Arena's Obesity Drug Not Likely to Make It

One of the drug targets for obesity that’s been kicking around for years now is a serotonin-receptor based idea, a 5-HT2c agonist. There are several lines of evidence that make this a plausible way to affect appetite – well, as plausible as any of the appetite-based obesity targets are. I’ve long been wary of these, since we’ve found (over and over) that human feeding behavior is protected by multiple, overlapping redundant pathways. We are the descendants of a long line of creatures that have made eating and reproducing their absolute priorities in life, and neither of those behaviors is going to be altered lightly. The animals that can be convinced to voluntarily eat so little that they actually lose weight, just through modifying a single biochemical pathway, are all dead. Our ancestors were the other guys.

Arena Pharmaceuticals (ARNA) is the latest company to give us more evidence for this point of view. Many drug discovery organizations have taken a crack at 5-HT2c compounds, as a look at the patent literature will make clear. But Arena got theirs, Locaserin, well into the clinic, and Monday they announced the results. And. . .well, it depends on how you spin it. If you’re a glass-half-full sort of person, you could say that twice as many people in the drug treatment group lost at least the FDA’s target of their body mass, as compared to placebo.

Unfortunately, the glass-half-empty people are probably going to win this one. The FDA wants to see 5% weight loss (versus placebo) with a drug therapy, arguing (correctly, I think) that showing less than that really doesn’t give you much risk/benefit over just plain old diet and exercise. Arena’s compound averages out at 3.6%, and I don’t see how that’s going to cut it, especially with a new central nervous system mechanism. By “new”, I don’t mean “new to science” – as mentioned above, this idea has been around for years. But it would be a new thing to try out in millions of patients if you let a drug through, that’s for sure. I think it’s safe to say that a certain fraction of those are going to react in ways that you didn’t expect. 5-HT2 receptors are involved in a lot of different things, and there's bound to be a lot about any agent in this class that we don't know. Locaserin seems to have been well tolerated in trials, but I personally would be jumpy if I were taking something like this out into the broad population.

That’s not why I think this compound won’t make it, though. The FDA doesn’t even have to talk safety; they can reject it just on the grounds of efficacy. And it’s hard to imagine a lot of insurance plans picking up the tab for something with only those levels of clinical support, too. Arena's CEO says that he's pleased with the results of the trial. No, he isn't. Of course, he also says that he's convinced that the company will get Locaserin approved and find a partner to market it with, too. But then, that's his job.

Comments

[biodummy:]

On the efficiency side, Lorcaserin had been actually better than fenfluramine hen used alone (~2.4 Kg = 5 Lbs placebo-adjusted weight loss from the meta-analysis); everyone knows that fenfluramine (Pondimine) when used as a combo with phenthermine was very effective - just deadly. FDA guidelines quite dfinitively offer a choice of two primary goals - >35% of pts losing >5% of weight, this the number being >2x of the placebo [Lorcaserin met this requirement], and placebo-adjusted weight loss of >5% [they did not meet it - but according to the PR and CC they pre-specified the first goal]. If you think some more, if you have a drug that works extremely well on say 40% of the population and not at all on the other 60%, you almost never will be able to reach the second type goal. To me, the key issue for the approval is if FDA forces ARNA to run a good size combo trial before the approval can be granted - Lief and Co. simply don't have money to do that.

Mar 31 11:37 AM

[User 386350:]

It should also be noted that all this fuss is over efficacy while this particular trial was designed to address safety concerns. Look at the details of the study: no controlled diet, no exercise, and 1 dosage. That is not a study designed to demonstrate efficacy! What they did get out of it was that even after two years, no adverse events were linked to prolonged usage (in fact, it demonstrated improved CV indicators, such as cholesterol, triglycerides, and blood pressure). Safety was the primary concern. Now, that has been sufficiently put to rest. If improved efficacy is necessary to pass FDA criteria or to make analysts/investors happy, then a trial that varies dosages, and includes diet and exercise will be added, but at this point I think that these results have been totally misinterpreted by the lay public.

Mar 31 12:36 PM

[PhillyDan:]

Don't bury Arena just yet. Recommend you read Ed Sussman's blog about the results he got on the Blossom trial. I strongly believe that his results are more indicative of what users of Lorcaserin will really see if they use it to lose weight. Ed is a Medical Writer for MedPageToday. I also strongly agree with User 386350 comments above, I could not have said it better. In addition, I do believe they will get a partnership deal and have the funding to be able to do a combo trial if necessary. As an example, if you look at the Vivus results for Onexa, you will see that their results were achieved with the higher dosages of Onexa. I'm willing to bet that if ARNA did a study with 20mg BID, their results would have been much better in terms of efficacy. I agree that investors missed the boat on the results and that the focus was on safety not efficacy.

