Posts tagged ‘pdufadate’

QSYMIA Approved

The FDA approved QSYMIA, the Vivus compound for the treatment of obesity.  As regular readers of this site will know, I have been opining for many months that I didn’t think this would happen soon, if at all.

There has never been a doubt in anyone’s mind that QSYMIA (nee QNEXA) was the most effective of the diet drugs that have been submitted to the FDA.  The issue has always been safety.  For some it was the cardiovascular risk particularly in light of the recent negative experience with fen-phen.  For others, it was the potential for neurological problems.  While a concern, I never felt these potential problems would be the obstacle to approval.  For me, it was the fact that this was an acknowledged teratogen and a large part of the population of patients who would use this drug would be women of child bearing potential.

The basis for my concern goes back to the very foundation of the modern FDA concern for safety.  The Food and Drug Amendments of 1962 were a response to the thalidomide tragedy in Europe.  The US was spared because the drug was not approved here.  The 1962 Amendments were enacted to prevent such a tragedy from happening here.  Some have said that since that time, the FDA has overemphasized safety, often criticized for keeping life saving drugs off the market because of a potential for harm.  With the approval of QSYMIA, those critics are silenced – for now.

mirabegron Advisory Committee Meeting

On April 5, 2012, the FDA Reproductive Health Drug Advisory Committee will discuss the mirabegron application from Astellas for the treatment of overactive bladder.  Astellas already has a drug on the market for this indication, VESIcare.

The FDA Briefing Document notes that the drug achieved statistical significance in all 3 of the Phase 3 trials submitted and the secondary efficacy endpoints were consistent with efficacy.

Regarding the safety of mirabegron, the FDA has raised several concerns.  There is an increase in both heart rate and blood pressure noted in both Phase 1 and Phase 3 trials that seems to be greater with higher doses.  The FDA further states that the size of the data base (presumably too small) prevents them from further evaluation of this observation so the question remains open. They also note an increase in neoplasms but this is probably not an issue as they seem to occur at high doses and seem to consist of neoplasm common to adults.  Hepatotoxicity, hypersensitivity and urinary tract infections are also noted but are infrequent and probably not an issue either.

This leaves only the cardiovascular safety issues that should be a concern when considering the benefit risk for this product.  How will the Advisory Committee respond to the FDA question regarding benefit risk for this product?

We think there will be a positive vote but it will be close.  Why?  While the efficacy is positive using the statistical significance measure, the clinical significance of the improvement seems marginal. In fact, if one compares the numbers reported by Astellas in the VESIcare package insert, it appears that mirabegron has slightly inferior efficacy.  There are patients who should not take VESIcare that seem to be indicated for mirabegron, so the Urologists on the Advisory Committee may see this as a necessary drug for those patients.  The big issue will really be how seriously the FDA takes the cardiovascular risks and how the Advisory Committee responds to those concerns.

It will be close, but we think the Advisory Committee will recommend approval.

Navidea Biopharmaceuticals, Inc. – Lymphoseek PDUFA Date

Correction to this Post.  

The comments from our previous post earlier today may have been misunderstood.  The post may be incorrectly giving investors the impression that Navidea Biopharmaceuticals, Inc. has not been given an “official” PDUFA date.  They have indeed been given a firm PDUFA date.  That date per the FDA’s official correspondence to the Company is June 10, 2012.  This is the date they have disclosed in their press releases and SEC filings and it is official.  However, as previously noted,  June 10th is a Sunday.  It is understood that  is that this date is calculated based on 10 months from the date the NDA was accepted, August 10, 2011.  As far as the actual “date”, it is unclear in this case since the PDUFA date falls on a Sunday whether or not the FDA would communicate the NDA status to Navidea before the weekend or on the next business day.

Original Post: Brent Larson, CFO of Navidea Biopharmaceuticals, Inc. (NAVB), told me today that they have not yet received a firm date from the FDA for the company’s PDUFA Date regarding Lymphoseek (Tilmanocept).  There has been confusion because the FDA issued a June 10, 2012 date in a letter to the company.  This date has been used in company press releases and its Form 10-k.

June 10, 2012 is a Sunday.

The company is hoping the actual PDUFA Date is close to the original date provided by the FDA. Past experience has shown the probable PDUFA Date will be the Friday before the intended date.

VOTRIENT (pazopanib) FDA Oncology Drugs Advisory Committee Meeting

On Tuesday, March 20, 2012 the FDA Oncology Drugs Advisory Committee will discuss the supplemental application for GSK‘s VOTRIENT (pazopanib) to use in the treatment of patients with advanced soft tissue sarcoma.

On it’s own, this drug would probably not get a favorable recommendation from the Advisory Committee because the FDA Briefing Document challenges the clinically meaningfulness of the results on PFS and OS.  However, when compared to the results they will have also reviewed for the Merck product for the afternoon session, these results will seem quite impressive in the same indication, ie, a three fold improvement in PFS and a 20% improvement in OS.  We think this will get a positive endorsement from the Advisory Committee.

TALTORIC Oncology Drugs Advisory Committee Meeting

On Tuesday, March 20, 2012, the FDA Oncology Drug Advisory Committee will discuss the Merck and Ariad‘s application for TALTORIC (ridaforolimus) in the treatment of metastatic soft tissue sarcoma and bone sarcoma.

This has to be one of the shortest Briefing Documents ever prepared by the FDA for an Advisory Committee Meeting, and rightly so.  There are just not that many good things to say about this drug.

The company tried to convince the FDA that PFS was an adequate surrogate for OS.  The FDA wasn’t convinced but they agreed in a Special Protocol Assessment to an improvement over placebo control of 25%   The company failed to meet this hurdle with only a very small numerical improvement that failed the agreed statistical mark, is of questionable clinical significance and  failed to achieve the expected target even for placebo of 6 months of PFS.  Match this non-significant improvement against the adverse experience profile and it’s impossible to see how this drug can be viewed as having a positive benefit risk.

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.

Transcept INTERMEZZO PDUFA Date

Transcept Pharmaceuticals (TSPT) is getting ready for it’s third Annual PDUFA Date coming up for INTERMEZZO for insomnia on Nov 27, 2011.  I think the results will be the same.  Why?  Because if you keep doing the same thing (submit NDAs with the same data) you can expect to get the same result – NFC from the FDA – Not Favorably Considered.

The FDA told them they had a problem with the dose in women, ie, it might be too high and there might be some carry over effects upon awakening that could present a problem.  In other words, the benefit risk ratio was tilted in the direction of risk.  So, the company lowers the dose in women by half, reducing the risk.  But what about the benefit side of the equation if you reduce the dose by half?  I don’t think they have the adequate and well controlled study on that.  So, we’ll probably get a chance to comment on this again next year when they celebrate their Fourth Annual PDUFA Date for this drug.

CONTRAVE Revisited

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.