How to Digest Alzheimer’s Data from AAIC 2021 $AVXL $ANVS $CRTX $SAVA

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!

Stock Markets Reaction Is ……..

There are two very basic reactions from stock market participants. A kee-jerk one where everybody buys in the rush of enthusiasm and damned be the price. “I just want to get hold of it at any price”. And the measured one where the price and acquisition are weighted against each other as the market digests the pros and cons slowly.

It is very hard to predict the extend of knee-jerk reaction. This is kind of the “madness of the crowd” moment. I am not going to predict either one, but I am going to provide information helping to digest the incoming information with background of results from the most advanced player in the field.

Let’s jump to it.

$AVXL has conducted trial of its drug Anavex2-73 later known as Blarcamesine to assess dosage and explore efficacy. The trial initially involved 32 patients, in three years this number dwindled to 21 patients. The illustartion divides the patients into the groups or classes based on MMSE scores, SIGMAR1 receptor and APOE mutations. The plot y-axis is in ADCS-Activities of Daily Living (78 points scale) and it follows the patients over period of almost 3 years (148 weeks). The numbers represent the improvement from baseline. Out of cohort of 8 people, with 75% carriers of APOE4, two without APOE4 (carriers of APOE3) responded very abruptly in just 5 weeks with jump of 6.5 points (9.3% improvement over base of 70 points) [1]

Source [1]

Conclusions on Efficacy Paterns

  1. The only take way point can be that a drug with efficacy against AD should make a very steep and quick recovery possible in just few weeks if they are to hold this patients steady.
  2. A second conclusion is that if it did not do that, after two years it should only slow the progression of the disease as it happend when the APOE4 patients were added to the mix.

Nota bene, in the population of Alzheimer’s sick the Group1 should include from 50% to 40% of patients.

If these two patterns are worth anything and we intend to view the other palyers through this lense tthen…

$ANVS

It shows the pattern number 1, to verify this see the Press releases from $ANVS. links: https://irpages2.eqs.com/websites/annovis/English/431010/us-press-release.html?airportNewsID=364451b1-06a7-4b96-a389-016f3ef3e6e3 ;

https://irpages2.eqs.com/websites/annovis/English/431010/us-press-release.html?airportNewsID=b6b5cfe1-123f-45fa-9ab2-fd42c8960048

$CRTX

As the picture conveys thousand words so the language improvent does. I would say that $CRTX displays the pattern number 1.

$SAVA

The improvement of -1.6 ADCS-Cog points over 6 months breaks away with the pattern number 1. We need to view more data from $SAVA to say anything conclusive. Nevertheless, $SAVA has been touted as the first company achieving something more than lowering or delaying the deterioration. The record does not corroborated this assertion.

It is actually $AVXL and $CRTX which are in head to head competition. At this point $SAVA is a PR darling. It has been reported that $ANVS drug might be involved in treating the infections such as P. gingivalis giving a competition to $CRTX. In the conclusion I can only say that $AVXL,$ANVS and $CRTX share similar pattern of responces in phase2. $SAVA is the odd man out, but that is not saying that it is better than former three. It will be very interesting to read data from $SAVA.

What $SAVA has going on for it is that its phase 2b dosed size cohort is ~50 patients with first reading of interim results and kind of serves as surrogate for phase 3.

Bibliography

[1] https://pubmed.ncbi.nlm.nih.gov/32318621/

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AAIC 2021 as Viewed Through My Prism of Expectations $SAVA $CRTX $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!

Monday 10:00 AM Eastern Time

$SAVA

  • Poster: “SavaDx, a Novel Plasma Biomarker to Detect Alzheimer’s Disease, Confirms Mechanism of Action of Simufilam”
  • Sounds like more of “curing Alzheimer’s with biomarker” or the best left for Thursday? Is there a change in narrative towards proteopathy? Proteopathy – Sickness of the protein making machinery. A bow in direction of those who are presenting at AAIC 2021, like $AVXL?

$CRTX

  • Poster: An update and baseline data from the Phase 2/3 GAIN trial of COR388 (atuzaginstat), a novel bacterial virulence factor inhibitor for the treatment of Alzheimer’s Disease
  • Of great interest to me, as I want to compare the data to $ANVS and $AVXL data.

$ATHA

  • Poster: Quantitative EEG as a translational measure for the assessment of ATH-1017 neurophysiological changes in mild-to-moderate Alzheimer’s disease
  • I hope for some new data. It would be very interesting to review it vs. the information I have already compiled on ERP/EEG.

Tuesday

  • $CRTX: Symposium, Dinner 5:30-7:30 PM MT – Wining and Dinnning in search of investors/buyers

Wednesday

  • $ANVS:

On Wednesday, July 28, at 8 p.m. ET, Annovis Bio will host a panel presentation which will include new efficacy and biomarker data from an interim analysis of the Company’s ongoing Phase 2a trials. The data presented will include:

·        Neurotoxic protein levels

·        Marker of axonal damage 

·        Inflammatory markers

·        Efficacy

Thursday

  • $SAVA:

On Thursday, July 29th, at approximately 11 am ET, simufilam will be featured in a live podium presentation at AAIC, including a brief Q&A session. This oral presentation will announce results of an interim analysis on safety and cognition for the first 50 patients with Alzheimer’s disease to complete 9 months of open-label treatment. Scientists for Cassava Sciences will also present biomarker data analyzed from cerebrospinal fluid (CSF) collected from 25 study subjects at baseline and again after completing 6 months of open-label drug treatment, including:

  • Biomarkers of Alzheimer’s disease: amyloid beta42, total tau, P-tau181
  • Biomarkers of neurodegeneration: neurogranin, neurofilament light chain (NfL)
  • Biomarkers of neuroinflammation: YKL-40, sTREM2 and HMGB1

