Cortexyme and The Brave New Ideas in Alzheimer’s Drugs. $CRTX $SAVA $ATHA $AVXL

Do not trade this blog as 4 billion years of evolution is against me and possibly even God laughs at it, He has a great sense of humor! And I am long $AVXL FYI

In the list of the banes of our brains neuroinflammation has its lion’s share. Indeed, only the Amyloid plaque can compete with it on cenceptual level in medicine nowadays. This ancient way of defending multicellular organisms from harm and infection can easly turn into the damage itself. Similarly, the probable etiology of Alzheimer’s can be traced to the infection of brains by the ubiquitous Porphyromonas gingivalis, this is the position of some researchers and $CRTX. I said “ubiquitous” since 65 million Americans are affected by P. gingivalis. The story gets even more twisted as many other bacteria are involved in gingivitis. From the statistical point of view the occurance of gingivitis is not a done deal for Alzheimer’s since 5 million of Alzheimer’s patients give ratio 1:13 to gingivitis sufferes, but this you can blame on the immensely intricate relationship between the host and the bacterium just like with the gut bacteria. And this can be two way street from bacterium to the disease and from Alzheimer’s innate neuroinflammaton to bacterium infection. Researchers looking into the causes of Alzheimer’s make this statistical connection and look only at this as a one way street. But I wonder, whether anybody looked for the bacteria in brains of people not affected by dementia?

Cortexyme has as its therapeutic target the Porphyromonas gingivalis secreted Gingipain (protease virulence factor) which the company in its presentation does not explained what its function to the bacterium is. Nevertheless this substance Cortexyme claimes is linked to Amyloid plaque/Tau deposits in the brain of mice introduced to the bacterium.

Since, some time ago an epidemiological link has been established between ginvivatis and Alzheimer’s the number of papers around this subject has grown giving Cortexyme reasonable confidence in the pursuit of physiology of Porphyromonas gingivalis as therapeutic target. They presented it in very compelling slide on their March 2021 Corprate Presentation.

Let us turn our attention to mouse models (murine). There is indeed strong evidence in the murine models. Playing here a devil’s advocate I can point out that as the cancer scientists quip, “we have cured the cancer in mice long time ago”. All these model are a bit artificial as in the case of gingivitis the bacterial load can be overwhelming to the mouse system just like anthrax can be to human beings. Humans rarely get infected with anthrax but if enough anthrax spors get into our lungs we might die from anthrax infection.

What is interesting is that 22 weeks corresponds to 5 months, which is a similar amount of time into the life of the 3xTg mouse model when first signs of cognitive deterioration appear. The other argument which I can make that there might be more to it than just gingivitis leading into Alzheimer’s is that only 90% of Alzheimer’s patients have the bacterium in the brain. On one hand all it could be that EOFAD (early onset familial AD) don’t and the sporadic form LOAD (late onset AD) is the 90%, on the other the 10% exception might mean that it is a secondary infection, just like the 30% of Alzheimer’s diagnosis do not carry into having Amyloid plaque post mortem. Dementia in general might be much more complex than we can imagine it yet.

Having cast so much doubt in the Cortexyme therapetic target it is now time to turn to the expaloratory phase 1b trial results of Cortexyme Atuzagistat COR388.

