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FORTRESS study shows possible link between in utero exposure to topiramate component of Vivus' investigational obesity drug Qnexa, increased risk of oral clefts

Thursday, December 22 2011 | Comments
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In utero exposure to the topiramate component of Vivus Inc.'s Qnexa, a once-daily, controlled-release formulation of low-dose phentermine and topiramate being developed to treat obesity and other conditions, appears to be linked with an increased risk of oral clefts, according to a preliminary analysis of top-line data from the FORTRESS study.

FORTRESS is a retrospective, observational study designed to assess the effects of topiramate, which is already approved for use as an antiepileptic drug (AED), on fetal outcomes. Co-primary endpoints of the study are the relative risk of major congenital malformations (MCMs) and oral cleft in children born to women exposed to topiramate during pregnancy relative to a control group. The study researchers are using existing electronic health care databases to assess the specified outcomes.

The oral cleft analysis included data for 1,945 mother-infant dyads who had been exposed to topiramate during the first trimester of pregnancy. In this cohort, 1,740 women took topiramate as monotherapy, while the remainder took the drug in combination with other AEDs.

In the cohort exposed to topiramate monotherapy, there were five cases of oral clefts, yielding a prevalence rate of 0.29 percent. Investigators compared this rate with the rate observed in a control group of infants born to women who took AEDs (including topiramate) before--but not during--the pregnancy (n=13,512; formerly exposed cohort). In this group, the prevalence rate of oral clefts was 0.16 percent. The prevalence ratio for the topiramate monotherapy cohort relative to the formerly exposed cohort was 1.88.

"The prevalence ratio for oral clefts in FORTRESS is within the recently reported range for topiramate from several large studies," said Peter Tam, Vivus' president.

The prevalence rate in the total topiramate cohort was 0.36 percent, and the prevalence ratio for oral clefts in the total topiramate cohort relative to the formerly exposed cohort was 2.36.

The researchers also compared the prevalence of oral clefts among the offspring of the total topiramate cohort versus the prevalence in a cohort of mother-infant dyads with medical profiles that were similar to those of the total topiramate cohort, regardless of previous AED use (n=13,614). The prevalence rate in this cohort was 0.07 percent, and the prevalence ratio for oral clefts in the total topiramate cohort relative to the cohort with similar medical profiles was 5.44.

According to Vivus, additional analyses of the cohort with similar medical profiles indicated that the prevalence of oral clefts in this group was probably an artificially low estimate resulting from random error, suggesting that the observed prevalence ratio for the total topiramate cohort relative to the cohort with similar medical profiles is an overestimate.

The MCM analysis is ongoing, the firm noted.

Vivus is developing Qnexa as a treatment for weight loss, type 2 diabetes and obstructive sleep apnea.

In October 2010, the Food and Drug Administration issued a complete response letter addressing the company's initial New Drug Application (NDA) for Qnexa, which sought approval of the drug for the treatment of obesity, including weight loss and maintenance of weight loss, in individuals who are obese or overweight and have certain weight-related comorbidities. In the letter, the FDA cited concerns pertaining to the potential teratogenic risks among women of childbearing age who might use Qnexa.

In May, Vivus and the FDA agreed on the design and objectives of the FORTRESS study.

Last month, the FDA accepted the firm's resubmission of the NDA after Vivus reached an agreement with officials of the FDA's Division of Metabolic and Endocrine Drug Products on the filing strategy for Qnexa. As part of that agreement, Vivus was able to resubmit the NDA prior to completing the FORTRESS study, which is being conducted as a requirement for full approval of Qnexa.

The resubmission seeks approval for use of the drug in obese (body mass index [BMI] greater than 30 kg/m2) or overweight (BMI greater than 27 kg/m2) individuals who have certain weight-related comorbid conditions, but the proposed labeling for the drug now includes a contraindication for women of childbearing potential.

The FDA assigned the resubmitted NDA a six-month review, with a Prescription Drug User Fee Act date of April 17. An advisory committee meeting for Qnexa is set to take place in the first quarter of 2012.

Vivus shares closed at $8.68, down $1.72, or 16.6 percent, in heavy volume on the Nasdaq.

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