On Wed, Feb 22, 2012, the Metabolic and Endocrine Advisory Committee will meet once again to discuss the Vivus QNEXA NDA for the treatment of obesity. This Advisory Committee met in July of 2010 to discuss this same NDA. Several members of the earlier Advisory Committee are returning either as full AdComm members or as temporary members.
The 2010 AdComm voted 6 to 10 against recommending approval for QNEXA. The reasons given were primarily safety concerns in the areas of neurological/cognitive, cardiovascular, metabolic acidosis and teratogenicity and the need for studies in a broader population of patients. The sponsor has responded to the concerns raised and has included a 1 year extension of one of the pivotal Phase 3 studies which measured both efficacy and attempted to address the safety concerns.
This is another example of a company doing more and proving less. The one year extension study was flawed. The FDA stated that the selection process for patients entering the study was biased and the results should be considered “observational”. None the less, the observation made is that there is no benefit from continuing patients beyond one year on QNEXA because even on the highest dose, patients start to regain the weight they lost in the first year.
NOTE: At 2010 AdComm, the Committee consistently noted that for each of the concerns they had, the risk in a broader population was unknown. The new 2 year data do not represent a broader population but rather a subjective selection of patients from the 1 year study, the results of which the FDA calls “observational”. I think “observational” means “we’re sorry you took the time to assemble these data because we had to take the time to “look” at it”.
Metabolic acidosis. 2 year safety cohort showed same reduction in serum bicarbonate.
Cardiovascular risk. The FDA concluded that while the results were “directionally favorable”, its unknown what would happen in a high risk population or during chronic use. Sounds like a limited indication, if approved at all, and more work to be done. But what kind of work? We won’t know and the sponsor won’t know until after the March AdComm which will be addressing the specific issue.
Suicidal/cognitive effects. 2 year extension did not report any additional concerns about suicidal tendency. Probably didn’t answer original questions either. The incidence of cognitive related adverse events was the same in the 2 year study as reported in the 1 year study.
Teratogenic effects. There is no doubt, the topiramate component of QNEXA is a teratogen. The sponsor agreed and amended the application to provide for a warning against use by women of child bearing potential. The FDA responded with the rejection of their proposed labeling. Why? Probably several reasons. One of which is if they excluded women of child bearing potential, the pivotal trials would be invalid as the majority of patients in the studies were women.
I’m surprised that the bulk of the questions from the FDA focus on the teratogenic effect. I’m surprised that the Risk Management review says that this is a concern for the patients taking topiramate for epilepsy. What is the problem people? Go back to FDA 101 – its all about benefit risk. Topiramate for epilepsy has one benefit risk while topiramate for obesity has another benefit risk. As a fraction, the former is 10/5 while the latter is 1/5. But that’s a problem for the FDA to work out for approval.
For the Advisory Committee, lets summarize, comparing what we knew after 2010 and what we know now:
-efficacy – no improvement in weight loss in second year, in fact, weight gain.
-metabolic acidosis – no new data, its still an unknown in broader population
-suicidal/cognitive – no new data, its still an unknown in broader population
-cardiovascular – no new data, its still an unknown in high risk patients and broader population
-teratogen – no new data and company acknowledges teratogenicity. Risk management program currently seems less stringent than controls the sponsor used in controlled clinical trials and they couldn’t make that work.
I doubt the Advisory Committee will be as generous with the “yes” votes as they were in 2010.