Posts tagged ‘teratogen’

QNEXA Advisory Committee follow up… Think about this

I’ve had a few days to think about this and still have a difficult time understanding the Advisory Committee vote. I admit that I didn’t see this coming. Maybe I should have. After all, this committee (with different members) gave a thumbs up to CONTRAVE. And what happened with CONTRAVE? The FDA went back to the basics of the drug approval process, the basics of benefit risk, and determined that the sponsor had not satisfied the regulatory requirements.

Will the same thing happen with QNEXA? I don’t know what the FDA will do, but I do know what they should do. Efficacy doesn’t seem to be an issue although there doesn’t seem to be any additional weight loss after 1 year of treatment. With the unanswered, it seems likely that if approved, use beyond one year will be limited.

But let’s look at the safety issues. The two biggies are sitting right out there – cardiovascular risk and teratogenic potential in women of child bearing potential. Both of these are unknowns at this time and both can be answered. The question for the FDA is whether the answers should come before approval or after approval.

Teratogenic risk: QNEXA is a teratogen. The population at risk has a high percentage of women of child bearing potential. The component responsible for the teratogenic risk is already available for the treatment or migraines and epilepsy in a population that contains women of child bearing potential. The issue here is not the approvability of the drug but rather the adequacy of the REMS program and the labeling. Can the FDA and the sponsor work this out before the PDUFA Date?

Cardiovascular risk. The FDA has raised this issue in both of their Briefing Documents. The previous Advisory Committee had this as one of the major outstanding issues they used to support its 6-10 vote against recommending approval. The FDA is concerned enough about cardiovascular risk with obesity drugs to call for another Advisory Committee meeting with this as the sole topic for discussion next month. Now, the interesting thing is that the upcoming Advisory Committee meeting is going to be another meeting of the Endocrine Metabolic Drugs panel, the same panel that just recommended approval for QNEXA. The FDA will probably invite a lot of cardiologists, more than were at the QNEXA meeting. The cardiologist vote for QNEXA was split, one for, one against approval. The negative vote was very negative. It is unlikely the FDA will make any decision about resolving the cardiovascular risk associated with QNEXA until after the March Advisory Committee. If the Committee continues to support the current FDA reequirement that studies that rule out cardiovascular risk must be completed before approval then the decision to be made by the FDA is obvious. If however, the Committee recommends that in some circumstances these studies can be conducted post approval, the question then becomes whether the FDA and the sponsor can work this out before the PDUFA Date. They would have to agree to the protocol for such a study and agree on labeling that identifies the absence of information that defines the population at risk.

I’m of a view now that QNEXA will be approved for the treatment of obesity. The questions of when and with what kind of a label still remain. It is unlikely it will be approved at its PDUFA Date. How long after the PDUFA Date is a question that can only be answered after the March Advisory Committee meeting. A point to keep in mind – while we are focusing on the approval of QNEXA, the FDA is also thinking about the precedent it will set for other drugs in the review/development pipeline.

QNEXA Advisory Committee 2012

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.

 Efficacy

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.

Safety

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.