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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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July 27, 2010

Alzheimer's and Amyloid, Again

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Posted by Derek

I wanted to mention this good article in the New York Times on the amyloid hypothesis and Alzheimer's. That's a topic I've covered often here, but this is a good overview of the field. And it's a good overview of the field's big questions, too: is amyloid really the cause of Alzheimer's? Do we have any therapies that can slow amyloid deposition, or not? If so, do any of them actually show any real-world benefit to patients?

This gets into the broader question of biomarkers as well. The FDA is insisting, as they should, that any potential Alzheimer's therapy should show improvements in memory or cognition, not just improvements in number of plaques or the like. Getting that sort of data is very difficult, but it's really the only way to avoid yet another "You'd Have Thought That. . ." moment. We've been having too many of those over the last few years. As the FDA's director of neurology puts it:

“You only care if down the road the patient gets better,” Dr. Katz said. “What we are concerned about is approving a drug based on a lab test and being wrong about what happens to the patient clinically.”

With Alzheimer’s, Dr. Katz said, “the great fear is that maybe amyloid has nothing to do with the disease.” If that were the case, and the agency approved a drug that blocked amyloid formation, millions of healthy people could end up taking something useless or even dangerous. And because it takes so long for Alzheimer’s to develop, it could be decades, if ever, before anyone knew the drug did not work.

“It is a conundrum,” Dr. Katz said. “We all hope to get to the point in our understanding of the disease process where everyone in the field says: ‘Look. We know it now. Amyloid causes Alzheimer’s, and we have drugs that decrease amyloid.’ But we are not there yet.”

Biomarkers, ideally, are supposed to speed up drug development. But validating a good one might just as slow a process as if you didn't have a biomarker at all. What I worry about is a situation where the first people to discover these things end up with no chance to benefit from their work, but actually end up helping out other groups much more. And while there's a place for altruism in medical research, I doubt if making it the driving force will lead to success. . .

Comments (17) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials


COMMENTS

1. student on July 27, 2010 9:40 AM writes...

The reason that 90% of researchers believe the amyloid hypothesis is that all these companies have bet the bank that it's so because there is no alternative target.

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2. Anonymous on July 27, 2010 10:40 AM writes...

Well I think Derek is on the money here. Until there is some prospect of a long-term return on investment Alzheimer's drug research is always going to suffer. The current patent life simply isn't going to be fit for purpose here - indeed I'd argue that it is a fundamental problem for almost all therapeutic areas now, but it is most acute for degenerative conditions where the industry is going to be expected to show a long-term benefit for their treatments through costly long term trials. A longer patent life (e.g. a guaranteed 15-20 years life from approval) would change this industry for the better and correct the current market distortion which is favouring research into biologicals over small molecules purely in the hope of extended product life. But that would require political vision and bravery of the highest order as it would be seen to be pandering to the whims of big business.

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3. Anon2 on July 27, 2010 10:50 AM writes...

Biomarkers are becoming opiates of the drug industry. Dangled by FDA as an attractive fruit, then extending the field as one approaches the goal post.

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4. Jonathan on July 27, 2010 11:50 AM writes...

I've asked you this over twitter, but what do you make of the Etanercept findings? http://arstechnica.com/science/news/2008/01/new-alzheimers-treatment-works-in-minutes.ars

Do you think an anti-TNF strategy might work in AD?

On the topic of biomarkers, I was at an interesting symposium at AAAS last year and one of the speakers was arguing that FDA will need to start accepting things like imaging as a biomarker for AD if we ever want to get drugs for it.

Anonymous - I don't think it's just patent life that's the problem. If AD takes 30+ years to develop, that's longer than most peoples' research lifespan, nevermind the patent life of the drug.

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5. UBT on July 27, 2010 12:43 PM writes...

The thing with biomarkers is that they only work/make sense if the biological processes behind a disease are fully or at least largely understood. Only then is it possible to choose a proxy (the biomarker) for the final result (optimally a cured patient). Since the processes behind Alzheimer's (more generally in the CNS) are badly understood this area is not well suited for biomarkers.

On a side note: Recently there was an article on hyperploid neurons and their connection to Alzheimer's in the American Journal of Pathology.
http://ajp.amjpathol.org/cgi/content/abstract/ajpath.2010.090955v1
Any thoughts?

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6. retread on July 27, 2010 1:36 PM writes...

#5 UBT: Even when pathogenesis is well understood a biomarker (even a biologically relevant one) might be misleading. Consider the history of AZT (azidothymine -- an early example of click chemistry? ) in AIDS. It certainly kept the CD4+ count higher than no treatment (the lower the CD4 count the more likely an untreated HIV1+ person was to get an infection). Yet there was no clinical benefit of AZT on survival or infectious episodes.

With other biomarkers, the chain of inference is more fragile. Could we improve the health of the general populace by giving everyone a yacht. Certainly, people with yachts are healthier, live longer and have fewer diseases (except alcoholism perhaps). The correlation of yachts and health is good (just as good as socioeconomic status which is the real underlying variable).

