, 0.9 percent vs. 0.7 percent, the FDA documents showed.

The most common adverse event related to cognitive dysfunction was disturbance in attention, drug reviewers noted.

Although there were no meaningful differences in the proportions of study participants per treatment group who experienced an adverse ischemic cardiovascular-related event, there were four heart attacks in the Qnexa group compared with none in the placebo group, regulators said.

In contrast, there were four cases of coronary artery disease in the placebo group vs. none in the Qnexa group.

The FDA noted that if Qnexa wins approval as an obesity treatment, Vivus has proposed conducting a large cardiovascular outcomes trial to assess the risk.

In addition to asking whether Qnexa's risk-benefit profile supports its approval, the FDA Thursday wants its panel to advise it on how best to monitor and manage the teratogenicity, metabolic acidosis and adverse psychiatric, cognitive and cardiovascular events associated with the drug, including what labeling recommendations the committee may have and any additional studies that should be conducted post-approval.

Published  July 14, 2010