PDUFADate.com

My webmaster is really excited these days.  He just looked at the numbers for June and the number of visitors we had for the month is incredible.  He also tells me that he has been receiving a large number of requests, some very specific, about QNEXA probability of approval.

We started this website 2 years ago with the idea that we would provide information free of charge for a while to see if there was any interest, determine what specific information our audience wanted and establish some credibility before deciding if we wanted to commercialize the website.  We’ve far exceeded our 3 goals as measured by visitors and feedback.  Unfortunately, we weren’t able to convince any of you to purchase a subscription when we offered and just a few lucky folks have purchased our special reports, thus making the business part of this venture a disappointment.  This is especially disappointing in light of the number of specific, very detailed requests we are getting for additional information that will be used to make decisions that will make you and your clients a lot of money.

If you have questions about QNEXA, I refer you to our website archives or invite you to purchase our special diet report.  I will not be adding any additional comments on the website.

If you still have questions, please consider scheduling a personal discussion.  The fee for such consultation is $100 per quarter hour.

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.

On Wed, Feb 8, 2012 the FDA Oncology Advisory Committee will discuss Amgen‘s supplement to their approved BLA for XGEVA (denosumab) for treatment of men with castrate-resistant prostate cancer at high risk of developing bone metastases.

This Advisory Committee discussion and the ultimate FDA approval decision comes down once again to the basic benefit risk decision.  On the benefit side, treatment with denosumab did not result in an improvement in overall survival or progression free survival but it did improve bone metastasis-free survival (BMFS) and time to first bone metastasis, both by about 4 months.  On the risk side, the incidence of osteonecrosis of the jaw with denosumab increased by about 5%.  So, the basic benefit risk question is does the 4 month improvement outweigh the 5% increased risk?

The other significant question raised by the FDA appears to boil down to whether treatment with denosumab in this setting offers any advantage versus “prevention of skeletal related events in patients with solid tumors metastatic to bone”, the approved indication.

The FDA review appears to be on the negative side of neutral.  While the company met the primary endpoint, the FDA review points out that at meetings with the company, the FDA noted that “overall survival, patterns of metastases, and the development of symptomatic metastases will be important review issues”.  There was no advantage in overall survival.  Also, of significant note is the statement in the FDA review that the study was not conducted under a Special Protocol Assessment, meaning there is no “contract” for approval just because the primary endpoint (improvement in BMFS) was met.

The application for XARELTO (revaroxaban), the J&J drug that was developed for it’s anti-clotting properties in preventing strokes is to be reviewed by the FDA CardioRenal Drug Advisory Committee on Thursday, Sept 9, 2011.  Those interested in the FDA view of the application need read no further than the summary of the FDA Briefing Document to learn that the FDA Medical team has significant reservations on both the safety and the efficacy of this drug.  How significant you ask?  So significant that if I were advising the company, I’d tell them to cancel the Advisory Committee meeting.  The FDA review started with a comment about readiness to issue a Complete Response Letter, that’s how serious!  The FDA review has requested at least one additional study, that’s how serious.  The FDA has said that any drug that expects to compete with Warfarin in these patients better be as good as Warfarin, that’s how serious.  It looks like the FDA thinks that XARELTO performs at less than 70% of the efficacy of Warfarin.

Regeneron (REGN) is probably still basking in glory of their recent unanimous recommendation from the Advisory Committee for EYLEA (aflibercept opthalmic solution) Opthalmic Solution for the treatment of age related macular degeneration.  The company should now be directing its focus on the upcoming PDUFA Date of Aug 20, 2011 and anticipating an approval.

Transcept Pharma (TSPT) reported that FDA issued a Complete response letter  to their resubmission of Intermezzo, a drug indicated for use in treating night time awakening insomnia.  The original NDA was submitted in 2008 and not favorably considered by the FDA because of concerns they had about driver impairment.  The company reported they did a driver impairment study and resubmitted the NDA.  The most recent PDUFA Date was July 14, 2011.

Transcept has reported that the second CRL still has questions about driver impairment.  This doesn’t look good for Intermezzo.  Either the second driver impairment study was inadequate in design (unlikely if the FDA had input and the company followed the FDA input), or it showed driver impairment.  Either case, it looks like another redo of the study.

