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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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March 31, 2009

Another Obesity Drug? Not Likely.

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Posted by Derek

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 are 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 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 yesterday 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 (34) + TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity


COMMENTS

1. Lucifer on March 31, 2009 8:04 AM writes...

Bupropion causes more sustained weight loss and has been used as an antidepressant for over 20 years.

The newer triple reuptake inhibitors (antidepressants) are also associated with reasonable weight loss.

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2. Darjeeling on March 31, 2009 8:51 AM writes...

Derek, this is great:

"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."

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3. Daniel Newby on March 31, 2009 9:09 AM writes...

Percentage weight loss is not all that relevant to health. It seems likely that a few of the obesity-generating pathways are particularly toxic. A single mechanism drug that causes spectacular weight loss is as likely as not to cause maximum reflex overactivity of a toxic pathway, resulting in a disaster.

A wise drug company would have tested locaserin for morbidity and mortality, preferably in Type II diabetics or neuroleptic users or some other very sick population. If it worked, it would be a shoe in for approval. Then, after it had been on the market a while they could "discover" that is causes modest but statistically significant weight loss, and let the popular press do their marketing for them.

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4. retread on March 31, 2009 10:41 AM writes...

It is remarkable that a drug could affect just one of the serotonin receptor subtypes (although to be fair, the brain has no problem distinguishing dopamine from norepinephrine) -- I stopped counting serotonin receptor subtypes at 14 (back in 2006), moreover the total ignores splice variants. It is miraculous that the SSRIs work at all. Does anyone know which serotonin receptor(s) is responsible for their effects?

It's easy to make an animal (or a human) lose weight -- just make them sick.

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5. Tuck on March 31, 2009 10:45 AM writes...

Hiya, Derek,

Actually, though Lorcaserin failed the 5% difference metric, it made it on the other metric that can lead to approval, the responder analysis. The particulars of the responder analysis metric are as follows: that a stat sig difference in response rate of 35% versus placebo is achieved, and said response rate is at least double that of placebo. One or the other metric must be prespecified. In this case, the responder analysis was prespecified (per the CEO on the conference call), so Lorcaserin is approvable on grounds of efficacy.

Your other concerns are widely shared, but it seems to me a combo might might be commercially feasible. As such, Arena might yet be able to partner this sucker, though not for the terms the CEO originally hoped for. And Arena will have to struggle for a while during the ensuing phase IV program.

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6. Tuck on March 31, 2009 10:58 AM writes...

One caveat to Lorcaserin passing the responder analysis test is that the while the dropout rates were historically low, and about even between treatment and control groups, analysis of the dropout rates in responders isn't yet done. A bad surprise there could derail Lorcaserin's success on this metric.

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7. Quick question on March 31, 2009 12:49 PM writes...

Does the FDA ever put new drugs on a more limited approval basis (in this case just for serious obesity, for a narrow segment of the population) b4 the drug is released to the general public? Or is this solely at the discretion of doctors prescribing the drug?

It always seems to me that this would be a good way to tread lightly - particularly when all the side-effects (or advantages of a new drug) might not be evident in phase I-III.

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8. Anon on March 31, 2009 1:50 PM writes...

And yet as a kid, my doctor gave me amphetamine-based diet pills that REALLY removed appetite and let me lose weight. I could be ravishingly hungry, take a pill, and in ten minutes not even stand to look at food.

I have no addictive tendencies and once I was finished with the diet after a few months, never became a raving drug addict. However, I can state personally, the amphetamines did kill appetite. Period.

Too bad others simply like the buzz and have caused use of such drugs to become illegal or nearly so.

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9. retread on March 31, 2009 2:01 PM writes...

Anon -- either you must be pretty old, or you had a rather borderline MD. That stuff stopped years ago. Speed freaks are usually pretty thin.

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10. Eleanor on March 31, 2009 2:17 PM writes...

Another effective appetite suppressant is Byetta, the new diabetes drug made from lizard spit.

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11. milkshake on March 31, 2009 2:26 PM writes...

too bad Byetta is a peptide so it must be injected. Small molecule GLP-1 drugs might be inhaler friendly (unlike the Exubera fiasco) but it has been pretty hard to find a small molecule ligands so far.


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12. Lucifer on March 31, 2009 3:01 PM writes...

What about Methylphenidate? It works reasonably well too.