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7. cliffintokyo on July 27, 2010 7:14 PM writes...

Agree this is a very good and lucid post on this topic. Plaudits to FDA for not running with the pack/company hype on amyloid plaques. Validation of biomarkers for Alzheimers seems like one of those basic research needs that was intended to be assisted by the Critical Path/ Translational Research Initiative. Industry stakeholders should be collaborating with academia on this one, for the reasons very clearly expounded in the post.
Nice one, Derek.

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8. Vasili on July 28, 2010 12:48 AM writes...

Article in Nature: Drug discovery Reviews about AD biomarkers

Biomarkers for Alzheimer's disease: academic, industry and regulatory perspectives

http://www.nature.com/nrd/journal/v9/n7/abs/nrd3115.html

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9. cliffintokyo on July 28, 2010 1:19 AM writes...

#8. Thanks. One comment: The 'Nature' article summary contains the following para:

"A catch-22-like situation exists in validating Alzheimer's disease biomarkers for use in drug development. Biomarker validation depends on effective drugs that target Alzheimer's disease pathogenesis, which are not currently available. At the same time, evidence from biomarker studies is needed for a new drug to be labelled as disease-modifying."

The person who wrote this does not fully understand biomarker validation.
Clinical improvement in a disease must be strongly correlated with a significant change in a biomarker for that biomarker to be considered validated, whatever treatment is used.

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10. vasili on July 28, 2010 2:45 AM writes...

I think the statement is referred to the special case of disease=Alzeimer's.

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11. cliffintokyo on July 28, 2010 3:47 AM writes...

#10 Yes of course.
I should have written:
".....for that biomarker to be considered validated from a regulatory point of view"

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12. Evorich on July 28, 2010 7:25 AM writes...

#9 - I think that's the point of the what the author is saying. There's no drug to modify the disease and simultaneously the biomarker. Has anyone actually got better from Alzheimer's ever?

Essentially then the biomarket is not yet validated.

The whole problem is due to the fact that the amyloid plaque development has never been linked to a mechanism of causation for the disease - only as a effect of the disease.

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13. cliffintokyo on July 28, 2010 9:22 PM writes...

#12; Yes and Yes!
You can measure every biomarker you can lay your hands on that might be correlated with disease progression when you screen your compounds, but if the changes, even when significant, cannot be shown to correlate consisently with a clinical response, FDA won't buy it.
RE: Amyloid plaque - cause and effect.....same old, same old.....
You can lead a *horse* to the *trough*, but you can't make him drink the Kool-aid!

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14. Anthony on July 31, 2010 5:47 PM writes...

retread - where do I sign up for the clinical trial of yacht therapy?

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15. Richard Hadden on August 11, 2010 10:59 AM writes...

I've sent a few e-mails in response to a few of Derek's previous Alzheimer's articles but I've never had a reply so I will try commenting instead.

I run a biomarker company in AD, based on the cell cycle theory of AD. Those hyperploid neurones are very important, UBT!

Re-entry into the cell cycle is a normal part of neuronal function but irreversible commitment to the S-phase is a very bad idea for a neurone, which is not capable of exiting the cell cycle via mitosis. The neurones end up in a living death in the G2 phase, the altered biochemistry of which (upregulated kinases, high tau concentrations, downregulated phosphatases) is permissive for the phosphorylation of APP and tau and the production of Beta-amyloid plaques and phospho-tau tangles.

We have shown evidence of G1/S checkpoint dysregulation in AD patients, in the CNS and in peripheral tissue. We have developed a blood test which examines the integrity of the G1/S cell cycle checkpoint in peripheral lymphocytes. Subjects with a positive test (dysregulation of the G1/S checkpoint) are at risk of AD. The test has specificity of 81%, sensitivity of 81% and an overall accuracy of 85%.

There is a wonderful US programme to examine biomarkers as a pre-competitive consortium of Pharma and the NIH. Check out the ADNI website.

Most AD biomarkers touted are disease biomarkers following phenomena related to amyloid or tau, e.g. CSF tau. The evolution in these markers with the disease ought to be altered by a successful therapy.

As long as you can relate your biomarker to a clinical outcome, like conversion to dementia, it is useful on a practical timescale in clinical trials. if you can only relate your biomarker to a neuropathological finding, it is going to take you a very long time to validate anything!

Imaging findings are a bit of an orphan - you can pick up volumetric changes in neuroanatomical structures early or plaque deposition but "brain shrinkage" or "brain plaque" is not a disease yet as far as the FDA is concerned. The recent hospice studies of the PET ligands have shown neuropathological evidence for the correlation of the PET image with real plaque - but plaque alone is not enough to diagnose AD....

Hope that helps.

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16. Kate Ziebell on September 5, 2012 3:23 PM writes...

I’ll complain which you have copied material from another source

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17. Joey Weadon on May 3, 2013 7:12 PM writes...

Hello.This article was really fascinating, particularly because I was investigating for thoughts on this matter last Thursday.

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