Vivus' Qnexa Panel Bodes Well for Arena's Obesity Drug

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Includes: ARNA, VVUS
by: Rockford Coscia

This post is a long one but I promise it’s worthwhile for the Arena (NASDAQ:ARNA) crowd. In order to more accurately determine the potential outcome of the Lorqess advisory committee meeting on September 16, I wanted to review the comments to go along with the votes for the Qnexa panel.

The transcript in its entirety can be found here (pdf).

First, some background on each panel. The panel for Qnexa consisted of both the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) and the Drug Safety and Risk Management Advisory Committee (DSRMAC). The Lorqess panel, so far, is listed as only the EMDAC. Each panel also has voting members in the temporary Center for Drug Evaluation and Research (CDER) category. The CDER temporary members appear to be members of other panels that are called in for the current panel.

The members that are most likely to be present in the Lorqess panel are the core EMDAC members. The other panel positions could be completely up in the air. However, the FDA may try to keep the panel similar to the Qnexa panel as both a fairness issue and since the Qnexa panelists would already be exposed to many of the same issues that will be presented for Lorqess. Regardless if that is true or not, examining the issues the previous panel had should give us insight into how a future panel will vote.

I will provide a more in depth preview of Lorqess’ potential issues in the future, but at the moment I am operating under the assumption that side effects are generally separate from the potential valvulopathy issue. The valvulopathy data, however, appears to be sufficiently powered to rule out an increase in valvulopathy as requested by the FDA. Efficacy surpasses the FDA guidelines for weight loss for Lorqess as well.

And with that, the voting members of the Qnexa panel, selected commentary, and my estimation of a future Lorqess vote:

Dr. Rogawski (temporary member, CDER): YES

Well, clearly we need more information about this medication. But I think that the type of medication we need, particularly with respect to teratogenicity, can’t be gained in a clinical trial setting. It can only be gained once the drug is on the market and large numbers of individuals are exposed to it.

So I think, overall, there’s a greater concern with respect to public safety if we have non-approval because that means that we don’t have the benefit of the additional information and education, risk mitigation strategies, and so forth, being presented to the public. So that’s the reason why I voted in favor of approval.

Dr. Ragowski appears to be a solid yes. He has concerns but he’s comfortable with those concerns being observed out of market, or Phase IV, use. He is also strongly in favor of treatments for obesity. This should be a yes for Lorqess as well.
Dr. Morrato (core member, DSRMAC): NO

So I definitely agree that there’s a significant obesity epidemic in the United States, and therefore the public health and medical need is great for effective and safe pharmacotherapy options to be approved. I also agree that the Qnexa was shown to be quite effective, and that the FDA’s guidelines for weight loss, it needs to be remembered, was in the context of a very proactive lifestyle modification and diet.

But my concerns were the public health consequences, given the long list of safety risks that were listed for the drug, and the strong pent-up market demand for effective weight loss pharmacotherapy. That is, the drug will be used by millions of patients over long periods of time, far exceeding the label indications for use and duration of clinical experience that we have.

Dr. Morrato also seems very supportive of obesity treatments but is concerned with the side effects of the phentermine/topiramate combination (suicidality, teratogenicity, cardiovascular events, etc.). She also makes reference to the FDA guidelines for efficacy. As Lorqess’ side effect profile is much more acceptable and exceeds FDA guidelines for efficacy, this too, should become a yes.

Dr. Henderson (temporary member, CDER): YES

I did vacillate between yes and no because of the lack of long-term safety data and also the real world applications that we all discuss we’re worried about.

But I voted yes because, number one, the sponsor did satisfy the criteria for the weight loss benchmarks. But mostly what made me vote yes is the quality of life survey data. Five out of the eight quality of life measurements were statistically significant in improvement.

A borderline yes. Again, side effect profile of Lorqess appears more acceptable and FDA guidelines for weight loss are met. Should stay a yes for Lorqess.

Dr. Goldfine (core member, EMDAC): YES

I would like to see the review of the two-year data before the approval of the drug.

Of all the things that concerned me most was the pregnancy issue, and that to me was veryproblematic because I don’t want a real world trial where the vulnerable are not the ones who agreed to the risk exposure that was enforced upon them. And yet I also clearly agreed that you would not be able to get this data from a clinical trial design, and I think that’s what finally swayed me.

