New Paradigm in Alzheimer’s and its Etiology Finally Revealed. $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.

An article was broght to my attention. I suggest you read this first. Heter is the link. https://medicalxpress.com/news/2020-11-neurons-identity-hallmark-alzheimer-disease.html?fbclid=IwAR2Rh9IhWc7CmdZagfB8m0eyWUQgxbJewl7A-FQt5mo0TfkOevXGxYzAOD4

If indeed the root cause of Alzheimer’s have been found then the implication for the field of Alzheimer’s drug studies and development are significant. First of all, it is the final death (!) of the plaque theory. This has beeen primary target for tens of years, but it seems that the root cause could only be elucidated with the knowledge of genetics and of cell differentaition during the fetal growth. The latter is of primary importance, I explain later why. Chromatin is brought into the picture here as the name of the therapeutic target but I suspect that the full insight can only be brought to shine once the mechanisms connected with the “bad” behavior of chromatin can be identified. Chromatin is only a cog in a larger mechanism.

I have been repeating that Blarcamesine (Anavex2-73) might be connected with some basic physiological mechanism involved in fetal development and aptly to my education (mechanical engineering) I called it “a quality control system” for protein synthesis in time of fetal development. Chromatin is here implicated. I also stressed the fact that the SIGMAR1 receptor seems to be most likely receptive to progesterone – the pregnancy hormone – since it is still unknown what serves as the natural agonist. In fetal development the single cell divides and differentiates into all the cells present in a newborn. This includes the CNS cells. The natural course of differentiation of cells and the ability to direct the transformations of cells into branches limiting the potential at every step has been a subject of research into so called stem cells therapies. At every step of the way a number of chemical signal with great effort has been curretly worked on. The are called growth factors. These growth factors stimulate the cells to go from one trasfomation into another. The far reaching promises is to cure old age frailty if not make us imortal. The promise is great like in any new field, so disappointments are also due, nevertheless this might be new reaserch area for therapetic compounds for degenerative disease of the CNS.

In cell biology a researcher can trigger a receptor and measure few biomarkers or compounds. Ultimately, he can monitor the health of a culture of cells due to a drug or agent. Much is obscured to the researcher, and much depends on his level of focus. Dr. Missling has never dealt extensively in biomarkers. Blarcamesine has been without any, at least approved by FDA, since it was a odd man out of the plaque paradigm. After phase 2a and its extension it became clear that Blarcamesine (Anavex2-73) might (cannot say yet “can”) rescue those who have not deteriorated below 20 points on MMSE scale, and have the right genetic make up, that is 80% of general population. The inklings is that SIGMAR1 agonist like Blarcamesine (Anvex2-73) is a drug working along the lines of the new pradigm. I start with the word of “inkling”, as I refrain form giving signs of full knowledge before the fullness of time . Efficacy of Blacamesine level has never been experienced in Alzheimer’s study. Yet, there is no direct evidence that Blarcamesine works 100% within the new paradigm so I stay true to form saying “inkling”. If we focus on the results with patients till now it seems we got the winner, wait for the results of Phase 2b/3. FDA has not allowed to select the patients on genetic markers, but the analysis after the adjustment might be very interesting. Up untill now, no study had shown that high Effect Size Cohen’s d like Blarcamesine. Pursuit of the plaque paradigm totaly absorbes the investsting public without exception for novel approaches.

The new pardigm talks of reversal in synaptic health. We can claim that Blarcamesine restores the synaptic health, and even acts as an enhancer of synaptic health as measured by amplitude of processing startling audible signal as the only biomarker available on Blarcamesine performance at this moment besides the improvement in cognitive scores in MMSE or ADCS-ADL .

In the light of the above article or rather discovery that the neurons of Alzheimer’s sufferes devolve, or lose thair ability to express genes neccesary to fulfil their fuction to create synapses and conduct the signal processing required of functioning neurons, Blarcamesine seems to be a drug theoretically and actually rescuing Alzheimer’s patients. Both the plaque in its amyloid and tau versions seems to be well down stream, and even the damage due to immflamuation seems to become a secondary aspect of the disease. In one great swoop a clear and logical etiology has been estblished for the disease. The reasons for the reversal of the function is yet unknown but instantly number of drugs either become totally obsolete or they become relegated to addressing symptoms and not the disease.

