Archive for the ‘William Kennedy’ Category.
This past week, the FDA told Santarus, Inc. that it was extending the review period for their ulcerative colitis drug UCERIS by 3 months. The FDA extended the PDUFA Date to January 16, 2013 because they need more time to complete the review.
I usually don’t comment on share price or share price moves but I’m making an exception here. The stock dipped on this news. I can’t figure these things out. It might not be negative news. I don’t think the FDA has a mind set that says “This application won’t be approved but we need more time to review the bad data”. I think the contrary holds. If the FDA sees some merit in an application, it will take the extra time to support the approval. There is still a PDUFA report card and extending the review period for a drug that will eventually be rejected doesn’t make sense.
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.
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.
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!
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.
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.
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.
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.
On Thursday, Feb 23, 2012, the FDA Cardiovascular and Renal Drugs Advisory Committee will meet to discuss Chelsea Therapeutics NORTHERA (droxidopa) NDA for use in the treatment of some very specific aspects of orthostatic hypotension. Chelsea asked for and was granted Orphan Drug designation.
The drug seems to have a positive short term effect but there are a lot of serious concerns about safety, both from data that have been reported in the clinical trials and from post marketing reports from Japan where it is approved although at a lower dose. At least equally important to making a decision are the unanswered questions about efficacy and safety. The FDA has listed the known problems as well as the deficiencies in the data base in their briefing document and conclude that the drug is not ready for approval.
The Advisory Committee will likely agree with the FDA conclusion on this drug.
On Thursday Feb 23, 2012, the FDA Pulmonary-Allergy Advisory Committee will discuss the Forest Laboratories, Inc./Almirall S.A. aclidinium NDA for the treatment of COPD.
I find it interesting when the FDA includes the regulatory history in the Briefing Document, probably because it usually focuses right in on the issues. In this case, it shows that the sponsor was given some advice on how to develop the drug by the FDA and chose to ignore it.
The FDA early on “suggested” that peak FEV and FEV AUC were the appropriate measures for a COPD trial. The sponsor chose FEV trough. Using this FEV trough, the sponsor provided an improvement of 60 ml vs the 150 ml they had offered in the Phase 2 trials. The sponsor offered 1800 patients for safety at the recommended dose which the FDA said might be ok if the data were robust. When the sponsor and FDA agreed that the 200 mcg dose was inadequate, the sponsor went back and did 2 more Phase 3 trials and then offered the FDA less than 1800 patients at the recommended dose of 400 mcg. In this meager data base, there were patients with cardiovascular problems.
Anticholinergic drugs carry a risk of cardiovascular problems. This is an anticholinergic drug. The data base was too small to evaluate the cardiovascular risk of patients taking the recommended dose as chronic therapy.
The sponsor has probably failed on the efficacy measure with the FEV trough measure, hence the question from the FDA on the “clinically meaningful benefit” of the 400 mcg dose. The sponsor failed to provide a data base that could adequately answer the question about cardiovascular risk for this anticholinergic drug. The sponsor will fail to gain the approval of the Advisory Committee.