If there are any comparable competitors these are in pairs:

  • $AVXL and $CRTX: both soon presenting top data on phase 2b/3 or phase 3. $CRTX Q4 2021; $AVXL H2 2022 Lifting Heavy Weights
  • $ANVS and $SAVA: battle of the phase 2 results; who looks better? Beauty Contest

As there seems to be some proteomic overlap between narratives of $AVXL and $SAVA, $AVXL in general faces more competition from $CRTX on basis that $CRTX reports phase 3 data first and that etiologically it presents completely different narrative. Yet, the $AVXL’s wide range of possible elements of MOA does not preclude possible partial acceptance of $CRTX etiology of Alzheimer’s. $AVXL MOA improves or rights some of the same cellular mechanisms the virulence of P. gingivalis affects. The real quest is to find a medication keeping people cognitevely fit longer than it happens now. Currently, the average MMSE score at diagnosis is 18.2+/-6.6 points. If the diagnose can be made before scores drope to the lower edge of this range the possibility of rescuing the patients increases. Also, this means that a slow decline in the aged population needs to be stopped or slowed down. Since I am best acquainted with $AVXL record I see it possibly fulfiling this requirement. Nevertheless, I want to get as soon as possible anything hinting as prospective performance of $CRTX.

The market’s darling is $SAVA at this moment. It would have to present relatively better data than it had presented till now. Even if it doesn’t, it might soar on lackluster performance, as it is common with the “beauty contest” stocks. The real heavy lifting is between $AVXL and $CRTX.

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Why Blarcamesine Might Be Working Against P. gingivalis $CRTX $AVXL $ANVS $SAVA

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!

I have been directed by the author to an article about $CRTX and the evidence that Alzheimer’s might be caused by virulence of the bacterium P. gingivalis. The bacterium can hitch a ride from the mouth on cells of the immune systen and enter the brain through the Brain Blood Barrier. Then it slowely makes its way infecting neuron after neuron. The article documents in exquisitely detailed manner many aspects of this infection. Indeed, the evidence is compelling.

Nevertheless, drugs like $AVXL’s Blaracamesine do make difference in the progress of the disease. If truly the disease had been caused by germ infection then how a drug which was an agonist to SIGMAR1 receptors and in very general terms worked by restoring autophagy, homeostasis and doing some work around chromatin remodeling seems also to work on a bacterial infection?

The answer is that the P. gingivalis is interacting with humans in very insidious and complex manner. It takes about 25-30 years from infection to the manifestation for the infection. But what is most interesting that the action of gingipains, that is the proteases which the bacteruim produces cut proteins into smaller fragments and feed on them. The P. gingivalis bacterium is not an ordinary prasite, it downregulates genes and upregulates gene on its feeding preference. The article beautifully documents this. Let me quote the author Gordon Gecko was a Commie (SeekingAlpha privet blog): link: https://seekingalpha.com/instablog/20791881-gordon-gecko-was-a-commie/5613017-cortexyme-s-gingipain-theory-of-alzheimer-s-disease-pathogenesis

  • Pg / gingipains display an astonishing ability to toggle our genes in ways that benefit their survival. A recent paper[xxiii] shows that of 15K genes studied, Pg upregulates 942 genes, and downregulates 1247 genes. Interestingly, this paper documents how Pg tends to upregulate the genes that code for proteins containing arginine or lysine, which are the sources of food and nutrition that gingipains can chomp on. The reverse is also true—Pg downregulates that genes that code for proteins lacking arg or lys that gingipains cannot attack. These upregulated and downregulated genes tend to be concentrated in the hippocampus; it is often observed that hippocampal volume shrinks in AD patients. The evidence seems to show that gingipains are especially active in this brain region, which would seem to explain why hippocampal shrinkage is so commonly seen in AD patients MRIs.

It is richly researched article. My admiration goes to the author for his deep knowledge. Had the alteration to chromatine be done by the bacterium would the suspected or rather documented chromatin remodeling by Blarcamesine would change this? We only have circumstantial evidence for the involvement of SIGMAR1 agonists with chromatin remodeling throught the results in the phase2a, the work on SIGMAR1 agonist cocaine, and its therapeutice effect on sufferes of Rett Syndrome. In previous post I gave link to paper documenting in research which concluded that cocaine block transcription of and the enzyme which broke down dopanine – feel good neurotransmitter.

Other papers (can be found on $CRTX website) described disruptions in autophagy and accumulation of proteins in the cytoplasm. Here again, the research on Blarcamesine show that it can clear the path to cellular health.

It might also be that the drugs from $CRTX, $ANVS, $SAVA and last but not least $AVXL can create a potent cocktail to cure Alzheimer’s once and for all. It seems that $CRTX drug binds to its proteases, $ANVS works in some unexpalined way still or cuts inflammation, $SAVA addresses the Filamen A and the cytoplasmic skeleton damage, and $AVXL reverses the chromatin remodeling done by the bacterium and also removes the barterium with its metabolism products.

I am not a scientist. This is both an advantage and a curse, since I barely have any detailed knowledge but I can see what escapes those who are entangled in mass of details, someties even contradictory. I am free to explore possibilities as I am unencumbered by amassed knowledge on any particular paradigm. This is both a strength and a weakness just the same applies to the mirror image of this dilema.

Please, take this post with grain of salt. Nevertheless, Dr. Missling himself has said that it is entirely possible that there will be a few drugs addressing Alzheimer’s as it is a very complex disease. I think that the results from the clinical trials shall prove Dr. Missling right.

