About this Author
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

Chemistry and Drug Data: Drugbank
Chempedia Lab
Synthetic Pages
Organic Chemistry Portal
Not Voodoo

Chemistry and Pharma Blogs:
Org Prep Daily
The Haystack
A New Merck, Reviewed
Liberal Arts Chemistry
Electron Pusher
All Things Metathesis
C&E News Blogs
Chemiotics II
Chemical Space
Noel O'Blog
In Vivo Blog
Terra Sigilatta
BBSRC/Douglas Kell
Realizations in Biostatistics
ChemSpider Blog
Organic Chem - Education & Industry
Pharma Strategy Blog
No Name No Slogan
Practical Fragments
The Curious Wavefunction
Natural Product Man
Fragment Literature
Chemistry World Blog
Synthetic Nature
Chemistry Blog
Synthesizing Ideas
Eye on FDA
Chemical Forums
Symyx Blog
Sceptical Chymist
Lamentations on Chemistry
Computational Organic Chemistry
Mining Drugs
Henry Rzepa

Science Blogs and News:
Bad Science
The Loom
Uncertain Principles
Fierce Biotech
Blogs for Industry
Omics! Omics!
Young Female Scientist
Notional Slurry
Nobel Intent
SciTech Daily
Science Blog
Gene Expression (I)
Gene Expression (II)
Adventures in Ethics and Science
Transterrestrial Musings
Slashdot Science
Cosmic Variance
Biology News Net

Medical Blogs
DB's Medical Rants
Science-Based Medicine
Respectful Insolence
Diabetes Mine

Economics and Business
Marginal Revolution
The Volokh Conspiracy
Knowledge Problem

Politics / Current Events
Virginia Postrel
Belmont Club
Mickey Kaus

Belles Lettres
Uncouth Reflections
Arts and Letters Daily
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

« Broader Impacts Indeed | Main | Precious Metal Time »

July 26, 2011

Alzheimer's: The News Is Not Getting Better

Email This Entry

Posted by Derek

Is there something going on with patients in Alzheimer's trials that we didn't expect? There have been reports of an unexpected side effect (vasogenic edema) in several trials, for drugs that work through completely different mechanisms.

It makes some sense in the case of antibody-based therapies like bapineuzumab (where this problem first got attention) and solanezumab. After all, the immune system is pretty powerful stuff, and you could certainly imagine these sorts of side effects (either directly or from some effect of clearing out amyloid debris). As those reports indicate, the problem may lessen with time, and may be more severe in patients with the APOE4 allele, a known (but not understood) risk factor for Alzheimer's.

But this latest report is for the Bristol-Myers Squibb gamma-secretase inhibitor avagacestat (BMS-708163). That shouldn't be involved with any inflammatory/immune mechanisms, nor, really, with amyloid clearance. A secretase inhibitor should just keep new amyloid from being formed and deposited, which should be beneficial if the beta-amyloid theory of Alzheimer's is correct, which is what we're all still in the middle of deciding these days. Expensively and excruciatingly deciding.

Meanwhile, the most recent big clinical failure in this area continues to reverberate. Lilly's gamma-secretase inhibitor semagacestat, the first that went deep into the clinic, imploded when the company found that patients in the treatment group were deteriorating faster than those in the control group. Seven months on, they're still worse. What does this mean for the BMS compound targeting the same mechanism? That is the big, important, unanswerable question - well, unanswerable except by taking the thing deep into big clinical trials, which is what BMS is still committed to doing.

For more on Alzheimer's drug development - and it hasn't been pretty - scroll back in this category.

Comments (21) + TrackBacks (0) | Category: Alzheimer's Disease | Toxicology


1. PharmaHeretic on July 26, 2011 8:22 AM writes...

Given that vasculature is the second most likely place for b-amyloid deposition, disruption of plaque deposits in it could result in a paradoxical increase in the concentration of soluble b-amyloid oligomers. Such an increase would then cause localized inflammation and cell damage as soluble oligomers have pro-inflammatory and mildly cytotoxic effects.

Permalink to Comment

2. johnnyboy on July 26, 2011 9:03 AM writes...

This is all a bit far back in time (and my memory fails), but I remember preclinical issues with a gamma secretase inhibitor in development at my previous place of employment. The lead had serious effects on the immune system (lymphoid) - can't remember if the team concluded as to whether it was mechanism or chemotype based. The body works in mysterious ways...

Permalink to Comment

3. Phil Stracchino on July 26, 2011 10:48 AM writes...

Is it just me, or do the functional names of a lot of these new drugs sound like mediaeval names of imaginary demons? Solanezumab, bapineuzumab, beelzebub.....

