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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: Twitter: Dereklowe

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March 30, 2009

Lilly's Latest Loses (This Time)

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Posted by Derek

Over the years of this blog, I’ve occasionally made comments about how no one really knows much about how drugs for the major central nervous system diseases work. Well, actually, I’ve stated things more forcefully than that, but you get the idea. And although many people who work in the area have written in to say that they agree, I’ve had questions from people completely outside it (journalists and others) about whether I’m serious when I say these things.

Oh, I am. For the latest piece of evidence, see what’s just happened to LY2140023, Eli Lilly’s new drug candidate for schizophrenia. The company was running a three-armed Phase II trial: placebo vs. their existing drug Zyprexa vs. the new one, which is a metabotropic glutamate ligand. And what happens? The placebo group performs about twice as well as the usual average in such trials, for some reason. And that not only swamped the investigational drug, but Zyprexa as well, which has been on the market for years.

Now, there's been a lot of argument about whether the current generation of antipsychotic drugs is really better than the older ones. But I believe that they're all supposed to come in better than a placebo. As Lilly points out, though, "inconclusive trials are common in neuroscience", and they're going to run another one and hope that the patients don't all start improving again on powdered sucrose or whatever the placebo was. But this is especially surprising (and disappointing) because an earlier Phase II trial, run in a very similar design to the latest one, showed the compound working very well indeed. How do you go from such impressive results to no better than placebo in the same sort of trial design? Easy - just make sure that you're developing a drug for schizophrenia. Or depression. Or chronic pain, or Alzheimer's. Stick with the central nervous system, and your drug discovery career will never be boring.

Oh, and one last note: after all the recent stories about buried clinical results, I'm glad to see a company fall completely flat with one of its most promising drugs - and then get up at a large scientific meeting and tell everyone about it in detail. It's not that it's so unusual, but it's good to show people that it happens, and how it's handled when it does.

Comments (16) + TrackBacks (0) | Category: Clinical Trials | The Central Nervous System


1. milkshake on March 30, 2009 7:37 AM writes...

It makes a good damage-control sense to publicize the reasons for a lack of observed efficacy in this study. (It was just a fluke, Zyprexa works fine and they will continue developing their new candidate, etc).

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2. Hap on March 30, 2009 8:04 AM writes...

People that distrust/hate pharmaceutical companies will continue to do so, likely without regard to evidence, but it might help with the undifferentiated majority for companies to be honest with their failures, both so that people see that there aren't many sure things in drug development and so that people might be more apt to trust their word again. Plus, it seems like bad news is better told by you (and in full) than by someone else, so that it doesn't leak out and so that then people don't wonder either how bad the news really is or what else you might be hiding.

There are lots of self-interested and non-self-interested reasons why Lilly might want to do this, but it's still helpful.

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3. RKN on March 30, 2009 8:34 AM writes...

I wonder, does anyone know what the phenotypic end point of a phase II clinical trial is, specifically to measure efficacy of a schizophrenia drug?

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4. Daniel Haszard on March 30, 2009 8:50 AM writes...


Eli Lilly is making positive PR over their $4 billion Zyprexa damages settlement while dragging their feet paying victims,many who are mentally challenged and less capable of advocating for themselves.As a matter of fact 8 Lilly employees who are supposed 'whistleblowers' are getting $ 10 mill each the real victims like me are being ignored.
Daniel Haszard used Zyprexa for 4 years and got diabetes from it.

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5. gyg3s on March 30, 2009 9:24 AM writes...

So, Thomas Szasz was right all along.

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6. Compliance Specialist on March 30, 2009 11:31 AM writes...

Its funny...our parent company reported the failure of one of our clinical trials (looking to see if there could be a new indication), and they ended up getting slammed on a recently closed pharma blog (though I have to admit, they were spinning it a little positive).

I do wish people would actually read a product insert to know the side effects.

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7. Anonymous on March 30, 2009 12:14 PM writes...

I think part of the problem comes down to animal models for determining the efficacy of a compound in some of these disorders such as depression and schizophrenia. Translating animal behavior in a supposed model of depression or schizophrenia to the human condition is always going be difficult.

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8. milkshake on March 30, 2009 12:42 PM writes...

Janssen found Haloperidol with a simple schizophrenia model: compulsive behavior of mice injected with a with massive dose of amphetamine. This was based on observation of professional cyclists doped up to their gills - they behaved much like schizo patients in the active phase

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9. Arjun on March 30, 2009 5:45 PM writes...


What's your opinion on the removal of placebo responders from trials?

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10. Jonadab the Unsightly One on March 30, 2009 7:36 PM writes...

Schizophrenia has a very large psychological component, so obviously any given patient can get better or worse for reasons that have nothing to do with the real or perceived value of any medication they may take for it. The only known reliable way to reduce this effect to ignorable statistical noise is to run the trials against a much larger population. But, of course, there's a substantial collection of reasons NOT to do that with new as-yet-unapproved psychoactive drugs.

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11. InfMP on March 30, 2009 9:30 PM writes...

People who come online and type very loud and hysterical sounding msgs (post #4) are really funny.
I think it's best to be constructive, then people will be more likely to listen.

no offense.

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12. Greg on March 31, 2009 6:55 PM writes...

I participated in a study that, among other things, tested the efficacy of Oxycontin v. acetaminophen and a placebo. For me, the sugar pill had far and away the best pain killing results, and Oxycontin had the least effect. :-)

Long live the sugar pill!

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13. srp on April 2, 2009 6:43 PM writes...

I definitely want to know what kind of standardization they have in manufacturing the placeboes. Maybe contamination at the factory accidentally got some unknown natural product into this batch.

Of course, this reminds us that a positive finding for the drug under investigation could also be a fluke.

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14. gyges on April 4, 2009 8:51 AM writes...

A few days ago I referred to Thomas Szasz. Here's a link to who he is from Mind Hacks.

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15. Sili on April 12, 2009 2:03 PM writes...

Well, srp,

You know what happened when French Boron accidentally swapped two of their homoeopathic remedies for half a year:

Absolutely nothing.

I, too, welcome this transparency. Let's hope it'll get more publicity in future. On blogs of course - MSM is crap in this area (too).

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16. gnown on April 23, 2009 3:24 AM writes...

@ RKN (#3 post):

Schizophrenia has symptoms which have been categorized into 2 main different types. Positive symptoms include delusions, auditory hallucinations, and thought disorder. These are classified as psychosis. Negative symptoms include blunted affect and emotion, poverty of speech (alogia), inability to experience pleasure (anhedonia), and lack of motivation (avolition).

I'm guessing these could be assessed somehow using questionnaires and visual analogue scales.

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