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Alzheimer’s, Due to Fatal Infection? Cortexyme vs. Annovis Bio $CRTX $ANVS

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!

The Most Important Question in Alzheimer’s Investing

The question is a simple one. Is Alzheimer’s a disease or a syndrome?. If it is a disease then it shall have one particular etiology with one drug to it. Of course, this is a great exaggeration but serves its purpose of illustration the difference between a disease and a syndrome, which is a set of symptoms that can have varied etiology. Talking more in terms of game theory, investing in Alzheimer’s drugs can be zero sum game or game where many are going to be winners, although fractionally. This view has been already expressed by Dr. Missling. I have also previously raised the question of disease vs. syndrome.

In very simplistic way the Alzheimer’s disease can be explained as the onset of cognitive impairment, followed by the plaque deposits and finally appearance of the tau tangles, all with continued decline in cognitive abilities. That is at least the scenario followed by the murine models of AD. Humans have a bit different response, as 30% those who had been diagnosed with AD at death had no amyloid plaque deposits. In regards to dementia itself and AD, we can see “three diseases”. The early onset AD, let’s say at age of 50 years and up to 10 years of duration, leading to death. Second, gradual cognitive decline with age. The third, with advancing old age and already age related congnitive decline, diagnosis of AD and the usual precipitous cognitive deterioration, often cut short by death due to other morbidity. This is the extremely simplified view of the epidemiology of dementia and AD. For reference see post link: https://piotrpeterblog.com/2021/04/11/the-ideal-dementia-drug-and-dementia-patients-population/

Etiology is the fancy name given in medicine to the cause of a disease or a condition. There are hundreds if not thousands of papers written every year about dementia and AD. Some are just reviews of literature on some aspect of the disease, some bring genuine new knowledge. But none of them are the full and complete answer to the question what are the causes or a cause of AD. Let’s for the sake of an argument claim that AD as a disease depends upon 100 interactions. A researcher can not follow all of them in vitro or in a murine model. He will concentrate on one or perhaps few to get a partial view of the disease. It is the clinical part of the search for new drug to give the final verdict on the benefits of the drug. The more limited is the scope of the study the less ambiguous are the results of the study and the more convincing they are. the caveat here is that much can lost in effort to limit the scope in order to lessen ambiguity.

I have written about some of the studies on AD. The etiologies given by them range from genetics mutations, epigenetic changes in genes during the life time of patients (chromatin remodeling), mitochondrial health, oxidative stress, neurotransmitters, misfolded protein, and neurotropic signaling molecules. They all can be aspects of one disease. The latest, I read about the possible etiology of AD due to infection by P. gingivalis, the same bacterium causing periodontal disease. If you shop for one and only cause of the disease it seems to the right place. Scientists at $CRTX claim that it is so and give studies to support their view. Indeed, it is a compelling evidence. It would explain the amyloid plaque failure and appearance in later times of tau tangles.

From ALZHEIMER’S DISEASE-LIKE NEURODEGENERATION IN PORPHYROMONAS GINGIVALIS INFECTED NEURONS WITH PERSISTENT EXPRESSION OF ACTIVE GINGIPAINS. JOURNAL OF ALZHEIMER’S DISEASE 2020.

Conclusion: P. gingivalis can invade and persist in mature neurons. Infected neurons display signs of AD-like neuropathology including the accumulation of autophagic vacuoles and multivesicular bodies, cytoskeleton disruption, an increase in phospho- tau/tau ratio, and synapse loss. Infection of iPSC-derived mature neurons by P. gingivalis provides a novel model system to study the cellular mechanisms leading to AD and to investigate the potential of new therapeutic approaches

Bacterium P. gingivalis might colonize the brains of the infected persons and stay there dormat for decades as expresed by researchers in words “viable but not culturable”, meantime the bacterium produces proteases which are sources of its virulences. Collectively, they called gingipains. Proteases are enzymes which cut proteins and peptides into parts, functionally destroying them or even producing toxic residue. These can also be found in the CSF (celebrospinal fluid) of infected persons. The in-vitro models provided by $CRTX suggest that the amyloid plaque and tau tangles are direct results of the infection.

About 50% of population of The US after age of 30 years is infected with the bacterium. The picture that the scientists at Cortexyme paint is that of bacterium taking a ride on some cells of the immune systen through brain blood barrier, and slowly spreading from neuron to neuron. Virulence of P. gingivalis causes neuroinflammation leading to production of A-beta amyloid plaque as defence mechanism and later on dissolution of microtubules resulting in tau tagles. Here, we can talk about the disruption of axonal transport, and loss of synapses. Ultimately, neurons are driven to cellular death called pyroptosis. The definition of pyroptosis says that it is the type of programmed cell death taking place in the event the cell has been infected and cannot be rescued.

This is a picture of low level infection which can be dormant for 30-40 years, which correponds to the murine model of 22 weeks incubation period to symptoms of AD. The murine and in-vitro utilize very high ratio of bacterium to cell ratio which makes the infection highly probable. Under real conditions these can never be achieved in a living person. Nevertheless, some people can be susceptible to the infection, as well as can have high levels of neuroinflammation. The authors conceded this truth.

The number of people infected with P. gingivalis is vast. Only minority develops Alzheimer’s. Let’s run the numbers. I estimate the population of the US after 30 to be at least 150,000,000. Out of that only 5 million have AD. So one in 30 develops the disease. Nevertheless, the infection is a risk for cognitive decline in general and AD in particular. The population which best illustrates the validity of Cortexyme’s claim is the Down Syndrome patients incidence of Alzheimer’s. I quote from a paper on the science section of Cortexyme home webpage.

