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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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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« "Taking the Ax to the Scientists Is Probably a Mistake" | Main | Information Density »

April 3, 2012

Bapineuzumab: An Alzheimer's Update

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Posted by Derek

The bapineuzumab saga has been going on for years now. (Every Alzheimer's therapy attempt either has gone on or will go on for years; it's such a slow-moving and heterogeneous disease that the clinical trials are some of the worst in the business). The results so far have not been all that encouraging, but they haven't been discouraging enough (given the state of the field) to give up on, either. Now there's another bit of data, and it's of a piece with the rest.

This Archives of Neurology paper has some results from two small 12-month patient cohorts looking at the antibody's effect on markers for Alzheimer's in the cerebrospinal fluid (CSF). (These were patients from two larger studies who agreed to be sampled for this part). And it's. . .well, you'd hope for better. Two types of tau protein (total and phosphorylated) were monitored, and while they did show an effect compared to the beginning of the study, only the phosphorylated tau was significant versus the placebo group. And what about soluble beta-amyloid? No change at all, looking over several forms (N-terminal modified, etc.)

The paper tries (in my opinion) to put a good face on these numbers, saying that the CSF phosphorylated tau levels have correlated with brain pathology in other studies, and that the amyloid levels may well reflect other clearance pathways or binding to bapineuzumab itself, and should thus be interpreted with caution. (If there had been any trend in the numbers, though, we probably wouldn't be acting so cautiously). But as the paper says, "An important question remains whether such changes in CSF biomarkers correlate with clinical benefit". That it does, and we're going to have to wait for the phase III results in order to say anything. That has been one long-running and expensive trial, for sure, and I hope that there's something worthwhile waiting at the end of it. Alzheimer's patients (and their families) really need something to give them some hope. Maybe the ApoE4 connection will help; I understand that the Phase III trials are focusing on that. But in any case, I'm hoping for a surprise, to be honest, because my expectations aren't high.

Comments (9) + TrackBacks (0) | Category: Alzheimer's Disease


COMMENTS

1. luysii on April 3, 2012 10:01 AM writes...

We ignore folk medicine at our peril. Here's a fascinating paper which actually removed plaques (in an animal model of course) using a preparation from Ayurvedic medicine. Proc. Natl. Acad. Sci. vol. 109 pp. 3199 - 3200, 3510 - 3515 '12 ]. Even more interesting is the fact that site of action of the preparation is the liver rather than the brain, obviating all sorts of problems with the blood brain barrier.

For more discussion see -- https://luysii.wordpress.com/2012/03/04/could-le-chateliers-principle-be-the-answer-to-alzheimers-disease/

Permalink to Comment

2. PPedroso on April 3, 2012 10:56 AM writes...

@1 Luysii,

that ayuverdic indirect approach is similar in concept to the bexarotene one talked about by Derek here:

http://pipeline.corante.com/archives/2012/02/13/bexarotene_for_alzheimers.php

Basically, by compromising the balance between soluble amyloid vs deposited amyloid one can get rid of the latter... It seems very well thought but it still is a long way from clinical benefits.

Permalink to Comment

3. MTK on April 3, 2012 12:32 PM writes...

All that assumes that reducing the plaque deposits is actually a good thing.

http://www.reuters.com/article/2010/05/12/us-alzheimers-idUSTRE64B4N120100512

I'm not an expert in the field, so I have no clue as to the validity of the opinions expressed in the above article.

Just putting it out there.

Permalink to Comment

4. PPedroso on April 3, 2012 12:42 PM writes...

I find it odd that no one has observed that previously since all forms of amyloid deposition, formation and dissolution have been investigated and monitored in alzheimer's subjects for the last 10 years.

Permalink to Comment

5. luysii on April 3, 2012 3:46 PM writes...

A certain degree of pessimism is appropriate. However, in 1970 when L-DOPA was first released in the US (and I was released from the USAF) I saw a few people get out of wheelchairs, and the rest markedly improved (in just a few weeks time)

There continues to be huge debates concerning the pathogenesis of the disease. Are the plaques and tangles (1) the last gasp of a dying cell, or neurite (2) a pile of spent bullets the cell or neurite has used to defend itself against the true culprit or (3) the true culprit.

If the plaques are the sand in the gears of the brain, it would not be out of the question to see rather dramatic results on getting rid of them.

Look how resilient the brain actually is. Think of the alcoholics and druggies conducting ceaseless chemical warfare on their brains for decades. Yet the brain survives and even rebounds once the assault is over.

Permalink to Comment

6. Rick Wobbe on April 3, 2012 4:19 PM writes...

#5 Luysii,
I haven't been directly involved in Alzheimer's disease research, but when you said "Are the plaques and tangles (1) the last gasp of a dying cell, or neurite (2) a pile of spent bullets the cell or neurite has used to defend itself against the true culprit or (3) the true culprit.", I must say that that is how it appears to me as an outsider. The comparison to Parkinson's seems apt. As such, is it fair to say that, unless we are incredibly lucky, current drug R&D, by its failures, is likely to tell us more about the mechanism of the disease than about the types of chemotherapy that will treat it?

Permalink to Comment

7. Michael Gold, MD on April 3, 2012 10:24 PM writes...

I would agree with the comment that "a good face" has been put on these data.

One can posit several explanations for the lack of any effect on beta-amyloid, the most parsimonious one being that the treatment had no effect, rather than convoluted hypotheses about alternative routes of clearance, oligomerization or re-establishment of equilibrium in the CSF. A lack of effect would be consistent with the data from 201 study where no dose-response relationship was identified.

From a technical perspective one has to wonder if the method of analysis (ANCOVA) is appropriate given the small sample sizes. In addition, one has to wonder how the results would look if the subject with the nearly 800 pg/mL change at week 54 were excluded from the analysis as an outlier. If a subject had that dramatic a change in their tau levels, it would be reasonable to expect that there would be a noticeable clinical correlate, but unfortunately, those data are not provided.

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8. Morten G on April 4, 2012 6:11 AM writes...

What exactly were you expecting? Why would soluble amyloid beta decrease if the plaques is being removed? Reduced levels of phosphorylated tau is one of the things I would expect if it actually was working so this is very encouraging IMO. Pfizer may survive after all (despair!).

Permalink to Comment

9. ed martinez on July 10, 2012 1:53 PM writes...

Are you aware of any clinical trial being done related to calcium transport or calcium channel blockers in the treatment of Alzheimer's? Zalicus has one or two for anti inflammatory pain killers. Since inflammation is common to pain and A.D. I wonder why not both?

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