The cons:

1. Short half life (multiple doses or controlled release)

2. Legal status - special prescriptions etc.

I have always wondered why someone does not create and test compounds that are very similar to methylphenidate (structural and pharmacological) but have longer half lives. Could also be useful to treat atypical depression.

Permalink to Comment

13. milkshake on March 31, 2009 3:39 PM writes...

methylphenidate also has a cardiovascular risk potential and for awhile it looked like it may get a black box warning for it.

There is one interesting concept for sustained release of stimulants - New River developed a lysine amide of d-amphetamine - the product has a decent oral availability and it gets slowly cleaved in plasma to its parents

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14. Lucifer on March 31, 2009 4:43 PM writes...

If you believe that methylphenidate has CV risk potential, then paracetamol should be banned for potential hepatotoxicity. The reality is that controlfreaks a**holes who write and enforce laws (and their josef mengeles.. I mean doctors) would never like to approve anything that had some potential, however small, to making people feel happy or good about themselves.

The economic collapse has exposed many unpleasant aspects of ourselves, but none more pathetic than the willingness to believe in authority. Do you really believe that your average FDA guy or MD is any more intellectually honest than the 'masters of the universe' who created this mess?

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15. S Silverstein on March 31, 2009 5:18 PM writes...

The reality is that controlfreaks ... who write and enforce laws (and ... doctors) would never like to approve anything that had some potential, however small, to making people feel happy or good about themselves

I suffer weight problems, gain under stress, and there was no more unpleasant scenario than my medical internship. Chief of Medicine (at now defunct MCP) and fellow residents simply could not deal with an overweight doctor. I was picked on, severerly.

Lost weight and left for residency elsewhere. The contrast was stunning in how I was treated.

Too many physicians really are bigoted jerks.

The economic collapse has exposed many unpleasant aspects of ourselves, but none more pathetic than the willingness to believe in authority. Do you really believe that your average FDA guy or MD is any more intellectually honest than the 'masters of the universe' who created this mess?

Some are. You can identify them to a great degree by their willingness to openly challenge the status quo. A whole parade of such people is catalogued at sites such as "HealthMemes" (/http://in3.org/health/).

Derek falls in this category as well.

Permalink to Comment

16. Jumbo on March 31, 2009 7:26 PM writes...

While arguments can be made that less than 5% weight loss on average is minimally necessary, we know so little about what makes someone respond to a 2C agonist that I am uncertain average is the right way to look at it. Sure, safety could become a problem once millions take this drug. But no serotonergic has ever undergone the cv scrutiny this drug has. If a Dr was presented with a substantially safe drug that gave an obese patient a 50/50 chance of losing 20-30%, and it would be evident that it is working within 4 wk, are we all so sure that we wouldn't want access to such a drug? People who aren't overweight can't appreciate the unmet need here. As pointed out by SSilverstein, obesity is one of the last permissible bigotries.

Permalink to Comment

17. Hap on April 1, 2009 8:07 AM writes...

"Do you really believe that your average FDA guy or MD is any more intellectually honest than the 'masters of the universe' who created this mess?"

Assume that people aren't at all intellectually honest - they respond to what benefits them, in most cases what makes them money. The MOTUs had rather large incentives to take large risks on the money of others - they made a lot of money doing so, and were paid really well when the risks panned out and well if they did not. The well-being of other investors was not their problem. Contrast to most FDA people, who have little incentive to either boost a drug through (because it doesn't help them much) or inhibit drugs (because they don't get money for doing that, either, though they may avoid embarrassment by doing so) - so even if their honest or conscience is deficient, they have less ability to get any benefit from their dishonesty. Dishonest people will probably choose jobs where they can use their lack of honesty for their benefit. (Some MDs shepherd and run trials, and the higher FDA people probably have greater incentives, though at least for the latter there is some oversight).

People are people to some degree - in the worst case, incentives and regulation determine their ability to be dishonest and do harm. The selection bias (people who wish to make money dishonestly will choose places where they can do so, and so other fields will have proportionately fewer intellectually dishonest people because there is little benefit in being so) would seem to indicate that most FDA people and MDs are likely to be more intellectually (and otherwise) honest than MOTUs.

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18. Joseph Hertzlinger on April 1, 2009 1:08 PM writes...

Would it make more sense to look for a laziness suppressant? Out remote ancestors had little reason to suppress appetite but those that couldn't suppress laziness on occasion got eaten by saber-toothed tigers.

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19. Joseph Hertzlinger on April 1, 2009 1:09 PM writes...

