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Roche, Biogen, And The Achilles' Heel Of Alzheimer's Drug Development

Feb. 04, 2019 2:51 PM ETBIIB, RHHBY8 Comments
Lane Simonian profile picture
Lane Simonian


  • Amyloid oligomers are only one of many contributors to Alzheimer's disease, so removing them does not help much even early in the disease.
  • Large pharmaceutical companies with diverse pipeline seem to be weathering Alzheimer's drug failures relatively well.
  • Biogen may be the exception in that it has consistently raised expectations that its anti-amyloid drugs will work.

Roche (OTCQX:RHHBY) recently announced that it has ended its phase three clinical trial for its anti-amyloid drug crenezumab because of a strong chance of futility. This result was, in essence, a double blow to the amyloid hypothesis of Alzheimer's disease as the drug targeted what is supposed to be the toxic form of amyloid (i.e. amyloid oligomers) and because it targeted those with early Alzheimer's disease when anti-amyloid drugs are conjectured to still be effective (before "it becomes too late").

The ironic aspect of this is that those trying to move the goalposts on anti-amyloid treatments may be partially right and yet still be wrong regarding the big picture. Amyloid oligomers are likely toxic because they bind copper and zinc. Zinc via its activation of a g protein-coupled receptor produces oxidative stress (zinc and Alzheimer's disease). Copper for its part contributes to the formation of the nitro-oxidant peroxynitrite early in Alzheimer's disease (copper and peroxynitrite).

Copper and zinc also participate in activating an enzyme (superoxide dismutase) that converts superoxide anions into hydrogen peroxide - an oxidant which contributes to the death of neurons. Amyloid plaques by entombing copper and zinc eliminate this particular route to brain damage. In essence, amyloid plaques are an effort by the brain to protect itself against metal ion induced toxicity (amyloid and hydrogen peroxide).

However, once superoxide anions cannot be converted into hydrogen peroxide, they combine with nitric oxide to produce peroxynitrite which causes brain damage as well.

So antibodies against amyloid oligomers should be more effective than antibodies against amyloid plaques. But the problem is that amyloid oligomers are one of several triggers that produce oxidative stress in the brain. It is the other triggers (high blood pressure due to high sodium levels, high glucose levels, air pollutants, pesticides, psychological stress, chronic bacterial, viral, and fungal infections along with many others) that usually lead to

This article was written by

Lane Simonian profile picture
Retired history instructor. Alzheimer's disease researcher for the past decade.My goal is to give investors solid advice based on the mechanisms of action of Alzheimer's drugs.  This advice is informed by  a background in biology (conservation, ecology, evolution, environmental science, and biochemistry) and seventeen years of a very in depth review of the research on Alzheimer's disease.

Analyst’s Disclosure: I/we have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

Seeking Alpha's Disclosure: Past performance is no guarantee of future results. No recommendation or advice is being given as to whether any investment is suitable for a particular investor. Any views or opinions expressed above may not reflect those of Seeking Alpha as a whole. Seeking Alpha is not a licensed securities dealer, broker or US investment adviser or investment bank. Our analysts are third party authors that include both professional investors and individual investors who may not be licensed or certified by any institute or regulatory body.

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Comments (8)

rt94103 profile picture
This is a nice overview of the current microbe based AD science:


"AFTER decades of disappointment, we may have a new lead on fighting Alzheimer’s disease. Compelling evidence that the condition is caused by a bacterium involved in gum disease could prove a game-changer in tackling one of medicine’s biggest mysteries, and lead to effective treatments or even a vaccine."
Lane Simonian profile picture
I have read only a little bit about the work of Brain Chemistry Labs. Their work primarily focuses on the role of the neurotoxin beta-n-methyl-amino-l-alanine (BMAA) which is produced by a cyanobacteria and can be found in various aquatic organisms (oysters, mussels, sharks, etc.) and plants (such as cycads in Guam). It is one of several neurotoxins that can contribute to Alzheimer's and other neurodegenerative diseases.


The mechanism for BMAA toxicity appears to be the following:

"We show that the mechanism of BMAA toxicity is threefold: it is an agonist for NMDA and mGluR5 receptors, and induces oxidative stress. The results provide further support for the hypothesis that BMAA plays a role in neurodegenerative diseases."


Brain Chemistry Labs is looking at L-serine as a possible treatment for Alzheimer's disease and Amyotrophic Lateral Sclerosis (ALS).


The "lab" avers that L-serine blocks "the misincorporation of BMAA in neuroproteins." L-serine then would seem to protect against one of the many causes of Alzheimer's disease. L-serine also seems to have antioxidant effects, but perhaps through a pathway that is largely blocked in Alzheimer's disease (the phosphatidyinositol 3-kinase/Akt pathway). So its larger application outside of people affected by BMAA toxicity may be limited.

Lane, have you tracked the progress of the nonprofit group "Brain Chemistry Labs" and their progress regarding AD? I believe they have a phase 2 trial out. Since, at this time, it seems Anavex might be the leading future treatment for AD, how do the results of Brain Chemistry Labs compare and who might get to market first if they both work? Thanks for the great analysis and I look forward to your response.
MickeyD77 profile picture
Thank you, Lane. Your synopsis on this subject is always very helpful.
We sure do need something to work as we all age.
Lane Simonian profile picture
I remain relatively optimistic that Anavex 2-73 will be an effective treatment for Alzheimer's disease. The drug appears to help stabilize cognition and activities of daily living in patients with mild Alzheimer's disease for at least two years (the caveat being the small number of people taking the drug).

Anavex 2-73 limits oxidative damage to the brain by inhibiting the release of intracellular calcium, may act as a direct anti-oxidant, and may increase the efficacy of other antioxidants.


www.ncbi.nlm.nih.gov/... (Anavex 2-73 is a tetrahydrofuran derivative; electron and hydrogen donation are a key to antioxidant activity).

what about avxl AD drug?
Lane Simonian profile picture
The potential problem for Biogen is the degree to which its drugs slow down the progression of Alzheimer's disease. If the BAN2401 numbers don't change significantly (a seven percent decrease in progression in those with early Alzheimer's disease in non-ApoE4 carriers) and the aducanumab numbers are similar, then the FDA is not likely to approve these drugs for the treatment of Alzheimer's disease in non-ApoE4 carriers. If the better numbers for ApoE4 carriers are confirmed, then the regulatory question is whether you approve drugs that may substantially slow down the progression of Alzheimer's disease, but which may also lead to serious side effects for ApoE4 carriers.
Biib has never passed its drug off as a cure or a reversal of the disease. It is designed to slow progression and if approved will be the first drug of its kind in the field. The stock will not drop it will move well north of the current pps.
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