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.
What I called the Unified Alzheimer’s Theory calls for the root cause of Alzheimer’s to be some hypothetical disturbance in cellular homeostasis, cascading into disfunction leading ultimately to wholesome destruction of neurons through/or with runaway autoimmune reaction.
I have been talking about the possibility that the SIGMAR1 receptors agonists, in varing degrees, bring back the homeostasis present in the growth during the embrionic development as if in some sense Anavex2-73 would be not unlike a rejuvenating agent. In my mind, I have made the connection but I do not have sufficient and detailed knowledge of cellular physiology to express it properly. If the idea indeed has any value then MCEP2 mutation which is connected with disabling the protein silencing genes expresion after embryonic development should demonstrably altere the course of Rett Syndrome in patients receiving Blarcamesine before the regression onset (about 18 months post birth).
Athira Pharma wants to use HGF/MET Hepatocyte Growth Factor/MET ATH-1017 to treat Alzheimer’s. From the name itself the protein should have something to do with growth of liver cells, and I believe that is where it was first identified. After reading Wikipedia page on HGF/MET one can see that it is present in wide set of growth or rather cellular differentiations in embryonic development. In adult physiology, it is connected with healing of wounds and regeneration of liver cells, hence the name. This protein is so ubiquitous in embryonic development and differentiations of cells that the Phase 1b conducted by Ahira Pharma was only 8 days of dosing. And no wonder why, since the same agent is connected with oncogenesis and with the ability of cancer cells to atain motility (ability to move within body) so that they can metastasize. Nevertheless, as measured this drug achieved astounding effects on Alzheimer’s patients.
The 8 days of dosing is a period too short to measure any difference in cognitive measures like MMSE or ADAS-Cog. There is intense search for benchmarks of the early onset of the disease. The most likely are connected with the time delayed in reaction time and the wave forms of neuronal firing, changing paterns of electric potental on synapses. A standard procedure is placing an earbud into the ear of a person and producing a startling sound ever so often. The brain of the subject reacts in a certain pattern to this stimuli. By comparing the average pattern between the diseased subjects and healthy differences can be found. Athira Pharma presentation from October 28, 2020 presents this on the slide 20.
Notice that the peak of wave after 300 milliseconds marks the benchmark for researchers looking into Alzheimer’s as it correspondes to the timing of accessing the memory in order to recognize the startling sound. Alzheimer’s hallmark sympotm is the gradual loss of short and long term memory.
Two aspects are measured, the amplitude and the delay between the healthy response and the diseased one. Of course, with the progress of the disease these discrepancies increase. The primary measure, though is the latency of P300 wave form. It in absolute terms it ranges from 300 milliseconds for healthy individual to 400 milliseconds for those in mild and moderate Alzheimer’s disease. The slide listes number of studies measuring the discrepancies in many combinations of disease progress and electrode placement on subject’s head. The measure is consistent and has been validated.
These are the results of dosing ATH-1017 for 8 days on latency of P300 wave form. The reduction goes form somewhere 380-400 milliseconds to about 300-320 milliseconds, that is from diseased to almost healthy.
Can we compare this with Blarceamesine? Anavex did measure the responce in P300 but only the amplitude which the above presentation described as less pronounced measure of deterioration of synaptic health.
This is just a long term plot indicating the return or even improvement over the healthy state. Notice the initial response and the resulting long term change separated by a period of some decline and stabilization followed by very unusual improvement over the healthy level (enhancement of mental abilities?). There is a correspondence between your neuronal processing speed and the most important to your cognitive skills indicator, that is IQ. Would Blarcamesine increase your IQ? This is the Holly Graal in psychology.
In just 6 days, comparable to 8 days, the amplitude is going from 6 microvolts (different protocol than used by Athira Pharma) to 7.8 microvolts (130%). The problem is that this is for P3a wavform present in word memory recall, not audio P300, hence the different range of voltages (different electrode locations?). What is essential here is that the patients experienced in both cases initial large improvements in commensurable amounts.
- $ATHA Athria Pharma ATH-1017 in 8 days of dosing caused comparable improvements as $AVXL Blarcamesine in the same time frame and measured by P300 latency/amplitude.
- Blarcamesine has 3 years of safety dosing. ATH-1017 seems to be involved in many places in the body to provide for potential safe drug profile. Involvement in oncogenesis might prevent long term dosing. Further testing will tell. Follow Phase 2/3.
- Blarcamesine sets in motion some fundamental process in cellular physiology, specific to cells with SIGMAR1 receptors. ATH-1017 is a growth factor working in multiple sets of cells, is not specific to neurons only. Two different types of MOA.
- Currently, great effort has been expanded in search in neuronal growth factor. As more is becoming known about embryonic development and differentiation of cells from stem cells new growth factors of that type can become considered as drug targeting neurodegenerative diseases.
- PRO $ATHA, the similar performance in 8 days as $AVXL Blarcamesine
- CON $ATHA, safety doubts for long term dosing.
- PRO $AVXL, proven record of patient improvements in multiple diseases, not only Alzheimer’s. Blarcamesine – prospective mental abilities enhancer?
- CON $AVXL, in this comparison Blarcamesine is held as the standard so we won’t list any.
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