The PDUFA Date for Astra Zeneca‘s Brilanta is still a ways off, not until July 20, 2011 but we think it’s safe to call this one an approval.  AZN has had it’s problems with this application since the original submission in 2009.  Initially rejected by the FDA for a variety of problems including manufacturing issues, their latest CRL only cited a reanalysis of some of the clinical data and required a post marketing safety plan, REMS.  We think that AZN has probably solved both issues with the FDA.  The earlier approval this year by the European Authorities and the approval earlier this month by the Canadians probably reflects the reanalyzed data.  We wouldn’t be surprised if the approval came before the PDUFA Date.

Yes, we know that all of the bells have tolled for Contrave – even the fat lady’s final notes have faded, but we feel compelled to comment on the Orexigen announcement that they have put their plans for Contrave on hold because they failed to convince the FDA that their plan to study the potential cardiovascular effects was sound.  Equally interesting to us was the comment made that such action by the FDA challenges the development of obesity drugs in the US.

We have been consistent in our opinion of the three obesity drugs that were before the FDA during the past year.  Uniformly, they either didn’t meet the very lenient efficacy requirement or in fact failed it.  Recall our cupcake commentary – 5% weight loss over the course of a year for a 200 pound person is the equivalent of one cupcake a week.  Remember also, it is all about benefit risk with the FDA.  With such a lenient efficacy requirement, it is understandable that the FDA expects a very clean safety profile.

There is a case for the continued evaluation of obesity drugs in the US.  With all the reports confiming that we are a society that is becoming more and more obese, dieting and will power don’t seem to be able to control the trend.  So how about developing a drug that is as effective as gastric by pass with 25% weight loss not uncommon in the year following surgery.  Such a weight loss with the accompanying reduction in co-morbidities associated with obesity may just get the benefit risk to a position that the FDA finds acceptable.

On Tuesday, April 12, 2011 the FDA Oncology Advisory Committee will discuss Pfizer‘s application for the use of SUTENT in patients with unresectable pancreatic neuroendocrine tumors.  SUTENT has 2 approved indications, including use in patients with advanced renal cell carcinoma.

Based on the issues raised in the FDA Briefing Document, Pfizer might want to spend some time explaining their regulatory/development strategy.  Specifically, the FDA seems to have challenged the company’s choice of a single Phase 3 study using Progression Free Survival as the end point instead of Overall Survival, especially since Pfizer chose not to avail themselves of an End of Phase 2 meeting with the FDA.  It doesn’t appear that Pfizer got FDA agreement through an SPA either.

The Advisory Committee will probably focus on the conduct of the study though and the role the DMC had in the decision making process other than safety.  The major issue seems to be the halting of the trail with only 28% of the subjects enrolled and the predictive value of this limited number of PFS patients from a single study.

One study with limited enrollment, PFS instead of OS – I think the discussion will be short and predictable.  The recommendation will be negative.

On Tuesday, April 12, 2011, the FDA Oncology Advisory Committe will hear Novartis and the FDA discuss the application for AFINITOR (everolimus) in the treatment of patients with advanced neuroendocrine tumors of GI, lung and panreatic origin.  The drug is already approved for the treatment of advanced renal cell carcinoma and after the Advisory Committee meeting, I think that Novartis will have to settle for retaining that indication for the time being.

The FDA has raised questions about the value of progression free survival in predicting overall survival as it usually/always does with oncology drugs, as well as questions concerning the censoring of certain patients and whether the 2 Phase 3 trials support each other.  Novartis will argue that the terms of the Special Protocol Assessment allowed for progression free survival as a valid endpoint.  And, here is where they lose the argument.  FDA will point out as they did at the Pre-NDA meeting that Novartis protocol amendments have made the SPA invalid.  It is unlikely that the FDA will give in on the sanctity of the SPA contract.  It is a contract between industry and the FDA, binding on both.  In fact, the value of the SPA to the industry is the binding of the SPA.  If the FDA bends on this, Novartis will win the approval and FDA will be able to say in the future that FDA can invalidate their agreements made under the SPA.

This is not the drug, nor the indication to test the contract.  AFINITOR is on the market already and patients have access to it if their physicians feel it necessary for their treatment.