Would it make more sense to look for a laziness suppressant? Out remote ancestors had little reason to suppress appetite but those that couldn't suppress laziness on occasion got eaten by saber-toothed tigers.

Permalink to Comment

20. disappointed on April 2, 2009 11:56 AM writes...

As someone who has done research in this area and has followed Arena's clinical trials through the years, I'm diappointed that it appears that Derek hasn't done his homework. I'd like to know how a 5HT2C agonist could be considered some new-fangled method of treatment for obesity - ever heard of dexfenfluramine? It's not like this is a mechanism that hasn't already been tested in a large patient population and shown to be effective. The problem with dexfenfluramine was not it's 5HT2C agonism, it's that it also hits 5HT2A, causing QT prolongation in some patients. Arena dialed out the 5HT2A activity with lorcaserin (note the spelling) and the compound has made it through rigorous safety trials to show absolutely no CV effects. In fact, this weight loss data was generated during the safety trial. While it was unexpected that the placebo patients would chart such a high rate of weight loss (higher than would be typically expected in one of these trials) thus throwing off the "magic 5%" numbers, the other FDA criterion was met (as another commenter posted) - it's an either/or. Additionally, over 20% of patients on lorcaserin lost over 10% of their body weight, which has been shown to significantly reduce mortality and morbidity. It sounds to me like Derek read a few analyst reports and whipped up a post without doing his research.

Permalink to Comment

21. doctorpat on April 5, 2009 10:40 PM writes...

Would it make more sense to look for a laziness suppressant?
That would ALSO be amphetamines.

Couldn't it be better in the long run just to forget about trying to save these junkie losers who restrict the rest of us to such a great extent? Once we write those guys off, the rest of society has access to such a huge range of extra drugs, freedom, reduced enforcement costs...

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22. Sili on April 10, 2009 8:55 AM writes...

I do realise that obesity is a big problem for some people. And that once weight has been gained, it's hard to get rid of again.

But I can't help but think that looking for a drug against it, is indeed one of those things that make 'Big Pharma' look bad.

Such a drug will be agressively marketed to just about anybody, despite the fact that for most people exercise and a proper dietician (not 'nutrionist') would be a far far better solution.

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23. Hap on April 10, 2009 9:35 AM writes...

I don't think the development of an antiobesity drug would reflect badly on pharma - its (alas) inevitable overmarketing would, but not the drug itself. Also, while there are lots of things that should change to get people not to be obese that are preferable to medication, people seem unlikely to do those things, and the means to compel them to do so are unpleasant and have enough side effects of their own to be unavailable.

People aren't going to be angels anytime soon, and removing some of the consequences of our bad behavior is a (large) potential problem (re: diet drinks, seat belts), but if a drug could decrease the bad effects of obesity on people's lives, it would probably be a good thing. You use the tools that you have to mitigate problems, because wishing we were not what we are isn't likely to improve matters.

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24. retread on April 10, 2009 10:53 AM writes...

MDs would love an obesity drug -- even granted that it will also be used for cosmetic reasons. Lower the weight of an overweight diabetic (which just about all type II diabetics are), blood sugar levels improve (a biologic marker to be sure, but so does outcome in terms of diabetic complications), lower the weight of an overweight hypertensive, blood pressure and complications drop. Lower the weight of someone with elevated cholesterol and triglycerides, and these drop as well (regardless of whether they were overweight to begin with).

However, there is one paradoxic effect to consider. After the imposition of bicycle helmets, the incidence of severe head injuries from bike accidents INCREASED. Riders thought they were safer and were less careful. Hopefully the nation wouldn't get even heftier if we had such a drug.

We accept 37 K deaths on the road (a new low !) yearly for the
ability to drive cars. People will misuse anything, but I don't see anything like this from an anti-obesity drug (assuming that it's reasonably safe -- which Fenfen and thyroid hormone, used for this in the past were definitely not). Apparently in the 50s amphetamines were widely used for weight reduction.

Permalink to Comment

25. Hap on April 10, 2009 12:50 PM writes...

People might eat more. When people at work told me diet drinks didn't help one lose weight I found it hard to believe, but my personal experience (which is obviously limited, so YMMV) is that it's true. People may just eat more - so diet drinks may help one substitute fat and protein for sugar (which might be good and might not) but not lower overall caloric intake. The same could happen with an obesity drug - "WooHoo! I can eat what I want and not gain weight!" - and so we might not get better. On the other hand, for people that want to lose weight or find a healthier equilibrium but can't, it would probably be useful. The worry would be that side effects in the larger market would destroy its use for the smaller group of people it could help.