Lorqess has two-year data and does not have teratogenicity issues. Should stay a yes.

Dr. Proschan (temporary member, CDER): NO

I think if we had had longer follow-up, I probably would have voted the other way. But I just don’t feel comfortable with one year follow-up.

Two-year follow up for Lorqess. Yes.

Dr. Burman (temporary member, CDER): NO

…I wouldn’t be upset if it were approved with a lot of explanation, as we mentioned.

As we know, obesity is a major health problem, and all efforts to address this issue should be lauded. Qnexa does meet or exceed the agency’s requirement for efficacy; I don’t think there’s any issue there. The related topic, though, of course, is that the patients will lose a percentage of weight, 6 to 10 percent, perhaps, and still may not reach their goal weight, but this will be helpful, especially in a longer term program.

On the other hand, the medication has serious potential adverse effects, including potential teratogenicity, increased suicidal ideation, cognitive issues, decreased bicarb, tachycardia, and possible renal stones. Some of these side effects are serious and could be life-threatening, and they have to be weighed against the potential of a relatively modest weight loss and its long-term health benefits.

Another pro-treatment response. Another allusion to the FDA guidelines for efficacy. Lorqess does not have the serious side effects of Qnexa. Should also become a yes. I have heard, however, that Dr. Burman is no longer with the committee and therefore will not be at the Lorqess panel.

Dr. Flegal (temporary member, CDER): NO

I think my views — I think it was both colored, maybe, by our experience with Avandia and the safety concerns that we should deal with them before rather than afterwards.

As Lynn McAfee said, this is like a public health experiment, a large gamble. And I think widespread usage even in inappropriate populations is difficult to prevent. We have one-year information, but this drug will likely be used for a long time.

Dr. Flegal appears to be the most conservative on the board. I’m going to go ahead and assume she would continue to vote no for Lorqess, especially if the valvulopathy data isn’t a slam dunk.

Dr. Thomas (core member, EMDAC): NO

So there’s a few things that I think have to be addressed, and I think it’s best that these are addressed before approval, or at least started before approval so that they can be finished soon after the medication is released.

The first is cardiovascular disease.

The second thing is I’m very concerned about bone health.

The third thing is the sponsor used a restricted fat diet, not a low carbohydrate diet. Most patients, when they’re going to use this, will pick a diet of their own, in spite of what we tell them.

We do need more information about suicide risk.

Then finally, I think we have to get away from the concept of usage for a short term. Obesity is a chronic disease.

Dr. Thomas is also fairly conservative with respect to Qnexa and lists a ton of concerns. Again, Lorqess doesn’t share these concerns, but due to the nature of the response and the emphasis on chromic disease I would consider Dr. Thomas to be a no to borderline yes response.

Dr. Bersot (core member, EMDAC): NO

Pretty much what’s been said are the reasons why I voted no. I realize that without a registry, the issue with regard to pregnancy can’t be resolved.

We need more evidence in the high risk cardiovascular disease patient. And then there are two elephants in the room that no one has mentioned today, and those are lorcaserin and the other drug that’s on its way to this committee that have probably not as great efficacy in terms of weight loss, but may be better risk factor profiles. But we don’t know that, and I would like to know more about all of these three different compounds before making a decision about any particular one.

Sounds like Dr. Bersot is strongly in favor of better risk factor profiles, which Lorqess is the clear front-runner of the three treatments. I don’t know if he is actually suggesting evaluating all three before making any decisions, but I think having viewed Qnexa and Lorqess he’d be more comfortable voting yes. I’m going to guess this as a borderline yes for Lorqess.

Dr. Weide (core member, EMDAC): NO

I voted no, and really, I’m glad to see… that we’re starting to call it a chronic disease.

And I think we just need longer term data with the people who are really going to be using it out there rather than a select group of patients in fairly good health.

Dr. Weide wants longer term data. Lorqess provides. Even so, the ‘chronic disease’ proponents seem to be more conservative with approval. I think this changes to yes, but it’s not a strong yes in my book.

Dr. Capuzzi (core member, EMDAC): yes… er NO.

I voted yes, but I actually made a mistake. I have to be very frank. This is my third meeting, and as Dr. Burman was jotting everything down and all the various concerns, my yes was predicated on the fact that these would all be met first. But I made a mistake, so it’s really no at this point.