PORPHYROMONAS GINGIVALIS IN ALZHEIMER’S DISEASE BRAINS: EVIDENCE FOR DISEASE CAUSATION AND TREATMENT WITH SMALL-MOLECULE INHIBITORS. SCIENCE ADVANCES, 2019.

In addition, sustained high levels of antimicrobial Aβ driven by chronic P. gingivalis infection of the brain may be toxic to host cells, and therefore, reduction of Aβ levels after treatment of the P. gingivalis infection should be beneficial. Furthermore, Down syndrome (DS), the most common genetic cause of mental disability, has been used to support Aβ as a therapeutic target because of the notably high prevalence of dementia with Alzheimer-type pathology in DS patients (greater than 50% after the age of 60) and the fact that the amyloid precursor protein gene, which gives rise to Aβ, is present on chromosome 21, which is triplicated in DS (65). However, in support of our hypothesis, an aggressive form of periodontitis with rapid progression and onset as early as 6 years of age is associated with DS, but not age-matched normal controls or other mentally handicapped patients of a similar age distribution (66). The occurrence of P. gingivalis has been found to be significant in the subgingival plaque of DS patients beginning around the age of 5 years when compared to age-matched controls, indicating that P. gingivalis abnormally colonizes DS patients in early childhood (67). The reason behind DS patients being susceptible to P. gingivalis infection at such an early age is unclear but may be due to the immunodeficiency that is associated with DS (68). Research is needed to determine whether P. gingivalis and gingipains are present in DS CSF and brain.

In the same paper the authors conclude that:

In summary, we propose that genetic polymorphisms of innate immune system genes in essential immune pathways may result in defective clearance of P. gingivalis and gingipains from the brain, resulting in chronic, low-level infection and neuroinflammation in susceptible individuals.

We are in the middle of Etiology Wars. There might be hundred and one things going on in AD patients physiology, one of them can be the infection with the bacterium which causes periodontal disease. Just beyond natural susceptibility, there might be other mechanism triggering onset of AD. For us, as the investors the most important thing is place our bets on a winning drugs. The AD and dementia etiology is so vast and complicated that it can be already plain to see that few drug at almost the same time are going to emerge as winners. Predicting where the money goes can be even more daunting question. I am not going to touch upon this.

Atuzaginstat (COR388) is the leading drug of Cortexyme. The drug binding to the gingipains thus making them defunct, leaving P. gingivalis infection toothless (pan intended). The infection itself is intact as no antibiotic has been found to reduce the numbers of the bacterium in brain or other colonized tissues. In other words the drugs has to be continuously dosed to have effect. This is going to be difficult to justify unless FDA conditionally approves the drug or a schedule will be given to dosing because there have been a liver reaction to the dosing of the drug over the course of the study (48 weeks). The company claims that these are transitory problems but FDA has put partial clinincal hold on Open Label Extension of the Phase2/3 GAIN study. More information can be found here, link: https://www.cortexyme.com/cortexyme-provides-regulatory-update-on-development-program-for-atuzaginstat-in-alzheimers-disease/.

Even as approved the drug would make it a duty of a physician to check on status of certain liver biomarkers making the drug cumbersome to dose. That in itself can be no surprise as Atuzaginstat binds to P.gingivalis proteases which might be similar to some liver enzymes. On the other hand, would the result in November 2021 (Q4 20121) be good enough and the climate politically accepting of AD drugs the NDA is not out of question.

I run by some notes on other drugs. Upon reading the material from Cortexyme $CRTX I realized that how limited is the terapeutic target of $SAVA. $SAVA Simufilam takes on a side show in the physiology of the AD as Cortexyme papers suggest demage to cytoplasme skeleton, and Simufilam acts on Filamin A cytoplasm skeleton element. The CEO of $SAVA has been awarded $3 million cash, it seems that options would be too long shot for him. One suspects that $SAVA’s result might be not on par. Nevertheless, it could be a good drug to add to drug cocktail a AD patient can use.

Another drug for those who think that infection with P. gingivalis is the way to go is the AVNS401 by Annovis Bio $ANVS. Reference to this can be found in this press release. https://irpages2.eqs.com/websites/annovis/English/431010/us-press-release.html?airportNewsID=d75fe079-a291-4623-83a1-7c760a2c8907

It seems that the results from $CRTX are not much different than from $ANVS.

The most interesting is the Winterlight Assessment (Prepositions & Conjunctions) showing real improvements in the use of language in just 28 days. I think it is a more sensitive way to measure some aspects of cognition.

When you compare the results from both studies they seem to agree on the cognition measures like MMSE and ADAS-Cog, but I think that ANVS401 is a better drug as it does not have yet any problems with adverse effect and presents comparable improvements. See Press Realease. To get MMSE scores from ADAS-Cog (rough estimates) divide ADAS-Cog by 2.33. The ANVS401 MMSE score is 1.88 points which is about the same for COR388. Link: https://irpages2.eqs.com/websites/annovis/English/431010/us-press-release.html?airportNewsID=364451b1-06a7-4b96-a389-016f3ef3e6e3

Nevertheless, as it is in the realm of phase2 studies in the Alzheimer’s disease most of them are conducted on samples size so small that the some results are not statistically significant.

I hope that the rally in AD stocks resumes as the uncertainty with FDA approval will be sorted out. There are great many stocks to invested in this field.

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AAIC 2021 July 26-30 $SAVA $ANVS $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!

Etiology Wars

The Aduhelm fiasco brings about the realization that it certainly isn’t a A-beta the reason for the dementia of Azheimer’s. The press still touts its sister the tau tangles. This narrative now goes through trasformation into the story of neuroinflammation with which are bound the two above-listed companies $SAVA and $ANVS. The transformation is simple, both of them are connected witht the A-beta physiology as a gateway to the neuroinflammation narrative. $SAVA indirectly, through Filamin A (illustration below).