Permalink to Comment

4. DT on July 26, 2011 10:53 AM writes...

Gamma secretase inhibitors have been used as a therapy for T cell acute lymphoblastic leukemia due to their ability to shut down the Notch signaling pathway, which is often activated in T ALL through the generation of a transcriptionally active fragment of Notch by gamma secretase. Since Notch is important for T cell development, I wonder if GSI side effects here have something to do with Notch signaling and not with amyloid cleavage.

Permalink to Comment

5. roym on July 26, 2011 11:08 AM writes...

Unless im very much mistaken, gamma secretase is a huge target to aim for. no reason just yet for other inhibitors to be thrown in the bin

Permalink to Comment

6. pete on July 26, 2011 11:17 AM writes...

@4 DT
Absolutely. Notch does have demonstrated roles in blood vascular integrity. And then again, gamma secretases are busy little enzymes and adverse events seen in Lilly's clinical trials could arise from affecting molecules other than amyloid or Notch.

Permalink to Comment

7. Anonymous on July 26, 2011 5:17 PM writes...

My understanding is that Avid Radiopharma and others have PET imaging F19 ligands that specifically target beta-amyloid that look very promising and are very close to FDA approval. Perhaps that technology should be combined with current therapies as a diagnostic and to monitor disease progression. This is a very interesting development...

Permalink to Comment

8. Rick on July 26, 2011 8:58 PM writes...

Hard to say what's up with the side effects profile, but I'd say the clinical trial results for gamma secretase inhibitors are pretty much exactly in line with what many of us expected long before these inhibitors got into the clinic: inhibiting gamma secretase could well be "shutting the barn door after the horse already got out". These results prove it. It was a hypothesis worth testing, but it's clearly dead wrong and we should move on.

Permalink to Comment

9. matt on July 27, 2011 3:44 AM writes...


So who let the horses out, in your opinion? You say, "Nay, nay." (Sorry, couldn't resist.) What's your hypothesis? Is your money on the tau horse?

Permalink to Comment

10. Rick on July 27, 2011 6:30 AM writes...

No person, unless you count Mother Nature as a person, let the horses out. With so few experimental tools to dissect the metabolic and physiological processes that eventually give rise to the disease we call Alzheimer's, it's been hard to sort out the causes from the effects. As a result, drug trials remain the only way to test hypotheses.

A lot of people have thought that plaque production coincides with, but does not lead to, onset of Alzheimer's symptoms. As such, blocking the plaque-making pathways might yield nicer looking histology and MRIs, but the cognitive problems will continue to progress because you didn't block the pathway leading to them. (i.e. lock the barn door early enough) Nonetheless, I think gamma secretase was a good hypothesis because at least it was testable, albeit only in drug trials. That doesn't mean the trial was a waste of time or that the scientists who come up with these hypotheses are stupid or misguided. They're doing the only thing you can do in an experimental science : experiments.

I think there are sufficiently good reasons to test the tau hypothesis in drug trials, even though there's genetic evidence that it too is downstream of the actual molecular trigger, in which case we'll see results similar to the semagacestat trial. But nature is completely indifferent to what I, or "thought leaders", or even (gasp) biotech stock analysts think, so we must do the trial.

If I had to bet, I'd bet tau is a loser, but it's a bet we have to make if we want to learn about this still-mysterious disease. I'd be delighted to lose the bet.

Permalink to Comment

11. bmartinmd on July 27, 2011 9:28 AM writes...

Derek, your point about gamma secretase inhibitors not clearing amyloid, per se, is well taken. My (and others') fallback explanation for the development of vasogenic edema with anti-amyloid mAbs is that they clear brain amyloid in total--meaning not just sheeted amyloid, but amyloid associated with cerebral vessels. And this latter type of amyloid clearing makes the vessels leaky, thus causing brain edema.

But GSIs don't clear, or at least are not intended to clear, amyloid, as you write; they prevent amyloid formation. So why then would GSIs be associated with brain edema? It may be, to make my explanation fit, that preventing amyloid deposition (around cerebral vessels) is akin to removing it--given that amyloid deposition is probably a dynamic, with a naturally continual process of deposition and removal. In the case of aging or Alzheimer's, for instance, deposition overwhelms removal, which may ramp up the amyloid-removal process (albeit fruitlessly). But when you throw in a GSI, perhaps the naturally ramped-up removal (with artificially blocked production) allows the clearing of vessel-associated amyloid in some cases, thus causing brain edema. Who knows? I certainly don't, but I'm sticking with the removal-of-vessel-amyloid theory as an explanation for brain edema until I hear something better--or at least more erudite.

