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DRugwatch Blog > December 2011 > A Not So Merry Xmas for Vivus’s Qnexa...

A Not So Merry Xmas for Vivus’s Qnexa...

Matt KileenContributor: Kate Sullivan

On average, the Christmas period can lead to a weight gain of around 5 pounds. Vivus’s Qnexa is the most efficacious obesity drug to have emerged from the pipeline in years, but the recently announced results of the FORTRESS study have dealt a blow to the weight loss hopes of many - at the time of year when it is needed most.

The Fetal Outcome Retrospective TopiRamate ExpoSure Study (FORTRESS) was a retrospective assessment of the teratogenic risk of the antiepileptic agent topiramate (Johnson & Johnson's Topamax), which comprises one half of Qnexa. In this study, the medical records of three groups were analyzed: mothers and infants who had been exposed to topiramate during pregnancy, mothers and infants who had previously taken topiramate before (but not during) pregnancy, and a control group with similar medical profiles, regardless of prior use of antiepileptic drugs.

The results of the FORTRESS study demonstrated that women taking topiramate during pregnancy were almost twice as likely to deliver babies with oral clefts than those who that had taken the drug before the pregnancy, but who stopped during pregnancy (prevalence rate of 0.29% versus 0.16%; prevalence ratio of 1.88).

So, from these findings alone, it seems clear that taking topiramate during pregnancy is not a good idea. What is even more concerning, however, is when the results of the third group are taken into consideration; the control group of mother and infant dyads with similar medical profiles had a prevalence rate of only 0.07% of oral clefts. This equates to a prevalence ratio of 5.44 for the topiramate pregnancy-exposed group, versus the similar medical profiles control group.

So, what does this mean for FDA approval prospects for Qnexa?

The results of the study obviously don’t look good in terms of clearing Qnexa from the potential to cause fetal harm. The teratogenic potential of topiramate was the major concern from the FDA’s Complete Response Letter for Qnexa. However, Vivus has only submitted an application to the FDA for Qnexa to treat men and women of non-child bearing potential. Therefore, we are continuing to forecast a 2012 launch for Qnexa, despite the results of the FORTRESS study. But, if Qnexa is approved for this population, very strict controls will certainly be put in place to ensure no off-label prescribing to women of child bearing potential, and this will no doubt impact Qnexa’s sales potential. Vivus was hoping to expand the indication to include women of child bearing age if the results of the FORTRESS study had been more positive, however, this is now looking very unlikely.

Overall, Santa did not deliver great results for Vivus with the FORTRESS study. But we will have to wait until the FDA’s review on February 22, 2012 to see if it will really be bah humbug for Vivus.
Posted on: 12/26/2011 7:28:49 PM | with 4 comments


Tags: Kate Sullivan, Metabolic Disorders

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Comments
Mike
Jan 9th 2012 - The FDA requested that VIVUS remove the labeling restriction for Women of childbearing age on their application. This was not an approval, but an application modification request. Still 2-22-12 for committee vote and Apr 17 2012 for FDA answer. But it is favorable for the manufacturer, if approved it would be for a much broader market.
1/14/2012 12:04:19 PM

ATLnsider
I had a chance to take a closer look at the FORTRESS top-line results. The results are very positive, and they are consistent with the results of the recent studies on Topiramate. All of these recent studies show that Topiramate is not a major teratogen. These studies include: Denmark, Wolters Kluwer, Slone / CDC, and now FORTRESS.

When Vivus submitted their first NDA for Qnexa back in 2010, the FDA was only looking at the teratogencity data from the North American Anti-Epileptic Drug (NAEED) registry and the UK registry. The NAAED registry showed a relative risk of 21.3 for oral cleft, and the UK registry showed a relative risk of 16.0. That was too high of a relative risk for the FDA to approve Qnexa for the full indication in 2010.

Since 2010, the NAAED has been updated with more women registering, and as a result, more mother / infant dyads (n) have been added to the registry that were exposed to Topiramate. The updated relative risk for oral cleft in the NAAED registry is 9.60. This is less than half of what it originally was (21.3).

However, for both the NAAED and the UK registries, you are still looking at a small number of mother / infant dyads (n) who were exposed to Topiramate. There were only 321 dyads in the NAAED and 61 dyads in the UK registry. These numbers are much too small to draw any definitive conclusions.

The newer studies (Denmark, Wolters Kluwer, CDC / Slone, and FORTRESS) looked at much larger numbers of dyads exposed to Topiramate. The results of these studies are a lot more representative than the NAAED and the UK registries.

I have included the table below, which shows: the name of the study, the total number of mother /infant dyads exposed to Topiramate, the number of oral clefs, the prevalence rate of oral cleft, and the relative risk of oral cleft.


STUDY, DYADS (n), Oral Clefts, RATE, RELATIVE RISK

North America Registry, 321, 4, 1.22, 9.60
UK Registry,61, 2, 3.20, 16.00
Wolters Kluwer, 778, 2, 0.26, 1.50
CDC / Slone, NA, 7, 0.21, 5.40
FORTRESS, 1740, 5, 0.29, 1.88

The FORTRESS study showed a relative risk of 1.88 when compared to one cohort, and a risk of 2.36 and 5.44 when compared to the 2 other cohorts.

The bottom line is, the relative risk shown in the FORTRESS study is significantly less than the 9.60 and the 16.0 shown in the NAAED and UK registries. This is consistent with the Wolter Kluwer study which showed a relative risk of 1.50, and with the CDC / Slone study which showed a relative risk of 5.40.

The FORTRESS study will not have much effect on the current NDA for Qnexa because women of child-bearing potential are excluded. In my opinion, the current NDA will be approved in April 2012.

FORTRESS will impact the current MAA for approval in Europe. The EU decision should happen during the first half of 2012. In my opinion, the current MAA will be approved in Europe.

All of the recent studies show that Topiramate is not a major teratogen, and the risks are manageable through labeling. I believe that Qnexa will be approved for the full indication in the USA during 2013, and Qnexa will be a Category X drug, and will be contra-indicated for pregnant women.
1/2/2012 10:56:24 PM

Darleen
Anybody know anything about the March 28th, 29th FDA discussion on cardiovascular issues with diet pills. Don't know why Vivus submitted Qnexa before this time.
2/16/2012 11:28:09 PM

Ben
Important to remember that these findings and measures of risk are for topiramate in epilepsy, for which the risk:benefit ratio is skewed in favor of benefit. Obesity is a different kettle of fish entirely, and raises the safety bar given the larger populations and greater potential for misuse. Therefore any small increase in risk for birth defects becomes an issue the FDA cannot ignore. REMS will be a major point of conversation on 22nd Feb.
1/31/2012 12:54:11 PM

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