$ANVS by the way of binding to messengerRNA for the precursor protein APP for A-beta, and some other enzyme related to it. quote from Alzforum on posiphen.

Posiphen, also known as ANVS-401, is the pure (+) enantiomer of phenserine. Both compounds were originally developed by Torrey Pines Therapeutics and licensed to QR Pharma in 2008. Both Posiphen and phenserine reduce production of amyloid precursor protein by blocking translation of its mRNA. Phenserine also inhibits acetylcholinesterase, while Posiphen does not. It is dosed by mouth and enters the brain.

Posiphen acts on iron-response element sequences in the 5′ untranslated region of APP mRNA to inhibit protein synthesis. It reduced APP and Aβ in neuronal cultures and brains of wild-type and AD transgenic mice (Lahiri et al., 2007Marutle et al., 2007). The drug was reported to be neuroprotective and neurotrophic in AD mouse models (Lilja et al., 2013Lilja et al., 2013), and to normalize memory impairment, learning, and synaptic function (Teich et al., 2018).

Posiphen reportedly also blocks translation of α-synuclein mRNA, implying potential application in Parkinson’s disease (Rogers et al., 2011Mikkilineni et al., 2012Yu et al., 2013). The compound reduced α-synuclein expression in brain and gut, and improved intestinal function in the A53T α-synuclein transgenic mouse model of PD (Kuo et al., 2019).

By a whole battery of biomarkers these drugs lower the level of neuroinflammation. I have to confess that upon viewing video, where a physician has injected AD patients with approved anti-inflammation drug into the neck, in order to have it then flow into the brain to make then partially recover from cognitive decline, I was so impressed that I thought it was the end of the search for AD cure. Unfortunately, the physician has been stopped from doing it by FDA. But for reasons given below this is not the end of pursuing AD cure.

Now, the etiology wars come to decisive battle, so it seems. It is not yet clear in the press and the among the laymen but the battle order in this war comes to two choices: Neuroinflammation or Epigenetics. I wrote about the Epigenetics and chromatine remodeling. Link: https://piotrpeterblog.com/2021/03/05/novel-etiology-of-alzheimers-linked-to-neuronal-loss-of-function-due-to-changes-in-cellular-transcription-mechanism-and-dna-chromatin-complex-avxl-sava-atha-biib/ [1].

I stole an article posted by Amateur17 on iHub. Post #319819. Link: https://www.spectrumnews.org/news/autisms-link-to-chromatin-remodeling-explained/ [2]. The aticle draws partly wrong conclusion as it suggests that CRISPR could help, whereas CRISPR is a method of gene editing and not fixing epigenetic chromatin remodeling. As I posted in the post [1] SIGMAR1 receptor agonist like cocaine alteres chromatin remodeling. Link to paper is inside post [1].

Nevertheless, I want to make certain predictions as new elements in this puzzle emerge. I think that neuroinflammation is just a symptom of neurodegenerative diseases. One fact is that, those who attack neuroinflammation do it indirectly and do not affect such wide spectrum of indications as $AVXL does, all by the virtue of addressing a symptom not a root cause. And even if it would be direct, it would be just only treating a symptom vs. wider systemic action (including chromatin remodeling) of Blarcamesine spread across many diseases. In this light the drugs which just temper neuroinflammation should produce immediate results with stagnation in the therapeutics effect with time, or even reversal. Blarcaesine should on the other hand produced slower and steady (to a point) recovery.

I will be watching the data from AAIC 2021 with that in mind. I am particularly interested in $SAVA’s data. If it shows any weakness I think this might bode poorly as well on $ANVS prospects, but only might.

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Parkinson’s Drug Delivered, Not Just Parkinson’s Disease Dementia Drug! $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!

Etiology Battle Won

The first paragraph says it all.

ANAVEX®2-73 treatment resulted in significant increase in the expression of the SIGMAR1 mRNA biomarker that significantly correlated with improvements in the primary and secondary clinical efficacy endpoints CoA (p = 0.029) and MDS-UPDRS Part III (p = 0.024) and MDS-UPDRS Total (p = 0.038)

Wherever Blarcamesine has been treating patients increased SIGMAR1 messengerRNA has been detected, this direcetly connects the drug with the biomarkers and the therapeutic effect. Clear and known Mechanism of Action has been established. Blarcamesine is a pathblazer for other SIGMAR1 drugs making iself the first of a new class of drugs. This warms considerably the icecold feet of FDA.

Parkinson’s Disease Dementia Addressed

.……which correlated with clinical efficacy as measured by primary cognitive efficacy endpoints, CDR system Continuity of Attention (CoA) (p = 0.029) and CDR system Power of Attention (PoA) (p = 0.015),….

Broad and statistically significant improvements in CDR system Cognitive Domain of Attention assessed by Choice Reaction Time (p = 0.039) and Digital Vigilance (p = 0.008) and CDR system Episodic Memory (p = 0.047), representing complex cognitive tasks with impact on quality of life such as making a choice between similar objects and remembering daily personal experiences, which are mostly impaired in both PD and AD.[15] 
Statistically significant dose-dependent (p = 0.003) improvement of Episodic Memory, which has been shown to be highly correlated (70%) with the Alzheimer’s Disease Assessment Scale–Cognitive score (ADAS-Cog; r = 0.7).

