Posts tagged ‘Vivus’

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.

Information Requests

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.

BELVIQ (lorcaserin) Approved

My webmaster tells me that we have had a record number of visitors to our website this week. Thank you all for visiting us. I suspect many of you were looking for some last minute comments before the June 27, 2011 PDUFA Date for lorcaserin. I didn’t post anything because I had nothing new to add. As I had said in the past, I thought Arena (ARNA) had a better chance of getting approval for LORQESS than did Qnexa because the cardiac problems could be monitored and managed while the teratogenicity issue with Qnexa was binary, ie, all or nothing on the teratogenic effect.

Well, Arena is rejoicing and ringing the BELVIQ! (nee LORQESS). The folks at Vivus (VVUS) and probably some of the analysts are seeing the BELVIQ approval as a sure sign that an approval for QNEXA is just around the corner. I say not so fast. If you remember, a major concern expressed here and raised by some at the Advisory Committee meeting was whether women of child bearing potential who were overweight would heed the warning to avoid getting pregnant, especially in light of the number of women in the QNEXA controlled clinical trials who became pregnant.

Well, those clever folks at FDA added a couple of things to the BELVIQ approval that might do two things. The first is a warning that women of child bearing potential should not take BELVIQ. If I were FDA, I’d try and find a way to monitor how many women and their physicians paid attention to that warning. Should be relatively easy to collect that information. If they find a significant pregnancy rate in women taking BELVIQ, they know the warning is not enough – all this done without jeopardizing an unborn child. The second thing that the FDA did was to recommend that the DEA assign a control classification to BELVIQ. Whether the DEA will do this is unknown at this time. If they do, there is a made to order distribution control for QNEXA should they decide to do it.

If your looking for the bottom line that I normally provide, this is it – if I had to lose 40 pounds in 2 years and had only the choice of waiting for QNEXA or diet, I’d start giving up the cupcakes tomorrow!

The Last Days of the Diet Drug Dilemma

Those of you who read our Special Report on Diet Drugs got a heads up on both the extension of the QNEXA PDUFA Date and the easy time that LORQESS had with the FDA Advisory Committee last week.  But now it’s crunch time and the folks at Vivus and Arena Pharmaceuticals are supplementing their diets with fingernail sandwiches.  Arena has the shorter wait at this time, June 27, 2012 is still their PDUFA Date for LORQESS.  By virtue of the extension, Vivus has to wait until July 26, 2012.

Neither the FDA nor the Advisory Committees have questioned the efficacy of either drug.  Neither set of reviewers have tried to say one is more efficacious than the other.  I agree and would call them equally efficacious.

Both drugs have reported or perceived cardiovascular side effects.  According to the Advisory Committee earlier this year, such drugs should be required to have cardiovascular studies performed before approval.  However, both drugs were submitted for approval and under review when the recommendation, and it is only a recommendation, by the Advisory Committee was made.  That being said, the FDA has a certain degree of leeway in forcing this requirement as an approval requirement.  In my opinion, the FDA will give both companies a break and allow the required study to be done as a condition of approval.  It will be the most closely watched event since the OJ trial.  One might think that QNEXA has the leg up on this because they went to the Advisory Committee first, but in this case, one would be wrong.  Both companies got the information at the same time – from listening to the Advisory Committee live and in person.  Who has the edge on having the protocol in final form?  I don’t know and neither does anyone else except maybe the FDA and I heard they ain’t talking.

FDA doesn’t have to talk about the cardiovascular protocol race because the race isn’t about the cardiovascular side effects, its about the teratogenicity risk.  FDA is breathing a sigh of relief with the data from Arena and the positive vote from the Advisory Committee for LORQESS.  The pressure is off – they have a viable diet drug alternative to QNEXA to satisfy those screaming for a new drug.  And they have an alternative that is not a teratogen.  Even if LORQESS gets an extension of the PDUFA Date from FDA to tidy up their cardiovascular study protocol, they will still be ahead of Vivus who has a somewhat longer struggle with the teratogencity issue.

