Contributor: 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.
Contributor: Matthew Killeen, Ph.D.
Multaq (Sanofi’s dronedarone) has had a turbulent time on the market since its launch in the United States in 2009. Given the high unmet need for safe and effective new drugs to maintain a normal sinus rhythm in AF patients, analysts had predicted peak year annual sales of up to $4 million for Multaq. However, a number of factors have restricted Multaq’s uptake thus far and will continue to limit its future commercial prospects.
Firstly, the key efficacy end point used in Multaq’s pivotal AF trial (the ATHENA study) was unconventional for this indication and we believe that the drug’s data failed to fully resonate with prescribers. This effect was compounded by Multaq’s modest efficacy on traditional antiarrhythmic measures, which interviewed thought leaders tell us is one of its key drawbacks. These issues aside, safety has been the watchword for Multaq in 2011 and we predict that one event in particular will have a major impact on the drug’s future outlook. While January witnessed a liver safety alert being issued by regulatory agencies, July saw the suspension of Multaq’s Phase III PALLAS trial in permanent AF patients; what was once seen as a strategic move to expand the drug’s share of the AF market, ended with alarming results – Multaq was shown to significantly increase the risk of mortality in patients with permanent AF compared to placebo. We expect that this event will be hard to overcome for Multaq despite the fact that very different patients were studied in the PALLAS trial compared to the drug’s earlier, successful, ATHENA study.
As the medical community begins to re-evaluate Multaq’s value proposition, what emerging therapies are in development for AF, and do they have the potential to address the remaining unmet need for safer and more effective antiarrhythmic drugs? In the sections below, I profile two key therapies that are in early stage development for AF.
- Oral vernakalant (Cardiome/Merck). The IV formulation of this new antiarrhythmic won approval in Europe last year (where it is marketed as Brinavess) for the acute cardioversion of AF. Oral vernakalant, on the other hand, remains in early clinical development. Cardiome had previously completed Phase II testing of oral vernakalant; however, Merck has since decided to study the drug in a new series of Phase I and II trials using higher doses. Although amiodarone’s high level of antiarrhythmic efficacy creates an important barrier to entry for emerging antiarrhythmic drugs for AF, we believe that oral vernakalant has the potential offer important benefits over existing treatment options.
- Vanoxerine (ChanRx). Vanoxerine was initially in clinical development for Parkinson’s disease and depression but recent preclinical studies have revealed its prominent antiarrhythmic effects. ChanRx, a startup company that was spun out from a CRO specializing in cardiac safety studies, recently announced that it had closed its Series A funding to advance IV vanoxerine through to Phase IIb development for AF cardioversion.
Oral vanoxerine remains in preclinical development, but a recent study provided the first insight into its efficacy for AF; the drug terminated AF and atrial flutter in a disease model of AF and prevented the arrhythmias from being re-induced.
In the antiarrhythmic drug arena, 2011 has been a year of re-evaluation, by physicians and regulators, of Multaq’s risk-benefit profile. Nonetheless, the diverse AF pipeline holds great potential. In addition to oral vernakalant and vanoxerine, several other companies are developing novel agents for AF that we anticipate will provide important benefits to patients and propel growth of the AF market. In particular, atrial-specific antiarrhythmic drugs, that are in early stage clinical development by Xention and Bristol-Myers Squibb/Teijin, could have an unprecedented level of safety and, therefore, satisfy a major unmet need in AF.