See my previous post on Episodic Memory as was reported initially. link: https://piotrpeterblog.com/2020/12/04/after-conference-of-3rd-of-december-2020-on-alzheimers/ . I have calculated the Effect Size for Episodic Memory which in my reckoning was supposed to be about 1.40. We don’t have and other data than what is given in the quotation. Firstly, CDR is composed from few subtests like Continuity of Attention, Episodic Memory, Choise Reaction Time, Digital Vigilance and Power of Attention. Those subtests measure errors and speed of response. The only metric given here is the p-vales of each subtest. P-values refer to the probability of the results being part of the characteristic dispersion of data among the placebo cohort. The lower the number the better results, or data points are better separated from placebo. They are both statistically significant, with Power of Attention being the best. Nothing more can be said at this moment. This calls for deeper research than done by me at this time, and a separate post.

Did Blarcamesine Put Parkinson’s in Its Bag of Tricks?

I shall not engage in speculation right now. (Just for a moment) Let me quote from the PR.

….and secondary Parkinson’s efficacy endpoints Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS)[4], MDS-UPDRS Part III (p = 0.024) and MDS-UPDRS Total (p = 0.038).

Let’s us analyze the MDS-UPDRS test. It consists from 4 parts. I read through the questionnaire and tried to evaluate the maximum score obtainable which equates with scoring the worst on all measures. I can approximate the number of points to be about 230-240. The average Parkinson’s patient in the Phase2 PDD trial scores about ~77 points (1/.189*14.51= 76.8)(at the end of 14 weeks). Quick search revealed this to be about right.

Let us engage in pure speculation. We have the two mean values at 14 weeks and one of the standard deviations. We could explore the possible values for the dosed cohort standard deviation in order to calculate Effect Size for the Blarcamesine as Parkinson’s disease drug.

  • The placebo score is 77+/-32.8
  • Dosed score is 62.5+/-30 (assumed sdandard deviation of +/-30)

The Effect Size @ 14 weeks is 0.45. This is almost enough to approve the drug (minimum) but we would expect this to increase witht the duration of the trial as Blarcamesine Effect Size in progressive neurodegenerative diseases increases with the duration of the dosing. We have to remember that Donezepil was approved with Effect Size of 0.28 after six months of dosing (24 weeks).

Not without a reason, Dr Missling singled out the Part III (p-value of .024) from the MDS-UPDRS Total (p=.038). Part III is the motor examination which loss of is characteristic for the disease. Here, the implication is that patients on Part III score “better” than on measures of dementia and daily living, and the drug is engaging the core etiology of the disease.

Additionally, Blarcamesine improvement has been twice the empirically established cutoff score for spurious improvement of -7.1 points of MDS-UPDRS. We have remember that all this is happening at 14 weeks of dosing. As I previously pointed out, Parkinson’s is a progressing condition so even staying in place makes for larger Effect Size with time. A relatively small Effect Size is due to large size dispersion around a mean. The same reason might be behind the empirical cut-off of -7.1 points as such small difference in between the two mean is not sufficient to separate the two dispersions for any meaningful effect. After pluging the numbers into the formula for Effect Size we arrive with the number of 0.22, which qualitatively is below small. I guess many trials produced somewhere below -7 points only ultimately to disappoint. One might compare it to gravitation and Blarcamesine breaking away from it to leave its pull permanetly.

The Phase2 PDD has given us enough of data to claim that Blarcamesine is not only able to treat Parkinson’s dementia but also Parkinson’s disease itself. The experience with the extension of Phase 2a Alzheimer’s give us confidence that the effect of the drug will not wane with time but might reverse the ravages of the disease.

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Intense Politics of Biogen’s Aduhelm and Companies like Anavex Life Sciences and Annovis. $BIIB $AVXL $ANVS

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!

“Phase 4” and Aduhelm

Biogen’s Aduhelm has been approved along the line of pratice in cancer drugs field where barely promissing drugs are allowe to go on with the caveat of phase 4 – post approval verification that the efficay is there when patient numbers are large enough. No wonder that Big Pharma loves this cancer treatment paradigm, test and approve drugs with ever increasing efficay but a long way from cure and be always under patent protection. All with sufficiently high price tag for people who face the stark choice between certain death and possible cure. The Aduhelm label did not limit the drug to carriers of APOEe4e4. It opened the gates for virtual everybody witht the diagnosis. Biogen claims that it needs a decade in order to confirm that the drug works against Alzheimer’s as it claimes. In 3 years there should be undeniable proof that the drug does not work, or works as $BIIB maintains. Due to the dispersion of testing data and outcomes after 3 years there should be sufficient data to determine the efficacy of any Alzheimer’s drug. You can find this information in a paper link: https://pubmed.ncbi.nlm.nih.gov/10404988/. This is a brazen raid on Medicare and by extension the federal budget. The politics around this will become intense. On one side we have Biogen, FDA reputation and lots of free money (see new allies sharing the spoils), on the other side almost dead politics of limited resources as represented by some in the Congress, honest scientists and doctors, perhaps rank and file FDA bureaucrats, may be even federal bureaucracy, and companies like $AVXL and $ANVS. Depending on the pull of one or the other side in this contest of clout the approval of other Alzheimer’s drugs can be either accelerated or delayed, and it is hard to say who will prevail here. I do think that Dr Misslings emphasis on Autism Spectrum Disorders might be a way of advancing Blacamesine forward without relying too much on the Alzheimer’s market alone to creat value as Alzheimer’s Phase 2b/3 slowly comes to its reading of top data.

Rett Syndrome Phase 2 (RS-001) Which was Really Phase 1 Which Turned Almost into Phase 3 $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!