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 follow up

I have to compliment the folks at Vivus, they did a great job.  Good enough to convince the Advisory Committee to recommend approval.  The big question is whether they convinced the FDA.  We’ll find out in a couple of months.

The AdComm does require a comment though.  If I had heard the commentary from the AdComm members without knowing their vote or the overall vote, I would have thought the overall outcome would have been negative.  Almost everyone of them expressed reservations about the CV signals and a concern about the teratogenicity. They used words like “trepidation”, “inconclusive”, “difficult decision”, “reservations” and the “risk is real”.  And those were the panelists who voted YES. Most interesting were a couple that deserve noting.  Regarding benefit risk, one panelist noted that because the drug is not 100% effective and presumably because those who will respond are not predictable, there will be patients who have the risk but not the benefit.  The most unusual comment from a YES voter who had reservations about the teratogenic potential was “the baby gets no vote”.  Dr. Lauer seemed to reflect my opinion best.  He viewed the results as surrogate outcomes…based on hopes not data and reminded everyone of previous similar enthusiasm for antiarrythmics that looked good but killed people.

It will be interesting to see which words resonate with FDA, the YES votes or the reservations.

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.

FDA Advisory Committee Schedule

As promised earlier, we are providing a more detailed listing of upcoming FDA Advisory Committee Meetings.

Of particular interest, Vivus‘s QNEXA is scheduled to be reviewed on Feb 22, 2012 by the Endocrinologic and Metabolic Committee for weight management.  Equally important, the FDA has scheduled another meeting of the Endocrinologic and Metabolic Committee for March 28-29, 2011.  Could it be that we might hear some discussion on revised guidelines?

Jan 30-31, 2012 Pediatric Advisory Committee Meeting

  • The Committee will discuss the status of the development of a number of drugs for pediatric use.

Feb 8-9, 2012  Oncologic Drugs Advisory Committee Meeting
The Committee will discuss:

  • XGEVA (denosumab) by Amgen for castrate resistant prostate cancer.
  • DACOGEN (decitabine) by Eisai for acute myelogenous leukemia.
  • PIXUVRI (pixantrone dimaleate)  by Cell Therapeutics for Non-Hodgekins Lymphoma

Feb 10, 2012  Cellular, Tissue and Gene Therapies Advisory Committee Meeting

  • No products are currently on the schedule for review.

Feb 10, 2012  Neurological Devices Panel Advisory Committee Meeting

  • No products are currently on the schedule for review

Feb 22, 2012  Endocrinologic and Metabolic Advisory Committee Meeting

  • The committee will discus QNEXA by Vivus for weight management

Feb 23, 2012  Cardiovascular and Renal Drug Advisory Committee Meeting

  • The committee will discuss NORTHERA by Chelsea Therapeutics for neurogenic orthostatic Hypotension.

Feb 27, 2012  Dermatologic and Ophthalmic Drugs Advisory Committee Meeting

March 12, 2012  Arthritis Advisory Committee Meeting

March 14, 2012  Pharmaceutical Sciences and Clinical Pharmacology Advisory Committee Meeting

March 28-29, 2012  Endocrinologic and Metabolic Advisory Committee Meeting.

QNEXA – Why the surprise?

Last week, an FDA Advisory Committee met to discuss QNEXA, the fixed dose combination drug from Vivus (VVUS) for the treatment of obesity.  While it is reported that there was Advisory Committee discussion that favored certain aspects of the drug, overall, the drug was not favorably considered by the committee.  The response to this NFC recommendation by the Advisory Committee was reflected in sharp drop in the share price in Vivus, down over 50%.  Does the drop in share price suggest that there were some investors actually expecting a positive recommendation by the Advisory Committee?  If so, we say why?  Did they think that a new fixed dose combination diet preparation could get out of the regulatory shadow cast by phen-fen?