Great attention has been placed on the doubtful success of $SAVA, but I think that only has been because $SAVA therapeutically follows the line of plaque etilogy and as all these drugs has been more successful in “curing” the disease when one looks at biomarkers than actual patients. Of course, these biomarkers became now instantly obsolete, or rather secondary or even worse. Yet the pardigm of the plaque will die slowly and the new pardigm is certainly to deliver the final blow once it produces great disparity in trial results between the apporoches, too many careers are at stake as well as money.

In this article I wrote about $ATHA. The company uses liver growth factor, just like in th myth of Prometeus, liver has great ability to heal itself and regrow. Please, read the post since it predates my knowledge of the above article. link here https://wp.me/p2IvqX-fI

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Cassava Science and The Numbers. $SAVA Simufilam

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.

For $SAVA it has been good to be known by Mr. Market. Just look at the share price performance. Nevertheless, the numbers are not that astounding as the price performance would have it.

Since most of my research has been dealing with MMSE scores, and I am most aquatinted with MMSE ranges for Alzheimer’s I tend to bring data into the MMSE scores to carry out analysis. I found a calculator for MMSE, ADAS-Cog and CDR-SOB scales in the paper, link provided here https://www.tandfonline.com/doi/full/10.1080/13854046.2015.1119312

Drawing lines and measuring the scales, I got that the initial MMSE score of 25 MMSE points for the trial baseline. Compare it with the published by $SAVA 22.1 MMSe initial score but then the readout from the plot is saying that 15.5 ADAS-Cog corresponds to MMSE 25 points. There can be a misinterpretation on my part as different measures of ADAS-Cog exists and the used by $SAVA is ADAS-Cog11 battery. Nevertheless the mean improvement is just 0.7 MMSE points as the scale of 30 MMSE to 70 ADAS-Cog would suggest. The published mean improvement of 50 patients was -1.6 ADAS-Cog11, no MMSE scale results were given.

Also in the press release $SAVA said that the label of Aricept (Donepzepil) gave the yearly decline to be 6 to 12 points on ADAS-Cog scale. Using the plot given above and chosing the values of 8 as mean. Starting with the ADAS-Cog score of 16 and going additional 8 points we have a correspponding decline on MMSE scale of ~3.0 points (from 25 to 22 MMSE). A quick and dirty measure of statistical effectiveness is the Effect Size, Cohen’s d. We are not given enough data to do so. In this case we resort to making educated guesses or what others call assumptions.

If we say that the MMSE score for 50 patients over 26 weeks was +0.7 with Standard Deviation +/-2.5 (comparable to SD SuperResponders in 57 week data for $AVXL) and take the ADNI MMSE -2.2 SD +/-2.0 as placebo then the Effect Size for $SAVA interim reading is: ~0.40. This is much better than ~0.28 achieved by Donezepil which was approved in 2004. This is not an absolute value of efficacy. It is provided here to give insight, not to be definitive guide.

For the worst and the best Effet Size in $AVXL Phase2b/3 trial for Blarcamesine in Alzheimer’s see my previous post https://wp.me/p2IvqX-ck .

I can also cite here Cohen’s d Effect Size taking into consideration already existing data and the results of genetic analysis of the patients in Phase 2a Alzheimer’s trial for Blarcamesine (Anavex2-73). Tne poster was displayed at AAIC 2018 Alzheimer’s Accociation meeting.

The Effect Size range can be read off this plot. You can download the PDF of the poster here.

Looking at $SAVA or $AVXL one can see that new generation of Alzheimer’s drugs are going into approval. $SAVA at this point might be the champion in valuation but $AVXL provides more value to investors.

Disclosure, I am long $AVXL.

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