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Arena, Lorcaserin, and the FDA

I’ve been getting a lot of objections to my opinion on Arena’s obesity candidate lorcaserin. Specifically, the first level of the dispute seems to be whether or not the recent clinical trial results met the FDA’s criteria for efficacy or not. So, let’s look at the details. Here’s how Arena press-released the results of the trial:

The hierarchically ordered endpoints were the proportion of patients achieving 5% or greater weight loss after 12 months, the difference in mean weight loss compared to placebo after 12 months, and the proportion of patients achieving 10% or greater weight loss after 12 months. Compared to placebo, using an intent-to-treat last observation carried forward (ITT-LOCF) analysis, treatment with lorcaserin was associated with highly statistically significant (p<0.0001) categorical and average weight loss from baseline after 12 months: -- 47.5% of lorcaserin patients lost greater than or equal to 5% of their body weight from baseline compared to 20.3% in the placebo group. This result satisfies the efficacy benchmark in the most recent FDA draft guidance. -- Average weight loss of 5.8% of body weight, or 12.7 pounds, was achieved in the lorcaserin group, compared to 2.2% of body weight, or 4.7 pounds, in the placebo group. Statistical separation from placebo was observed by Week 2, the first post-baseline measurement. -- 22.6% of lorcaserin patients lost greater than or equal to 10% of their body weight from baseline, compared to 7.7% in the placebo group. Lorcaserin patients who completed 52 weeks of treatment according to the protocol lost an average of 8.2% of body weight, or 17.9 pounds, compared to 3.4%, or 7.3 pounds, in the placebo group (p<0.0001).

Now let’s go to the FDA’s 2007 draft guidance for weight management therapies. Regarding the primary efficacy endpoint in a Phase III trial of such a new agent, the agency says:

The efficacy of a weight-management product should be assessed by analyses of both mean and categorical changes in body weight.
• Mean: The difference in mean percent loss of baseline body weight in the active-product versus placebo-treated group.
• Categorical: The proportion of subjects who lose at least 5 percent of baseline body weight in the active-product versus placebo-treated group.

And here’s the part that people keep wanting me to highlight:

In general, a product can be considered effective for weight management if after 1 year of treatment either of the following occurs:
• The difference in mean weight loss between the active-product and placebo-treated groups is at least 5 percent and the difference is statistically significant
• The proportion of subjects who lose greater than or equal to 5 percent of baseline body weight in the active-product group is at least 35 percent, is approximately double the proportion in the placebo-treated group, and the difference between groups is statistically significant

So lorcaserin showed 47.5% of patients losing at least 5% of their body weight, versus 20.3 for placebo. And yes, that does appear to meet what the FDA’s looking for in terms of categorical efficacy, which is why the company highlighted that result in their press release. And yes (here it comes, Arena fans), the FDA does say (“in general”) that an agent can be considered efficacious if a compound meets either the mean or the categorical standards.
But (and you knew that this paragraph was going to start with that word). . .but the FDA does not say “efficacious enough for approval“. In general, to use their phrase, the agency does approve things that are efficacious and show safety. But they do that on their own terms, and they are (for better or worse) completely within their rights to turn around and ask for more details – for example, how well a compound like this performs as a combination therapy (which is how many physicians would likely wish to prescribe it).
Then we have the issue of “efficacious to interest a partner”. Arena is surely looking to do that, since (as noted the other day) it does not appear that they have the resources to push the product through on their own. Given the potential size of the market for an effective obesity drug, we can be sure that a number of potential partners have been approached, and have taken a meaningful look at the data. So far, no one has taken them up on it. And whatever one thinks about the press coverage that lorcaserin has received (or the reaction from analysts who follow the stock, which has also not been good), it’s for sure that these opinions don’t count for much when it comes time for two companies to do a deal. Put more directly, if Arena sits down with Merck or Pfizer, what I say on this blog means nothing at all once the door closes. Heck, what they say at JP Morgan means nothing at all, either, because we’re all outsiders. Potential partners are getting a chance to look over Arena’s prospects, and if the numbers look convincing, someone will bite. If no one bites, we can assume that no one was convinced.
Or perhaps they’re waiting for Arena to get even more cash-strapped and desperate. That isn’t a very nice way to do business, but isn’t unheard of, either, and I can tell you that these aren’t very nice times in the drug business. At any rate, for those Arena fans who have been waiting for me to say something about all this, well, here you are. This is as good as you’ll get from me – but really, you’re wasting your time. You need to be hoping to persuade the people who can initiate nine-figure wire transfers.

