Why You Should Count On Cortexyme To Deliver The Alzheimer’s Drug! $CRTX

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!

Jitters of The Biotech Investors and Their Cure

In most PRs companies give some measure of improvement of patients, with the number of subject and the p-values. The certainty of the improvemnts are judged mostely throught the prism of p-values as it is a number with a threshold once attained a semblence of certainty is holly assumed. Alzheimer’s trials are the widowmakers of too many hopes to count. Many a times a promising phase 2a drug turns into disappointment in phase 3 trials. Companies, therefore make their phase 2a trial just as light on subjects count, to cut costs, as proverbial trial baloon. These results are short on certainty and make the investors to look for clues in the bevavior of the management which can be faked or genuine. The hopes connected with $SAVA’s drug Simufilam in the eyes of investors carry higher certainty than those from phase 2a by companies like $AVXL or $CTRX. I have tried to evaluate their chances to deliver the Alzheimer Drug. Maybe, such a drug does not exist but everybody believes that their favorite CNS company has the best horse in the race. A sign of pure lack of certainty, is to hold them all.

Power Of A Trial And One Patient’s Story

The management of $CRTX is fond of saying, or rather all they can say about the trial, that it is powered to detect 50% decrease in the rate of decline among the Alzheimer’s patients treated with Atuzaginistat. When I parse this assertion, it occures to me that this is the least of benefits to patients the management expects to detect with p-values smaller than .05 but this is my interpretation. The hint is “it is better than BIIB drug”. I might be wrong on this one, at least in the second part.

I have already looked into the APOE4 allele and its connection with allegedly increased virulences of P. ginvivalis in brains of some Alzheimer’s patients. $CRTX and the papers on the interacton between the bacterium and the APOE4 protein give the most plausible explanation of the accute character of dementia in individuals carring the APOE4 allele. They are the most quickly declining patients and are the most likely to drop out from trials.

However, you would try to discount the 28 days and n=9 phase 2a and short on duration and subjects number trial, there is very interesting effect of Atuzaginistat on the launguge abilities of the 6 patients who were in the dosed cohort. Let’s see the slide from the $CRTX AAIC 2021 Symposium.

The Winterlight Assesment of Propositions and Conjuctions achieved p-values smaller than .05 just after 15 days and the p-values decreased to less than .001. Would that suffiece to engender certainty in investors? We have here the one from the three (p-values). Missing is the good n number and the measure of efficacy as Winterlight is a black box. I had very few tools to assess the efficacy of Winterlight, because I did not know anything about the inner-workings of the test. Nevertheless my understanding was that there was a consistent separation between the two cohorts, both in magnitude of change and the dispertion around the means for both groups. Ergo, low p-values and high Effect Size, which I calculated to be about 3.8. This is way beyond huge. Fortunately the company published something to giving us insight into the Winterlight Assessment. Let’s see next slide.

The inriched lauguage examplifies the speach pattern of an elderly patients treated with Atuzaginistat over period of 28 days. The patern present in many trials is to exhibited immediate therapetic effect followed by either decline or slower movement toward improved cognitive scores, the latter has happened in the case of Blarcamesine by $AVXL. A similar early effect has taken place with Atuzaginistat where in just 28 days the patient experienced such change in speach pattern that the only conclusion to be drawn here is that we deal with deep recovery of severly deteriorated language and cognition patient, not just 50% decline in the rate of deterioration. The recruitment requirments listed the patients as being between MMSE-2 14 and 25. From the speech pattern one would expect the patient to be closer to the lover limit of recruitment.

As a person myself struggling with disability, especially with language, I recognize here somethig akin to phase change in physics in the language pattern of that patient. For those who have never suffered mental deterioration this might seem trivial or constitute marginal improvement. I consider these two slides anecdotal evidence of very strong therapetic signal. No doubt, that this is the strongest example $CRTX mangement could choose. Nevrtheless, for me it is a very strong argument to expect better results than just 50% decline in the rate of deterioration.