To start talking about the 15 person dosed cohort in RS-001 Phase 2 one has to get on the subject of the dose right away. At 5mg/daily, it seems that $AVXL thought it was dispencing poison to the girls, when the maximum dose is 50mg/daily. By all accounts, that is only 1/10 of the maximum dose. I am of the impression is that we were really dealing with phase 1 trial turning into phase 2 which might then turn out to be phase 2b/3. Was this by Dr. Missling design or by FDA’s? Nevertheless, we have three trials cascading. Of course, there was a bit of a specious reasoning in what I said. Nevertheless it illustrates the astounding results and the relationship between dose and the results.

The companies PR on the results reads like a scienfific paper on the merits of SIGMAR1 platform not just regular PR with few data points dispersed words of “statistically significant” and “clinically significant”. The earlier analysis of the 6 pharmacokinetics patients seemed to imply slightly higher scores to the RS-001 but they were lacking depth. Link to Post: https://piotrpeterblog.com/2020/12/07/rett-syndrome-data-already-out-anybody-pays-attention/. The extremely low p-values suggest that the probability of these results being just part of dispersion of placebo is very low, if none. Moreover, almost all measures point to improvement over placebo.

Quoting from the PR:

The RSBQ demonstrated balanced improvements across all the instrument’s subscales during the trial period of 7 weeks, including general mood, breathing, hand behavior, repetitive face movements, body rocking, night-time behavior, fear/anxiety, walking/standing.

This is unidirectional change leaving no possibility to some statistical event, or rather what we call a fluke. The most important is the night time behavior. The sufferes of Rett Syndrome often wake up in the night and scream or moan. Sleep belongs to the most underappreciated CNS functions, unless you don’t sleep deeply for two or three nights. Depriving somebody of sleep is a form of torture and can even lead to death. On YouTube one can find the horrific results of Soviet experiment with sleep need-stopping gas. The whole thing reads like a horror story, not a scientific experiment. This anecdote conveys the importance of sleep like no other. Through all the trials of Blarcamesine the thread of sleep quality weaves from one trial to another but never becomes the main story. In RS-001 it becomes salient, for care-givers it is very disruptive of the their lives and the lives of the girls. It testifies to the ability to assuage the suffering of the girls.

I wanted to point to a type in the data and one important point. Let’s see the slide.

in the data for CBI-I those for the dosed with Anavex2-73 the none responders should be marked 15.3% not 60%. Just a remainder but an essential one.

These scales are very subjective. You can see that when you compare CGI-I and RSBQ scales and the resultant numbers of none reponders. CGI-I is completed by medical practitioners. RSBQ consistes with responses from care-givers. The practitioners saw only 2 cases with no improvement whereas the care-givers saw just 5. This discrepancy spreads to the evaluation of those on the placebo arm, practitioners seem more improvements than care-takers. No wonder, paractitioners must rely heavily on memory for assesment, but on the other hand, care-givers will not notice subtle changes as they are easly habituated to them.

Comparing results on RSBQ scale with the pharmacokinetics cohort we see that we have the same fraction of the non-responders as in the previous release of data. we don’t have the initial RSBQ or CBI-I scales to give any percent improvement vs. the initial score. On average, the RSBQ score of a patient with Rett Syndrome is about 45 points. Phamacokinetics cohort specified this at 50 points on RSBQ scale. So we have 29% improvement in just 7 weeks on miniscue dose of 5mg/kg daily.

Though, the number of reponders on ADAMS scale is just 60% of the 15 patients vs. 66% on RSBQ scale the same pattern of unidirectional improvement follows.

ADAMS is 84 point scale, improvement of 12.9 points makes 15.4% of the scale. Usually, the average patients is somewhere on the scale so that improvement starts from there. If it is comparable to RSBQ we couldd have about 27% improvement from the average initial score. Larger Cohen’s d (1.31 vs RSBQ 1.11) suggests even greater improvement from the initial score or lower initial score on severity of Anxiety, Depresion and Mood Scale.

What is important, is that Cohen’s d Effect Size is 1.31 for ADAMS and 1.11 for RSBQ scales. In the land of drug development these are very good number meaning very large and large respectively Effect Sizes. Effect Size ~.50 is considered large enough to warrant an approval.

That is all folks, on a trial named Phase 2 but being more of a phase 1 and turning into phase 3 by Effect Size alone.

SIGMAR1 is a platform, not a drug. Blarcamasine is the first drug interacting with SIGMAR1 receptor. The sigma 1 receptor from an obscure begining has evolved to position of providing explanation to incidence of CNS degenerative diseases as solely connected with its expression and action. That makes sigma 1 receptor to be another player in the etiology wars for AD. The response in AD and PDD happens only with the maximum dose but in Rett Syndrome it appears at just 1/10 of that. If indeed the SIGMAR1 platform drugs are ubiquitous in their actions against CNS diseases, as it can be seen in their abilities to improve patients in AD, PDD and Rett, we might soon be addressing the need for the disease under the umbrella of Autism Disorder Spectrum diseases. Autism Disorder Spectrum might be an concoction, and the underlying etiology might be different for similar phenotypes. I am not stating that this is the case but it is the worst case for disease as it might see diversity of yet not fully known or unknown etiologies. But there is possibility that SIGMAR1 platform drugs can address them.

The arena of AD and PDD is crowded. It is my perception that the ADS field is not that full of competition as AD’s. The numbers of patients and the need might be even larger than AD. The results in Rett Syndrome and soon Fragile X might have ushered the need to raise additionally money as opportunities in ADS field need to be explored.

Moar Beer Money!

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Aduhelm (Aducanumab) Value vs. Its Truly Restricted Market, and The Same for Blarcamesine $BIIB $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!

