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Cortexyme: Positive Lessons To Be Learned From Disappointing Results

Lane Simonian profile picture
Lane Simonian


  • Cortexyme's Alzheimer's drug candidate atuzaginstat appears to help those in the early stages of the disease who have an active P. gingivalis infection.
  • Some antibiotics that act as direct antioxidants may slow down cognitive decline in anyone with Alzheimer's disease at any stage.
  • Strong scavengers of the nitro-oxidant peroxynitrite have largely stabilized Alzheimer's disease, often over long periods of time.
  • Trappsol Cyclo and Anavex 2-73 (blarcamesine) are most likely strong peroxynitrite scavengers and therefore Cyclo Therapeutics and Anavex are best posed to deliver effective treatments for Alzheimer's disease.

MRI Brain Scan of head and skull with hand pointing

haydenbird/E+ via Getty Images

Cortexyme (CRTX) recently announced that it failed to meet its primary endpoints for cognition and activities of daily living for its Alzheimer’s drug candidate, atuzaginstat. However in those with detectable levels of P. gingivalis, there was a 57 percent slower decline

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 (38)

Ventureshadow profile picture
The 2004 anecdote from Joy K. describes relief of delirium not dementia. The two can occur together. The anecdote is too incomplete to know if dementia was also present, and the improvement described does not indicate the absence of dementia. Dementia severity changes over months and years not hours. Delirium severity can change over minutes or days. Delirium can often be treated, but the diagnosis is often missed.
HyperbolicSTONK profile picture
SAVA is on top in this race IMO. Still heavy and bullish on SAVA after recent run up. Short interest has actually increased… I think we see 100+ soon. However, I have been buying CRTX on these lows. After the drop it can benefit from other AD stocks doing well - or perhaps come up with an additional catalyst on their own.
I wrote an update article on why I bought the dip in CRTX

Thanks Lane
Another great article based on fact.
Lane, do you think cyth is on yo something with what they are doing and has a good chance at with a combination of another slowing down the progression of Alzheimer's?
Lane Simonian profile picture
I do believe cyth is on to something. In theory, if you combine drugs with similar mechanisms of action (such as those being studied by Cyclo therapeutics and Anavex) the results should be better, but whether this is actually the case is uncertain.

This is the general goal:

The inflammatory mediator peroxynitrite, when generated in excess, may damage cells by oxidizing and nitrating cellular components. Defense against this reactive species may be at the level of prevention of the formation of peroxynitrite, at the level of interception, or at the level of repair of damage caused by peroxynitrite...


The more that you accomplish this, the more that you likely slow down the progression of Alzheimer's disease.
@Lane Simonian I am invested in cyth because I believe in them. Mainly because I have a sick family member and as I did some research I think they have the best shot at helping them. It seems like they are still well under the radar. Would you consider writing or researching an article in them to help them gain some traction? I think the world needs to know what they do. I just want to find a cure (slow down the progression) I know marketwatchtrends has some significant information that may help (he commented here) and maybe you two could team up on an informative post? Thanks for all you do and consideration. Let's slow down this awful disease!!
Lane Simonian profile picture
It is important to keep relentlessly seeking answers to this devastating disease for our family members and for ourselves. I will keep doing research on the most promising treatments. The mice studies provided by MarketWatchTrends are certainly helpful and promising even when considering the limitations of mice studies. I am somewhat at the mercy of when additional studies and news become available, but I try very hard not to miss anything. I look forward to writing more about cyclo therapeutics in the hopefully near future.
MarketWatchTrends profile picture
Thanks for another great article Lane. Very informative.

The Cyclodextrin Alzheimer's mouse data is simply unparalleled.