Mar 31 01:17 PM

[Sam25:]

Surely people at ARNA have been under the microscope with Lorca because of Fen-Fen, so safety is great news rather than efficacy at this point. Bottom line, if seratonin levels with Lorcacerin are balanced, then weight loss is surely possible. In general, weight loss for obesity is a long process; that is why a gradual, yet steady weight loss is important. A higher dose of the drug would surely meet FDA standards. Thanks to Fen-Fen, though, Lorcacerin has more safety obstacles to overcome than any other obesity drug has. This is to say that the drug will be around for a very long time after trials.

Mar 31 02:05 PM

[desmin22:]

i'm holding april call options on arena so i'm biased. but i have to say, what a jackass statement to make. "Arena's Obesity Drug Not Likely To Make It!" what exactly are your credentials to pronounce judgement like that from so little to go on? a small dose coupled with virtually no diet and exercise program and you are the fourth "authority" to label it a waste of time. you are all, and by all i mean you, Fuerstein, the J.P. Morgan analyst, and the Lazard analyst, doing your "extropolations" in one direction, to the negative side. if you are going to "extropolate" do it in both directions, or it just smacks of a "Hatchett Job", if you know what i mean. what do you perceive your funtion to be in the scheme of things? are you a reporter of facts or are you in the business of speculation? either is acceptable provided you balance both sides and do not slant in one direction or the other. if you do it brings the phrase "Ulterior Motives" to mind and makes everything you say, suspect. matter of fact, let's look at your three MAJOR concerns;
1-the FDA is too stupid to realize this test was biased towards safety
2-it's HARD for YOU to IMAGINE the insurance companies wanting to pay for a safe drug.
3-then, after spending years and millions to get it to this point, the person at the forefront of the effort announces to the ENTIRE PLANET that he is pleased with the results but you know better, not because you spoke with him at great length, but because you READ HIS MIND!!! and pronounced him a liar and his efforts a waste of time.
your criteria for rejection is juvenile Derek and excuse me for pointing this all out but you are the one who set yourself up as a so called "PUNDIT"

Apr 01 12:57 AM

[Grumann:]

Derek, You appear to have the credentials and experience to write a more complete analysis of the prospects for Lorcaserin. This "article" is a simple opinion. You've shown your bias already, but I'd still be interested in hearing your thoughts on what might be the next steps ARNA could pursue here. With the safety issues resolved, isn't ARNA set up nicely (except for cash) to pursue more aggressive weight loss studies? And hasn't the safety issue been the primary reason they haven't yet entered into a partnership, so now that may be more likely? Isn't your declaration that Loraserin won't make it a bit premature? How about a SWOT analysis (Strengths, Weaknesses, Opportunities, Threats)?

Apr 01 10:18 AM

[Michael Murphy:]

Derek - the FDA cannot reject lorcaserin on grounds of efficacy, because as biodummy pointed out, the FDA has TWO standards for efficacy and the drug only has to meet ONE of them. It is "either/or" and I have not seen this distinction in ANY media writeup on the results.
But the idea that this trial was "biased towards safety" is also wrong. This was a Phase III trial to prove efficacy AND safety, with the microscope on safety due to the phen-fen disaster. Arena passed the safety tests with ease - that is big news - and also hit every one of their primary endpoints INCLUDING efficacy. That is bigger news
Assuming the BLOSSOM Phase III results due in September are similar to the BLOOM Phase III results just announced, which is my expectation, there is little doubt that lorcaserin will be approved. Even the negative analysts on Wall Street admit it will be approved. Their bearishness is based on a belief that either the drug won't sell well because it didn't hit the 5 percentage point (not 5%) separation from the placebo for percent of body weight lost, or Arena won't be able to get a partner for the same reason.
As I told my subscribers, that is baloney, to use a family-friendly word. Doctors want a drug that patents will stay on (note the low side effects profile for lorcaserin) and will work. Losing more than twice as much weight as the placebo or, to put it another way, cramming two years of weight loss into one, encourages patients to continue and makes doctors happy.
You are welcome to read my more detailed write-up on my website. You can login with a temporary user name and password good through April 10:
UN: newuser
PW: 04/10/2009
I challenge you to read my March 30 analysis and April 2 Radar Report, and then respond here with any other reasons you have why lorcasrin will not be approved. The efficacy argument won't hack it.
In fact, I am going to submit an article to Seeking Alpha on this. You can respond here or there.

Apr 03 04:04 PM

[hoopdreamer...:]

Mike Murphy: i didn't know you still had a newsletter. I'll bet you a subscription that Derek is right and it won't get approved.

Apr 05 11:44 PM

[Grumann:]

Link to MedPage article: www.medpagetoday.com/P...
Ed Sussman lost 52 pounds (17%) and eliminated several meds for diabetes during his 1 year trail. Assuming he was on Lorcaserin, it appears that the drug, combined with dietary counseling and very light exercise can have significant results.

Apr 06 01:22 PM

[Michael Murphy:]

Done.


On Apr 05 11:44 PM [e-mail] wrote:

> Mike Murphy: i didn't know you still had a newsletter. I'll bet you
> a subscription that Derek is right and it won't get approved.

Apr 24 03:47 PM

[User 412093:]

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May 11 09:00 PM