9 comments on “Arena, Lorcaserin, and the FDA”

  1. hell to the chief says:

    I take the opportunity to give positive feedback. A much more balanced view.

  2. anon-e says:

    “This is as good as you’ll get from me – but really, you’re wasting your time. You need to be hoping to persuade the people who can initiate nine-figure wire transfers.

    Yes, but you are a name with a face (like Adam Feuerstein) and therefore are a convenient target for those whose folly it was to invest so much in a company with no products on the market.
    I really dont get the mentality of a lot of investors out there who are so quick to demonize anyone who voices a contrary opinion about their prized stock. Is that what money does to people?
    Yes, it’s all your fault, Derek. You and your manipulation of the stock market.

  3. Morten G says:

    I don’t really know anything about Arena but the FDA guidelines are dumb. There was a very good article from a group in Copenhagen about how waist measurement is a better indicator of health care expenses.
    Earlier they had an article about how waist measurement and BMI combined gave a much stronger correlation with morbidity than either alone.
    And the FDA only cares about reduction in total body weight? If you exercise you can easily put on a bit of weight while reducing your abdominal fat and increasing your health.

  4. drug_hunter says:

    Conspicuously absent from this entire thread in the popular press (and on this blog) have been reliable comments from KOLs — practicing physicians who know what they’re talking about — about Lorcaserin. To oversimplify: If the drug is reasonably safe, and it causes obese people to lose 10 extra pounds, does that have enough positive medical impact to excite the KOLs? Or not?

  5. Jumbo says:

    It isn’t Derek’s fault that the stock is being pushed down. Speculators see a massive short opportunity, and the financial press basically endorses that value proposition with their articles in negative tone. ‘drug_hunter’ is right and I have also posted before: If prescribers perceive the drug safe and provides 20% of their patients with a good chance to lose 10-15% of their weight, they will prescribe it. I predict FDA approval and eventual blockbuster potential because it will work with phentermine. No one doubts fen-phen worked, but fen caused the valvopathy. Loraserin is a more selective (and potentially more effective) fenfluramine. This is in many ways a horrible business where an essentially arbitrary, non-appealable entity (the FDA) holds the fate of companies and their shareholders in their hands. If you didn’t realize that when you decided to invest in small biotechs, then who is the fool? Motley or otherwise??

  6. Still Scared of Dinosuars says:

    drug_hunter doesn’t understand what KOLs are. In the areas I’ve worked in they are almost exclusively academically based men in their 50’s for whom actual practice is a small part of what they do. Yes, they are the ones you want saying good things about your potential drug but they aren’t the ones who are actually going to write a lot of prescriptions for it.
    And in most groups of 8-10 KOLs you work with you’ll end up with at least one who is an idiot, an A-whole, or a complete slimeball. Unfortunately your marketing types will never let you run trials or have KOL meetings without that guy, though, because they are too “valuable”.

  7. CMCguy says:

    Still Scared based on what I hear from Clinical your implied percentage of “at least one” KOL of “8-10” being invaluable jerks is too low as 50-75% more typical (leans higher side if include Surgeons). I may depend on area but at the same time some of the academic KOLs types do have very active practices and will write lots of scripts themselves or do influence others to try/use something as unfortunately most MDs often too busy to do thorough education by themselves so end up to relying on such experts to guide them.

  8. Anonymous says:

    Thanks for the clarification of your position, and for actually doing a little research on the subject this time around. You made some good points, but I still think much of what you said is inane. Yes, FDA makes the rules and they can change them midstream — how does that differentiate this case from all others? The FDA can change the rules for ANY drug, for ANY company, and at any time. And yes, like ALL small companies reaching the point of commercialization Arena will have to form a partnership or else wise obtain funding. So what’s your point, really? Should all investors stay away from biotech? Be afraid, be very afraid? Should we all be shorts? Arena may fail, they may linger-on, or they may be wildly successful — this also could be said for ALL small companies. But since I said it here, when one of those three outcomes emerges, I will also look quite bright (I did only say May afterall).

  9. JohnJ says:

    I would think that out of some of the other diet drugs currently in trials that Lorcaserin would have a pretty good chance at making it past the FDA. I think the FDA has been more strick about passing diet drugs as of late due to the fact that Rimonabant was cut by European markets (albeit Rimonabant is chemically structured differently) I think that if Lorcaserin passes the FDA that a future med could be Lorcaserin and Phentermine mixed… Obviously would need testing but could be interesting.

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