And to Anonymous: Lilly has been using the PET amyloid tracer, florbetapir, to monitor amyloid clearance with its investigational anti-amyloid compounds. Moreover Lilly bought Avid Pharmaceuticals for the purpose of acquiring florbetapir, which is in sort of an approval limbo.

Permalink to Comment

12. johnnyboy on July 27, 2011 11:44 AM writes...

@11: vasogenic edema is due to passage of blood proteins (and associated fluid) through the blood-brain barrier. The BBB's first line is the endothelial cells and the tight junctions joining them, which effectively seal the inside of the vessel. Your hypothesis of GSIs being causal of the vasogenic edema would require that vessel-associated amyloid deposits would have both replaced the tight junctions, AND taken on their functional role of sealing the vessel wall (so that amyloid removal would lead to vessel leakage). Both of these suppositions seem extremely far-fetched to me.

A more plausible explanation would be that vasogenic edema, if it is really linked to the GSIs, is due to a drug or metabolite-induced dysfunction of the fluid-regulation functions of endothelial cells or of the glial cells that wrap the outside of all brain vessels.

Permalink to Comment

13. Anonymous on July 27, 2011 8:53 PM writes...

beta-amyloid theory of Alzheimer's is not correct.

Permalink to Comment

14. bmartinmd on July 28, 2011 3:13 PM writes...

The removal of vessel amyloid as an explanation of vasogenic edema with anti-amyloid drugs is simplistic perhaps. Nevertheless the idea that vessel-associated amyloid disrupts the integrity of the vascular wall is neither a new idea nor is it far-fetched--as in the case, for example, of cerebral amyloid angiopathy ( Therefore it seems probable, in fact, that the removal vessel-associated amyloid, at least in advanced cases, would lead to vascular edema.

Permalink to Comment

15. Angela on July 29, 2011 8:11 AM writes...

Although there is significant evidence of inflammatory processes being involved in the pathogenesis of AD (yes, some clinical trials were disappointing) it appears that there is not enough focus on these processes as potential treatment targets. Perhaps, more emphasis should be placed on them?

Permalink to Comment

16. Jay on July 29, 2011 10:26 AM writes...

Stumbled upon this page, and just wanted to say how encouraged and awestruck I am to see the comment section. It's all over my head, but so very glad to see people passionately trying to solve this problem so openly. Godspeed!

Permalink to Comment

17. PacRim Jim on July 29, 2011 11:22 AM writes...

Obviously we humans are dosing in the dark. We only have an inkling of how the human mind works, and until we understand the human body as a complex system of systems, we will be helpless.

Permalink to Comment

18. JCP on July 29, 2011 2:50 PM writes...

Could someone give an opinion on why this wasn't detected during animal trials?

Permalink to Comment

19. scythe on July 29, 2011 4:34 PM writes...

Possibly because the animals in the trials had human-induced alzheimer's, not natural alzheimer's, at least to my knowledge. When we induce alzheimer's in a creature, we use our current theory -- beta-amyloid plaque buildup -- and basically do whatever causes beta-amyloid plaques to form. However, if this theory turns out to be wrong, we haven't actually given the animals Alzheimer's, we've given them some other disease that looks like Alzheimer's but isn't, and this other disease is going to act differently in response to a certain drug.

Permalink to Comment

20. srp on July 29, 2011 9:13 PM writes...

Could the amyloids be a damage-control response of the body, so inhibiting them makes things worse? Like trying to block ambulances to reduce car-crashes?

Permalink to Comment

21. Otis Blanchard on August 3, 2011 11:03 AM writes...

IL-1beta, IL-6, IL-16, as triggered by the immune system activate mTOR which reduced recycling of Beta-amyloids & Tau proteins.

The most recent research out of Indiana, I believe. It shows that production of BA's don't increase in Alzheimer's. It goes down slightly, but recycling goes down 30%. Accounts for Tau, BA, and the Apoptosis as well as inflammation, that will go up with an increase in misfolded proteins making it worse. Add AB, which will increase inflammation you have a positive feedback loop.

However, the new data would lead to new grants. What to do with your old RO1? Better get it renewed than do something useful in this grant environment. And as long as the AB therapies support the stock prices, why change the pipeline?

Scythe is dead on the mark.

Permalink to Comment


Remember Me?


Email this entry to:

Your email address:

Message (optional):

The Last Post
The GSK Layoffs Continue, By Proxy
The Move is Nigh
Another Alzheimer's IPO
Cutbacks at C&E News
Sanofi Pays to Get Back Into Oncology
An Irresponsible Statement About Curing Cancer
Oliver Sacks on Turning Back to Chemistry