For investors to reach the comfort zone, the troika of n number, p-values and clinicaly meanigful effect has to be present in the data. Otherwise, tea leaves reading of mangement maneuvers, statements, or comings and goings issues. Sometimes, for some, all it takes is to present anecdotal evidence by just few patients to dispell the statistical uncertainty. In case of $CRTX we have it all save the respectfull duration, p-values on known measures and n numbers in the trial. For certainty, this is just incomplete picture. For me the language improvements or rather the phase change in cognition associated with the language of those dosed presents a very persuading argument to make me lean towards expactations of large therapeutic effect. $CRTX second market (periodontal disease) might be so large that the Alzheimer’s is just a fraction of it. Nevertheless, the seond market might not be of the same urgency as Alzheimer’s it can make up for it in numbers, so the bet is kind of asymetric but inherently safer than many others.

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Is There More than Just Alzheimer’s, Parkinson’s and Rett Syndrome in Blarcamesine Bag of Tricks? $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!

See press release from Anavex Life Sciences. https://www.anavex.com/anavex-life-sciences-announces-notice-of-allowance-for-u-s-patent-application-anavex2-73-blarcamesine-for-the-treatment-of-cardiac-dysfunctions/

Heart has its own little nervous system which in part is independent from the brain. Blarcamsine as SIGMAR1 agonist does its work as far as we know primarily in the nervous cells. Yet, the SIGMAR1 receptors are expressed in different organs too. I was trying to provide a detailed list but unfortunately it is much harder task than a quick search. Leaving this aside, is there general health advantage to Blarcamsine besides CNS health? We can speculate on this due to the nature of Blarcamesine action on SIGMAR1 receptors as detailed in this post https://piotrpeterblog.com/2021/05/13/1372/ .

To just shortly explain, agonists of SIGMAR1 cause the release of large number of health improving signaling molecures. Is there already evidence that Blarcamesine can alter the general health of those receiving it? I looked at certain data from reference study https://pubmed.ncbi.nlm.nih.gov/10404988/.

I created an illustration and published it two weeks ago without extensive explanation. I am attempting to provide some logic under which I constructed the graph. Let’s see the graph.

  • There are two lines. One (dashed) is for probable Alzheimer’s patients numbers remaing in the reference study over a period of 7 years. The other is the controlled group consiting in 50% of healthy spouses or volunteers reporting every year for check up.
  • Both groups are very similar in make up, the only difference being the probable Alzheimer’s diagnosis. For the Alzheimer’s cohort the reason for no showing up can be deterioratiom due to demantia, death, or general health deterioration. For the controls cohort it can be the same, save the dementia.
  • The number of no-shows is expresed in percent of starting cohort group population still reporting. 32 patients in Phase 2a study is consitent with the minimal sample of a general population. The reference study used about 300-400 participants to arrive at these plots.
  • The first year Phase 2a loses more patients than the reference study so arrow is red and pointing down.
  • The second year, the phase 2a numbers are comparing favorably with the precentages of participants staying with Alzheimer’s staying in the study so arrow points up and is green.
  • By third year the patients from the phase 2a study are in the Open Label Extension for two years. The procentage of popluation of Phase2a OLE still within the study seems to emulate the population of the healthy cohort in the reference study. Can we state that the morbidity due to Alzheimer’s has been removed from the Phase 2a participants?
  • We do not have data for the 4th year of the study.
  • We now reach the 5th year of the study. In the statement by Dr. Missling the number of patients within the study has been set between 10 and 21. With 10 patients we “remove morbidity due to Alzheimer’s”, but with more than 10 patients left with the study the implication is that the general health of the patients improved over the level of those participating in the healthy controls cohort of the reference study.
  • Caveat: The Phase 2a study has not been designed to answer this question. Neither, we know for sure the doses received by the patinets in the OLE extension.
  • A word of caution, this is a very creative way at looking at the data but the word “creative” has as on its other side the meaning of something unbecoming. This is just an excersize in free style data analysis. I could be close to the truth or can be way off, so please take it with grain of salt.

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