- HP-β-CD reduced cell membrane cholesterol and amyloid-β production in a cell model overexpressing APP

- HP-β-CD improved learning and memory in Tg19959 mice

- HP-β-CD significantly reduced Aβ plaque load and microgliosis in Tg19959 mice

- HP-β-CD decreased Aβ production and amyloidogenic processing of APP in Tg19959 mice

- HP-β-CD reduced tau pathology in the brains of Tg19959 mice

- HP-β-CD corrected lysosomal abnormalities in the brains of Tg19959 mice

- HP-β-CD treatment up-regulates genes involved in cholesterol trafficking

$CYTH's drug is a HPBCD formulation. Cyclo Therapeutics is submitting its Phase 2B IND application to FDA between now and end of the year. Should get started with Phase 2B Alzheimer's trials within the next few months. Keep an eye on it.
smikhail profile picture
Mouse data? LMFAO.
MarketWatchTrends profile picture
@smikhail That's what companies base their IND applications to FDA on. What's so funny. No one enters clinical trials with real human data,
A very helpful summary of What We Have Learned. Thank you.
Cyth will be last man standing imho. Under the radar and on the verge of ind application for AD. Should go straight to phase 2. Proven safe. Stars will align for this emerging wall street CEO run company. Mark it. The more I research the more there is to like. More insider buys today.
@Solistocks What does CYTH have to do with alzheimer's ? Nothing.
@dixie haha. Get ready. NPC is considered baby Alzheimer's. They will submit IND application this year and FDA will respond within 30 days. There medication is crossing the blood brain barrier so do a little research. U mite like what you see. Hidden gem.

Now why would a company that has nothing to do with Alzheimer's do this?

Cyclo Therapeutics Names Preeminent Neuroscientist and World-Renowned Researcher, Cynthia A. Lemere, PhD, as Senior Advisor for Advancement of Alzheimer's Disease Asset
HyperbolicSTONK profile picture
SAVA is my pony in this race. But I just added CRTX on the low. Recently entered AVXL as well. GL to all.
@HyperbolicSTONK check out cyth. Most upside potential.
Yes, the news is that infectious disease can cause alzheimer's. And yes, it makes sense that it might be other things as well, but the CRTX trial suggests 40%+ is p. gingivalis accelerated or caused, so it's one of the major guilty parties. Others have considered other bacteria, as well as HSV-1, and yes, fungii. Now that we know that AB is a microbial stress response, it all makes sense.

You reference that Doxycline could be helping chemically, or could be purging bacteria - it is one of the few that is supposed to be pretty effective on PG, so maybe it's both. Will be resistance issues on that over time though as it's broad spectrum, at least on the bacterial side.

I do think treating underlying chronic infections is going to be better when they can be precision targeted. Less collateral effects on metabolism, and in many cases, these infections may be screwing up other unknown things and damaging health.

As for CRTX itself, couple things:
1) The liver issues are only substantially concerning with the 2 patients that also had bilirubin elevations along with the liver issues. The others apparently weren't so bad, and without the bilirubin, less concerning. The company has said they think this is PG clearance releated - that the PG is being destroyed and releasing endotoxin. That suggests broad systemic infection, and you really should want to clear that out. If true, it's going to be worth it, and it's also going to be titratable. The fact peolpe had peaks of liver enzymes at 6 weeks, then saw them go down after that, is consistent with this hypothesis. And, other antiobiotics would have the same issue if so, even if bacteriostatic (CRTX's drug is a slow kill by causing gradual starvation).

2) Their trial showed 37% of their patients had PG in saliva. They probably had some false negatives (method they used would not have many false positives). That's is not a small percentage, that's probably 40-50%.

So, I think CRTX has the potential to be a strong preventative (AD risk + PG infection - risk likely APOE4 status, or family history) and treatment (PG+) that mitigates the rate by at least 50%. Add in a few of these others, and disease rates will be quite low. But I don't think CRTX is out, I Think they may surprise, and quickly. Their drug does work on the right target, and if safety can be resolved, it's an obvious thing to move forward with.
MikeFromNZ profile picture
@Careless Investor I agree, thanks for the excellent summary.
you bashed CRTX to pump AVXL. Not very ethical Sir.. Let the drug deserve its merit.
Lane Simonian profile picture
I look at it somewhat differently: I was somewhat critical of approaches that go after a single factor that can contribute to Alzheimer's disease and supportive of approaches that likely partially reverse oxidation and nitration (whether drug or natural product). I believe the Cortexyme approach has some merit, but that better treatments are available.
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