I’m guessing yes, but who knows? He didn’t give a whole lot of explanation, so I’ll give this a 50/50 chance of yes with a possibility of leaning more towards yes.

Dr. Kaul (temporary member, CDER): YES.

My yes vote comes with a lot of conditions. And I will not hold it against the sponsor if they interpret my yes vote as a no vote.

First of all, it should only be approved for low to medium dose, not for the high dose, because all the safety signals appear to cluster in the high dose.

There should be a clinical outcome study designed to rule out cardiovascular risk.

An extremely borderline yes for Qnexa. Dr. Kraul seems to have a lot of concerns and seems to be of a more conservative mindset, but because of the ‘yes’ vote I will assume Lorqess also gets the yes vote.

Dr. Hendricks (temporary member, CDER): YES

I voted yes. I agree that the population at large needs to be protected from dangerous drugs; however, one-third of that population is already obese, and there’s a very large segment of the population who are headed that way.

I think that Qnexa does meet the FDA efficacy thresholds.

I think it does fill a gap in our treatment spectrum. I think if the drug is disapproved, we’re going to send a very board message to the obese and the overweight, and that that will further drive them away from medical solutions to this problem to all the various quackery things that are out there.

Solid yes for Qnexa. Mentions meeting the FDA efficacy guidelines. Solid yes for Lorqess.

Ms. Coffin (patient representative): YES

And I do believe that the side effects that were listed here were reasonable, with a doctor’s care.

The funny stuff that’s on the market that does not go through FDA, people are clamoring for it hand over fist. And so, again, I do feel like we’re letting perfect get in the way of possible. If there are 100 drugs out there for high blood pressure for doctors and patients to choose from, there should be more than half a dozen for obesity and overweight treatment.

If side effects for Qnexa were reasonable, Lorqess will be fine. Solid yes.

Dr. Cragan (temporary member, CDER): NO

I voted no, and I also found it a very difficult decision. This drug is clearly effective and has the potential to change many people’s lives. And I really hate to be on record voting against that.

But in the end, I couldn’t really justify widespread use with the reproductive outcomes concerns that we have.

Again, no reproductive issues in Lorqess. I think there is a strong possibility of yes for Dr. Cragan for Lorqess.

Dr. Heckbert (temporary member, CDER): NO

We’ve talked here about how these two medications interfere with a number of different biological pathways. And as such, it’s very highly effective; that was clearly demonstrated by the sponsor, highly effective in achieving weight loss. But at the same time, we have a number of signals of adverse effects that really can’t be ignored that need more exploration. And the ones I’m most concerned about are the suicidality risk, the potential for cardiovascular risk based on the mechanism of action of these drugs and the heart rate signal, and of course the teratogenicity.

Dr. Heckbert has big concerns with a number of issues for Qnexa. Again, Lorqess has none of the serious side effects mentioned and should be sufficiently powered to rule out valvulopathy. This should move to yes.

Summary

So given my review of the explanations, I’m going to say that the most likely voting outcome is 12 yes, 2 no (Flegal and Thomas), and 2 that would be a toss up (Burman and Capuzzi).

So again, the most likely range of votes are:

12-4 to 14-2 for approval.

That, in my own estimation, seems extremely optimistic, and yet, the data seems to support that conclusion. However, let’s assume the yes votes I called borderline shift to no; whether it be for efficacy (I think unlikely) or unresolved valvulopathy issues (again unlikely) or some issue I haven’t completely considered to this point (slightly more likely). That means a ‘bad’ outcome would mean Bersot, Heckbert, and Weide joining Flegal and Thomas as no votes. Moratto, Proschan, and Cragan seem closer to approval so they would go to yes. In that case:

9-7 to 11-5 for approval.

For non-approval, Lorqess would have to receive the Qnexa vote total or worse. I think this is unlikely as Lorqess meets FDA efficacy guidelines, has a much lower side effect profile, and is sufficiently powered to rule out valvulopathy when BLOOM and BLOSSOM trial data are pooled. The only thing that worries me at this point is a demand for Lorq-Phen data – which the FDA has advised against collecting. I’m calling this a high probability of approval by the panel come September 16.

Disclosure: Long ARNA