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Amylyx And ALS: Muddied Results

Apr. 03, 2022 5:58 AM ETAmylyx Pharmaceuticals, Inc. (AMLX)25 Comments
Lane Simonian profile picture
Lane Simonian


  • Problems with the trial design make it difficult to determine the effectiveness of Amylyx's AMX0035 against ALS.
  • AMX0035 combines two compounds - sodium phenylbutyrate and tauroursodeoxycholic acid - that inhibit and scavenge peroxynitrite. This may be the key to the treatment of several neurological diseases.
  • Compounds that are better inhibitors and scavengers may produce better results than AMX0035.
  • The FDA will likely follow their advisory board's recommendation not to approve AMX0035 based on one trial.
  • Amylyx's stock would then drop further. Phase 3 clinical trial results for ALS (and perhaps eventually for Alzheimer's disease) will likely determine the fate of the company.

Neuron system disease

koto_feja/iStock via Getty Images

Oxidative stress mediated by nitric oxide (NO) and its toxic metabolite peroxynitrite has previously been associated with motor neuron degeneration in amyotrophic lateral sclerosis (ALS)… Motor neuron death was largely prevented by NOS inhibitors and peroxynitrite scavengers but not by

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 stock, option or similar derivative position in any of the companies mentioned, and no plans to initiate any such 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 (25)

gjackoh profile picture
@Lane Simonian Do you have any perspective on the Canadian approval of AMX0035? It would seem to add some pressure on the US FDA to approve but maybe it would harden FDA’S position. I haven’t observed Canada leading the US in approving a drug. Better ALS lobbying in Canada? Any precedents you are aware of? Thx
Lane Simonian profile picture
@gjackoh I apologize, I was travelling much of June and forgot to come back here after that. It looks likely now that the FDA will grant accelerated approval to AMX0035.

gjackoh profile picture
@Lane Simonian Thanks. Appreciate your reply. The FDA would have a hard time rejecting the drug after the advisory committee vote. I certainly hope the Phase 3 trial is successful. But investors need to remain conscious that even if approved, there is a non-zero risk of the Phase 3 trial failing and manage their risk.
Lane Simonian profile picture
@gjackoh This is very sage advice.

Thank you for patiently waiting for my reply.
@Lane Simonian what are your thoughts on today's FDA extension?

Amylyx Pharmaceuticals Receives Notification Of PDUFA Date Extension For AMX0035 For Treatment Of ALS; New PDUFA Goal Date Scheduled For September 29, 2022 To Allow Time To Review Additional Data
Lane Simonian profile picture
@Poophands I am not sure what to make of it. I suppose that the FDA needing more time to look at additional data could be taken as a positive depending on what that data is and how the FDA interprets it.
"I want to reemphasize that the combination of inducible nitric oxide synthase inhibitors (inducible nitric oxide combines with superoxide anions to form peroxynitrite) and peroxynitrite scavengers is likely the key to treating a series of neurological diseases including ALS, Alzheimer's disease, multiple sclerosis, Huntington's disease, Rett syndrome and other autism spectrum disorders, and Parkinson's disease (peroxynitrite in neurological diseases)."

Interesting statement under an article describing that such a candidate is about to fail. The author should make clear that this is his humble opinion or give the laboratory/clinical data he produced in his research. I am generally a bit sceptical regarding the author's statements since I could not find any entry in the Pubmed scientific literature database covering data generated in the field by this "Alzheimer's disease researcher for the past decade".
Lane Simonian profile picture
I have been reading studies on Alzheimer's disease for nearly twenty years now. My understanding of other neurodegenerative diseases is much more limited but I do know some of the similarities and differences between them.

Not coincidentally, the current treatments for ALS--riluzole and edaravone-are in the same mold as AMX0035. Riluzole inhibits the activation of Protein kinase C which limits the formation of peroxynitrite and edaravaone is a peroxynitrite scavenger. Of the two, edaravone seems to have a little more impact on ALS when given early.

Amylyx says that its drug candidate produces benefits independent of riluzole and edaravone, but the question is to what degree AMX0035 outperforms the other two drugs. Since edaravone is likely a better peroxynitrite scavenger in the context of ALS, I would not expect the added impact of AMX0035 to be great.

For Alzheimer's disease, the removal of Protein kinase C and/or the removal of inducible nitric oxide synthase largely cures an Alzheimer's-like disease in mice.



But such an approach is not an option for human beings in part because the pathology is more complicated than in mice and in part because one cannot "extract" Protein kinase C and inducible nitric oxide synthase without harmful consequences.

Find the best compounds for inhibiting the formation of peroxynitrite, removing it, and reversing part of its damage, and you can at least significantly slow down the progression of various neurodegenerative diseases. This works better early in diseases when the damage done is still fairly limited. In the case of Alzheimer's disease, four treatments applying this approach have lead to initial improvements in cognition that have been largely sustained for long periods of time: Trappsol Cyclo (case study), aromatherapy (case studies including my mother), panax ginseng (open label clinical trial), and Anavex's blarcamesine (open label clinical trials to date). The same treatments may help slow down the progression of other neurological diseases as well.
Amyotrophic Lateral Sclerosis (ALS) (Lou Gehrig's disease) is a neurodegenerative disorder characterized by the death of motoneurons (MNs) with a poor prognosis. There is no available cure, thus, novel therapeutic targets are urgently needed. Sigma-1 receptor (Sig-1R) has been reported as a target to treat experimental models of degenerative diseases and, importantly, mutations in the Sig-1R gene cause several types of motoneuron disease (MND).


