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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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June 11, 2010

Alzheimer's: Extracting Data From Failed Trials

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Posted by Derek

It's no secret that Alzheimer's disease has been a disastrous area in which to do drug discovery. Every large drug company has had failures in the area, and many smaller ones have gone out of business trying their hands. (I had several years in the field myself earlier in my career, trying three different approaches, none of which panned out in the end).

Now the Coalition Against Major Diseases has announced an open-access database of clinical trial results from failed drug candidates in the area. J&J, GlaxoSmithKline, Abbott, SanofiAventis, and AstraZeneca have contributed data from 11 failed drug candidates, and more look to be on the way from other companies. I hope that Eli Lilly, Merck (their own compounds and those from Schering-Plough), and Pfizer all join in on this - right off the top of my head, I can think of failed drugs from all of them, and I know that there are plenty more out there. (Pfizer seems to have dodged a question about whether or not they're participating, to judge from that Wall Street Journal article linked to above).

It'll be difficult to comb through all this to extract something useful, of course. But without sharing the data on these compounds, it would be utterly impossible for anything to come out of their failures. I think this is an excellent idea, and well worth extended to other therapeutic areas.

Comments (12) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | Drug Industry History


COMMENTS

1. retread on June 11, 2010 12:41 PM writes...

Excellent idea. It's basically a neuropharmacological autopsy, and medicine has learned a great deal from this sort of thing. It's much easier to debug a program that you can cause to fail under known conditions, than one that is randomly failing.

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2. rtw on June 11, 2010 2:32 PM writes...

I don't think much will come from this. The failures might just be because the drugs are not effective against Alzheimer's because the selected targets have little to do with disease progression and its root cause as Derek has often expounded in other posts.

In pathology you have actual tissue samples, measurable tests results and such. Clinical trial results you are looking at statistical data and fuzzy correlations of what I suspect in this case are very subjective end points. Its not easy to measure them I would expect.

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3. retread on June 11, 2010 4:56 PM writes...

#2 rtw -- not so for a real clinical effect. There was only one trial of the Salk vaccine for polio, and watching people get out of wheelchairs on L-DOPA for for Parkinsonism is all you need. The effects of the early Alzheimer drugs (like Cognex) were undoubtedly real, but so small as to be clinically meaningless.

A reversal of the cognitive changes of Alzheimer's would be obvious in a week. Slowing the decline is another matter (and do you really want to be kept alive a little longer in a little less demented state?). This last is a cultural decision and not a medical one.

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4. ex-Pfizerite on June 11, 2010 8:00 PM writes...

Retread, slowing the cognitive decline and maintaining it at even a slightly higher level is important because caretakers would be interested if the patient could remain potty trained for a little longer or remain at home and functioning a little longer which would save vast amounts of money.

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5. doglotion on June 11, 2010 10:59 PM writes...

It's not clear what kind of useful data one conceivably could extract from a series of failed AD trials. Other than that therapeutic approaches X, Y, and Z don't show any significant difference between treatment and control groups.

I suppose you could get some useful historical data on how the endpoints (ADAS-cog, or whatever they use now) change over time, which could provide insight into designing/powering a new AD trial appropriately. But any clinician worth his salt should know that stuff three ways to Sunday anyhow.

I'm with #2, this probably isn't so useful. And you can bet that if the players involved thought the data was worth anything, they wouldn't be giving it away.

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6. fred on June 12, 2010 4:58 PM writes...

Correlation does not imply causation. We don't even know for sure that blocking Abeta will have ANY effect on disease progression. Unless I missed a Nature somewhere along the line.....

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7. kristall36 on June 12, 2010 11:06 PM writes...

Pfizer and Merck are collaborating with Sage Bionetworks and providing their preclinical and clinical data to build an open-source network.

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8. retread on June 13, 2010 10:00 AM writes...

Absence of evidence is not evidence of absence. The negative studies are valuable precisely because they are evidence of absence. The various pharmacological approaches to therapy (even those arrived at by massive compound screening) all had some theoretical basis. The fact that a particular drug didn't work casts some real world doubt on that theoretical basis.

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9. RTW on June 14, 2010 8:06 AM writes...

retread -

I in no way was indicating that I though the clinical trials where useless... Or that there isn't a need for drugs to treat this condition. I have friends and colleagues that have worked in this area in the past as well as currently directing such efforts at a major institution.... Parke Davis was one of the first with a drug that seemed to slow progression and I had several friends working on second generation drugs.

My stated position was that I don't beleive much information can be gained from failed trials towards new drug leads, or an understanding of the underlying mechanism if the disease based on the statistical information presented. I feel actual pathology would prove to be more useful than analyzing fussy statistics. And dont get me wrong. I understand a thing or two about statistical analysis. Have had many discussions on the topic with a Biostatatician (sp?).

As a medicinal chemist I have to take exception to your statement:

The fact that a particular drug didn't work casts some real world doubt on that theoretical basis.

Statistically speaking this is not true. There are many reasons a drug fails other than the fact that it didn't effect its target or the theoretical basis of selecting this target was incorrect. Its usually hoped that by Phase III trials most of these reasons are already eliminated but one can never be quite sure.

Drugs that work great in animal models and thus hit their target but for a myrid other reasons fail human phase III.

Currently based on what I have read and reading what Derek has posted as someone who has worked in this area of research, I am at the moment inclinded to beleive that a lot of people unfortunately were pursuing the wrong targets. Time will tell. Unfortunately this doesn't help the millions of people effected by this condition and the aging of world population.

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10. doctorpat on June 14, 2010 10:08 PM writes...

And you can bet that if the players involved thought the data was worth anything, they wouldn't be giving it away.

Alzheimer's is different from most diseases in this respect. There are a lot of senior drug executives who will be personally affected by Alzheimer's. (Either themselves, a family member or friend) A cure appearing several years earlier could be personally worth it to them.

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11. retread on June 15, 2010 10:47 AM writes...

#8 RTW -- excellent points, and worth a (future) post rather than a discussion here. I said "casts some doubt" which shouldn't be taken to mean 'disproves'.

As a very strong example of your point, consider the terrible history of animal models of stroke in predicting therapeutic success of drugs in man. Here, at least, the model (e.g. tying off an artery to part of the brain) is pretty good for human ischemic stroke. Even the fact that rodents can survive, feed, mate and reproduce without any cerebral cortex at all (see "Tolstoy was right") doesn't cast much doubt on the model, yet no drug useful for humans has come out of this work (to my knowledge).

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12. Leeanne Earhart on March 1, 2012 2:19 PM writes...

Its like you learn my mind! You appear to grasp so much about this, such as you wrote the ebook in it or something. I think that you simply could do with a few % to force the message house a little bit, however instead of that, that is wonderful blog. An excellent read. I will certainly be back.

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