Just 9 patients divided into 6 dosed cohort with 3 placebo. The placebo cohort of 3 is kind of riduculous but the p value lower than .05 on the languge measure is astounding. The MMSE is irrelevent with that few participants in that time span, so is CANTAB. The Winterlight Lab is sepcializing in software which picks up the differences in languge usage of elderly people in order to determine whether they succumb to dementia. The entire description given to the results is “Winterlight Assesment Prepositions & Conjuctions”. From my own experience I realize that use of such is indeed connected with the incidence of dementia but on the other hand this is just a part of the whole cognitive landscape. The Effect Size of 3.6 given to this measure outcome might much more be dependent on the scale itself as the placebo stays on the same level during this ultra short period of 30 days of dosing. Much needed comparison with other standard measures is lacking. This astounding result in languge analysis might be the mouse that roared or the real McCoy. Simialr testimonials to sudden recovery from Alzheimer’s related drugs can be seen on YouTube. One involved a doctor making injection into neck’s spinal cord of anti-inflammatory drug and then tilting the patients so that the drug would flow into their brains. The effect was immediate and patients testimonial were drawing an image of mental fog receding. He was sactioned by FDA as the proceedure was deemed unsafe, and the video was removed. Another one involved the drug Anavex2-73 (Blarcamesine) and was made by Australian television. Link: https://youtu.be/hZEVSxLQbbk . Recoveries in just days are not uncommon in Alzheimer’s Bold New Ideas drugs trials ($AVXL (5 weeks), $ATHA (8 days), and $SAVA (28 days)) the real problem is will the recoveries hold for years, and the other is that all those four, including $CRTX (28 days), have different measures to jump start their respective therapeutic promises for the afflicted and the investors. The closest to revealing its full potential is $AVXl with Blarcamesine (Anavex2-73). The phase 2a has been extended to 148 weeks with following results.

If we align all these Companies along the line of distancing them from the pure Amyloid removal therapetic target of let’s say $LLY $BIIB we get: $SAVA, $CRTX, $ATHA and $AVXL. They start from trying to return health Amyloid accumulation and inflammation indirectly $SAVA, work on inflamation and Amyloid plaque direcetly (hypothesis of Amyloid being a defense mechanism) $CRTX, indirectly on inflammation and direcetly on cell health $ATHA, and all of these above, indirectly, through improvement in protein misfolding mechanism, and into cell trascription mechanism (the latter is just well supported hypothesis) $AVXL. All these are promissing new drugs for the dementia/Alzheimer’s field. Some overlap but do this in different ways.

The company $CRTX is selling its stock to investors based on the hopes of helping the sick with dementia and Alzheimer’s and investors selling their stock once it reaches its fair value upon company profit. Their argument is on one hand is very strong but on the other there are doubts about the duration of the effect and of the measure itself. It is only after the phase 2/3 that clearer picture to its efficacy can emerge. All these theories of the disease can not be true as the one and only exclusive cause, although they can supplement each other.

$CRTX recently released news regarding the futility interim data. The release can be found here: Link https://www.cortexyme.com/cortexymes-phase-2-3-gain-trial-of-atuzaginstat-cor388-in-patients-with-alzheimers-disease-successfully-advances-past-interim-analysis/ .

The p-value of .005 is below the threshold of .05 so results can be called statically significant, which in statistical parlance means that there is difference in performance between the dosed cohort and the placebo cohort. In other word also that there is 0.5% probability that on repeat of test the results will turn false on random events. The smaller the number the better, the greater the number of participants in the study the easier to achieve lower p value number. But on the other hand $CRTX management is a bit disingenuous claiming “overwhelming efficacy” already. The data points in this direction but it is not a clear indication of it. If indeed p=.005 for then we can expect some efficacy and this can be easly measured with Effect Size Cohen’s d, which I tried to use in this post on preeliminary results from $CRTX and $AVXL. The latter has 3 years of dosing 8 patients and measuring this in the above given cognition tests which are the industry standards with p=.00001 as the number diminished with time due to increased efficacy but itself it is not a measure of one directly. $CRTX started right now to do the same. Only with these results we can comapre all these comapnies. If I am not wrong $CRTX will release data in December 2021 and $AVXL in June 2022. Nevertheless, the true performance shall be seen in a long distance run against the disease.

Two thirds of all dementia and Alzheimer’s sufferes die because of other comorbidities, only one third dies because of severity of the disease. The largerst cost of the disease lies in the length of time a given person needs to be institutionalized or cared by the family. If you can make then to retain their cognitive skills you can cut these costs signifinatly and collect the prize.

If you feed your dog or cat wouldn’t you feed me and drop me a fiver so that I can buy my wife a french pastry? Thank for reading and come again.

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