Anavex's Blarcamesine, Anavex 2-73 and/or Anavex 3-71 are both potent Sigma-1 receptor (Sig-1R) agonists.

Good luck and GOD bless,
NDHT profile picture
Good to read.

There is a key discrepancy on the percentage of patients on placebo, who took the marketed drugs for ALS between this author and another here at SA.

Not sure who is right. However, it is my understanding that these drugs don't do much anyway, maybe it is a mute point regarding their impact on the results of AMX0035.

The author,

"...14 out of the 89 people in the treatment group were on the ALS medications riluzole or edaravone whereas only two out of 48 in the placebo group were on these drugs."

Another author, Avisol in an article of March 29:

"...possibility of bias because a much higher proportion of placebo patients took edaravone or riluzole even during the trial."
Lane Simonian profile picture
@NDHT The following is an important correction on my part.

Here is the information from the FDA document:

"Another point of concern is the higher proportion of patients starting
edaravone or riluzole post-baseline in the drug arm (14/89 [15.7%] ITT)
compared to the placebo arm (2/48 [ 4.2%] ITT)."

The numbers at baseline are contained in the following link:


The percentage of individuals taking both edaravone and riluzole was higher in the placebo group at baseline.

Amylyx has recently contacted me in regards to changing this information as follows:

"As shown in Table 1 (below) published in The New England Journal of Medicine, while more placebo participants were taking other ALS drugs at baseline, more participants receiving AMX0035 vs. placebo (13% vs. 4%) initiated one of the other ALS drugs during the study."
NDHT profile picture
@Lane Simonian Thanks!

So, the difference may be evened out over the six months, which may not have much an impact on the results, even though the patients on the treatment arm may be on the approved drugs for a shorter period of time than those who were on the placebo, more or less.

A "non issue", would you say?
Lane Simonian profile picture
@NDHT I would say it is likely a non-issue, too.
Lane as you know there are commonalities between many neurological diseases. There are also many differences! Please stop exporting your oxidation theory to ALS! For your information ALS is likely to be a group of diseases currently with only 1 name as the specific cause is not yet known. However there are genetic causes that are known and yet most are suffering with a non-genetic (or at least not yet identified) cause. Disease progression is distinctly different for each group and has the common feature of muscle faciculation (involuntary twitch).
These are all in contrast to the progression of ALZ, and do have a different pathway (possibly some shared features).
Do us all a favour and start any piece stating it is your hypothesis. As nothing is yet proven even insilico let alone invitro/vivo.
Oi Lane, What do you think of Longeveron Inc.?
Lane Simonian profile picture
Longeveron is trying to treat Alzheimer's disease (and other "aging" conditions) by "infusing" medical signaling cells taken from the bone marrow of young, healthy donors into older, unhealthy individuals. One idea is that this would combat neuroinflammation.

I am not sure exactly how these signaling cells work, but the use of growth/trophic factors have not been successful in the treatment of neurodegenerative diseases because the pathway through which these growth factor signal is inhibited or blocked in various neurodegenerative diseases.
@Lane Simonian thank you.
Happy Investor profile picture
Awesome article Lane! Thank you.

You said "...phase 3 clinical trials rarely if ever produce outcomes that are better than those from phase 2 clinical trials." Would you care to explain why this is the case? With increased N in P3, the results should be more stat sig than those from P2 if everything else is the same? /is it fair to say P2 is like a mini P3?
Lane Simonian profile picture
Thank you.

My explanation is that the numbers in phase two clinical trials are sometimes insufficient to pick up on relatively rare side effects or are too short in duration to track decline over time. The problem of outliers can sometimes skew results as well in phase 2 clinical trial.

This article provides some additional explanations for why phase 3 clinical trials often produce poorer results than phase 2 clinical trials (some of which I had not considered before).


The article suggests that less than 50% of drug candidates at the phase 2 level succeed at the phase 3 level. This is higher than I would have expected, but maybe that is a reflection that I mainly follow trial results involving Alzheimer's disease.
Happy Investor profile picture
Thank you so much Lane! Really appreciated 🙏
Gordon Gecko was a Commie profile picture
@Lane Simonian this is a nice paper, but I would suggest that there is a big difference between drug trials for cardiovascular disease (where we know A LOT) about the true root causes of the disease vs. many neurological diseases (where for the most part, we simply do not know what the root causes of the diseases are). So from my reading, it sure seems that most drugs fail for neurological diseases because they fail to show efficacy. But that is not the true reason for failure--it is because we do not know the underlying biological mechanisms of the disease very well. Let us hope that some of the trials testing novel hypothesis can help shed light on these diseases in coming years.
Hi Lane. I own shares in the French company AB Science. This company has drug against ALS in its pipeline. In fact it's on the brink of possible FDA approval. Matter of fact its been approved by the Canadian Health authority. What's your take on this?
Lane Simonian profile picture
I know of AB Science from its work on Alzheimer's disease, but the principle is the same for ALS.

AB Science's drug candidate masitinib is a selective receptor tyrosine kinase inhibitor and tyrosine kinase over-activation can play a role in both Alzheimer's disease and ALS. For ALS, masitinib does appear to slow down the progression of the disease, and to increase survival when given early.


Masitinib has had some safety issues in regards to ischemic heart problems (coronary heart disease) in the past.


It is hard to predict how the FDA will deal with all the data for masitinib.
@Lane Simonian Thanks very much Lane for your reply. Re the ischemic heart problems, I believe that they had cleared the issue with all the relevant health authorities such as FDA and EMA.
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