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26. weirdo on April 10, 2009 6:28 PM writes...

As only a bystander with no skin in this game, I am disappointed with "disappointed". For someone who claims to know this area well, he/she seems woefully misinformed.

". . . it also hits 5HT2A, causing QT prolongation" makes absolutely no sense. (None. Nada. Zero.) The two topics -- 5HT2A and QT -- are completely unrelated. More "disappointing", neither seems all that relevant to the topic at hand.

Phen fen caused valve damage, not QT prolongation. And the valve damage has been attributed, by some, to 5HT2B, not 5HT2A.

Time to do some more research, "disappointed".

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27. Sili on April 12, 2009 2:38 PM writes...

I realise I'm too idealistic about what people should do, yes.

And I hadn't thought about getting rid of obesity will help deal with other illnesses.

But any death will still be laid at the foot of 'Big Pharma'.

Even if it is much safer than gastric bypass:

complications are common and surgery-related death occurs within one month in 2% of patients.

I don't see how the FDA would ever accept that for a drug.

Permalink to Comment

28. Hap on April 13, 2009 7:26 AM writes...

I don't think the FDA would accept that high a death rate for an obesity drug, but I thought that bariatric surgery was usually done for desperately overweight people, who have no other (effective) options for weight loss. The acceptable effects of a drug being given to people with terminal cancer (and no other treatment) are substantially larger than those for obesity where other options are available, where the (immediate) consequences are significantly less severe, and where the target audience is significantly larger.

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29. Sili on April 13, 2009 2:14 PM writes...

I think the point I was trying to make, was that if an effective anti-obesity drug was made that could help the "desperately overweight" it would still not get accepted as an alternative to surgery - even with a deathrate of 1 or 0.1%.

In part likely because it's use would never be limited to the desperately overweight.

Permalink to Comment

30. Hap on April 14, 2009 8:23 AM writes...

No, you're probably right - on the other hand, that would be where risk-benefit analysis would actually be useful and not just a spin job (since the benefits and risks actually can be compared in the same terms), though it would seem to be rather optimistic of me to assume people would be willing to admit risks on taking a drug.

The concept that drugs (or anything) can be absolutely safe is an awfully pernicious belief. With that expectation, it is unlikely that any long-term treatment could be sold. Of course, the cost of drugs and their overselling (to people unable to understand their risks and rewards, and to those less likely to see significant benefit) doesn't help either.

Permalink to Comment

31. Aggie on October 20, 2009 11:16 PM writes...

Losing 5% of one's weight is insignificant in terms of improving health. Someone who weighs 300 pounds and loses 5% of that is still quite obese.

Odd that we have decided fat is so toxic since the life expectancy of people in the industrialized nations has increased along with average weights. The war on fat has much more to do with prejudice than it does with science.

Good book on the subject - The Obesity Myth by Paul Campos (ignore some of his whackier theories and just read the science stuff). One more book - Worried Sick by Nortin Hadler, MD.

Also check out junkfoodscience.blogspot.com There are several posts on the paradoxes of obesity.

Permalink to Comment

32. Lorcaserin on January 5, 2010 2:22 PM writes...

I think I am along the same lines as you here... Lorcaserin although apparently a relatively "Safe" medication in terms of side effects does seem to barely make the cut. However, one should point out that I think there is a good chance that it could be prescribed along with Phentermine, an already existing proven prescription for fighting obesity. There is no talk of that per say yet, but chemically, it makes sense to do so. This would greatly improve its effects and it would be up there with Qnexa and Contrave with regards to effectiveness. Another note to those who simply think obesity if just for the lazy... there are some conditions that prevent people from losing weight, (or make it extremely difficult) such as cushing's disease. People with this could really benefit. But yes there are people like with many drugs who want to abuse them or take them when they are not actually intended for such.

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33. Lorcaserin on July 1, 2010 1:51 PM writes...

Judging by the discountinue rates of the other meds compared to Lorcaserin I would say that it has a good chance of appfoval.

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34. Contrave on December 9, 2010 2:33 PM writes...

Well well, it looks like Contrave is the winner in the race to create an obesitiy medication. Just a few days ago it was approved in a vote.

Permalink to Comment

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