Archive for the ‘Uncategorized’ Category.

We’re Back!

After a long hiatus, we are pleased to announce that we will begin posting opinions about FDA events again.  We also would like to announce the addition of  two new contributors to our site, Dan Heathwood and Tim Shields.  Both are private investors with previous experience working as research analysts for some well known investment firms.  Their past contributions outside of pdufadate.com  have  helped translate our opinions into sound stock trading advice.   Our first post will probably deal with Durata Therapeutics (DRTX) as we continue to receive numerous emails about dalbavancin.

There will be lots of changes to our site so keep checking back.

Diet Drug Special Report is Available

With the Vivus‘ QNEXA PDUFA scheduled for April 17,2012, we have created a special report that reexamines all of the obesity drugs that have been reviewed by the FDA and the Advisory Committee since 2009 to determine if any additional insight could be gained regarding the expected action the FDA will take on QNEXA. The report can be purchased by clicking here or by going to http://www.pdufadate.com/premium-reports.

We changed our automated delivery method with the NORTHERA report so when you do purchase the Diet Drug Special Report, please make sure your spam filter accepts email from pdufadate.com.

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.

PDUFA Date dapagliflozin

Well, the FDA has ruled on the AZN / BMY drug dapagliflozin for the treatment of diabetes.  It comes as no surprise that they feel the benefits do not outweigh the risks.  As was pointed out here in July 2011, the unknowns about safety that were also raised by the Advisory Committee, make for a difficult approval.  The only good thing that can be said for this new class of drugs is that the FDA has set the bar for approval.  Those that follow AZN and BMY with NDA submissions are well advised to clear the bar.

PDUFADate.com 2012

As we look back on the last 18 months, we are very pleased with the steady increase in visitors to our website.  We attribute this to the needs of the financial community to seek as many opinions as possible before they make their recommendations or decisions for their clients.  We are pleased that many of you keep coming back to us for help with these decisions.  You are returning because of the high degree of success we’ve had with our opinions on FDA Advisory Committee deliberations and ultimate outcome of FDA actions on pending applications.

Since the initiation of our website, we have had a limited offering of information.  We have provided a short term listing of FDA activities, either Advisory Committee Meetings or PDUFA Dates.  We have provided our opinions on some of these Advisory Committee deliberations and our opinion on some PDUFA Date actions.

As we look forward to 2012, we are evaluating enhancements to the website that we will introduce during the first quarter of 2012.  Some of these include a complete list of the FDA Advisory Committee calender with a link to the Briefing Documents as soon as they become available. In the past, we limited our opinions to those that seemed to have very clear outcomes, even though on several occasions they were contrary to the majority of opinions being expressed.  In some cases, we weren’t sure of the outcome and didn’t provide an opinion.  We have heard from some of our visitors that such a “non-decision” would be valuable for them.  Therefore, in response to your need, we will provide more opinions, some of which may state that we don’t know the outcome.  As in the past, we will provide our rationale.

We are also evaluating the addition of a resource center which will provide a listing of all drugs that we are aware of that are pending approval at the FDA.  Included in this listing will be what we know about actions that may have been taken by regulatory authorities around the world.  We are considering also, a separate listing in the resource center of drugs that are in Phase III development.

From time to time, we may go outside of the boundaries that we’ve established for PDUFADate.com by providing an opinion on broader issues facing the Pharmaceutical Industry.

One of the most exciting additions to the website will be the addition of a Reader’s Forum.  Readers will be provided with an opportunity to ask questions or make comments that can be responded to privately or to the public.

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.

AZILECT (rasagiline) Advisory Committee Meeting

On Tuesday, Oct 17, 2011 the FDA’s Peripheral and Central Nervous System Advisory Committee will discuss TEVA‘s NDA for AZILECT (rasagiline) for use in slowing the progression of Parkinson’s disease.  AZILECT has been approved since 2006 for treating the signs and symptoms of Parkinson’s disease.

The FDA’s Briefing Document raises multiple regulatory issues which seem to support a negative view on approval by the FDA.  These include study design, adherence to protocol (especially regarding the analyses) and interpretation of the results. The FDA conclusion seems to be “We don’t know if there is an adequate study that can be done.  We don’t think the major study was designed to support the indication.  The major study did not adhere to the planned statistical analyses.  We think that the other study was even less well designed to support the indication.  The results of both studies do not support the indication for disease modifying.”

I think the most interesting discussion will be around Dr. Paul Leber’s paper on the design of trials to study this indication.

Seattle Genetics – An Up and Down Week

Seattle Genetics had an up and down week last week.  The FDA’s Advisory Committee gave a positive recommendation for the company’s Hodgekins lymphoma drug ADCETRIS (brentuximasb) yet the stock went down.  The Seattle Genetics Chairman is quoted as saying he is still positive about the drug.  We tend to agree with him.  Some of the press has been questioning the approvability of the drug because there are only two small studies in support of the application.

There are several things that are very much on the positive side for Seattle Genetics on this.  The first is the indication – refractory Hodgekins lymphoma, refractory being the operative word here.  The second thing is the data.  Yes, the definitive trial presented is a Phase 2 single arm study with only 102 patients but the results were outstanding, clearly much better response rates than literature results for other treatments that have been tried in these patients.  The third thing appears to be the dialog that the company has been having with the FDA during the course of the development of this drug.  In the Briefing Document for last weeks Advisory Committee, the FDA seems to imply that the company has met all of the agreements they made with the FDA to get to this point.  The final point is also a reference the FDA makes in the Briefing Document to the February 2011 meeting of the Advisory Committee in which the criteria for acceptability of a single arm study were discussed.  Seattle Genetics seems to have met the criteria discussed and agreed to during that AdComm meeting.  So, the only thing standing in the way of approval is company agreement and FDA acceptability of the necessary confirmatory trial.

We think it is likely that Seattle Genetics will continue to listen to and agree with the FDA, particularly with regard to the design of the confirmatory trial.  That being the case, FDA seems inclined to approve the drug.