Biogen surge of $15bln in market capitalization due to Aduhelm approval does match the restricted market the drug faces. I am taking off where Lane Simonian left without giving any numbers in its latest SeekingAlpha article, link: https://seekingalpha.com/article/4435705-post-biogen-post-amyloid-world-for-alzheimers-disease .

Following Bazilian study looked at the incidence of all allels of the APOE gene in Late-Onset Alzheimer’s Disease (LOAD). Link: https://pubmed.ncbi.nlm.nih.gov/22068907/. This is the table with the distribution of APOE e4 gene in the LOAD population.

The control group lists something like the number of APOE e4e4 people in the general population. It is indeed a miniscule number, but due to its high odds to develop Alzheimer’s the poplution of LOAD sufferes with both e4 alleles is at 13% of all cases. You can expect that discrepancy in the light of odds almoet 14 times larger to develop LOAD than general population.

Annually, about 500,000 new cases of Alzheimer’s are diagnosed. I would add that Aduhelm should not be prescribed to those who a advanced into the disease more than that. This gives 56,000 patients to be dosed at $56,000 a year. Is this any numerlogical coincidence? The revenue from the drug might reach ~$3.16bln. Looking at cool 1/3 going towards the bottom line ~$1.05bln, with 20 P/E ration gives $21bln market capitalization. Indeed prized like an orphane disease.

If the inital success of Blarcamesine in Phase 2a High Concentration Cohort will be replicated and even improved in Phase 2b/3, what can we expect? Let’s make some assumptions; average length of dosing 5 years but we only will consider 1 year, 50% of those diagnosed (50% of 500,000=250,000) on the drug as the drug works on 80% population at the least, annual cost $20,000 (a off the patent generic CNS medication cost about that $8,000/y ) and half the revenue goes to bottom line. $AVXL Market capitalization could reach ~$50bln initially.

This analysis does not involve the idea of all the 50’s old people taking small doese to gaurd against senescence. I have pointed out that there are the three Alzheimer’s epidmics. Those with healthy bodies getting early disease and after 5-10 years dying of Alzheimer’s, those slowly deteriorating due to senescence and those who start deterirating rapidly from low cognition level already (due to age) and dying due to other comorbidity. The incoming evidence in basic research points that SIGMAR1 receptors agonist could tackle the three populations of dementia patients making dementia a rare occurance in later life. You can look at the previous posts on this blog which document the outpouring of possible etiologies of Alzheimer’s, all connected to the SIGMAR1 receptor mecanism of action. If the numbers of patients taking Blarcamesine can be extended to general population the calcuation of the $AVXL bottom line become too spectatula and speculative to ponder even if Congress will put restrictions on drug price .

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Post On “Multi-Targeted Ligands (MTDLs) Binding the SIGMAR1 Receptor as Promising Therapeutics” $AVXL Blarcamesine Anavex3-71

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!

The paper of the same title, link here https://www.mdpi.com/1422-0067/22/12/6359 , described number of compounds and their chemistry, among them it mentioned ANAVEX 2-73 and 3-71 as examples of the most studied drugs in the class of MTDLs drugs. It also listed number of other drugs and their targets besides SIGMAR1, touching here on the logic of pain-relief and fighthing cancers which might be connected with the functioning of the Brain Blood Barrier.

There are two types MTDL drugs. Hybrid Drugs which are synthesized from two drugs with “weak bonds” between them to be easly metabolized by the liver producing two metabolites acting on two different receptors. The other type is Chimeric Drugs which are combination of two or more acting domains with strong bonds, acting on two or more receptors. They have better pharmcokinetics and better interaction with the targets.

The paper describes trials at synthesis of such drugs, all working on SIGMAR1 and on other receptors. What is very interesting is that in Mitochondria Associated Membranes where SIGMAR1 protein most likely resides the protein itself occures in oligomer structure. This has very interesting consequences as agonist and antagonist are not clearly defined by binary like action. Agonists tend to lower the number of copies of the protein in these structures more than the antagonists, in very gradual manner from drug to drug. This creates a situation where different agonist and antagonist can have varying therapeutics effect based on the minutia of their chemistry. The therapeutic effect can be dependent on the chemical structure of the drug and be very specific to the drug itself. Quote:

…..the different oligo‐ meric structures could be responsible for the many activities performed by these versatile receptors, with agonists and antagonists differently influencing the association among protomers: agonists produce lower oligomeric structures such as monomers and dimers, while antagonists produce higher ones [29].

There is plethora of very specific to chemistry information, of SIGMAR1 and drug design in this paper.

I want to quote the paper on the location of the SIGMAR1 receptor in human body. This is very interesting as number of organs might be ultimately under the beneficial influence of the SIGMAR1 drugs. Yet, I have to add that these can be either beneficial or harmful.

σ1 Receptors have been found in the central nervous system (CNS), particularly in the granular layer of the olfactory bulb, in many cortical layers, and in the dentate gyrus [6], where they exert their most important activities. A slightly lower expression has been also found in some pyramidal layers of the hippocampus, various hypothalamic nuclei, the septum, the central gray, the motor nuclei of the hindbrain, and the dorsal horn of the spinal cord [6]. At the cellular level, σ1 receptors have been found in ependymocytes, which border the ventricular compartments, and in neurons located within the CNS parenchyma [6].

In peripheral organs, σ1 receptors have been found in the gastrointestinal tract [7], vas deferens [8], in liver and kidney [9], heart [10], adrenal medulla, pituitary, testis, and ovaries [11].

The olfactory bulb referece to the sense of smell. Haven’t we all heard about the peanut butter smell test for Alzheimer’s?

Another quote from the paper.

The neuroprotective action of σ1 receptor agonists is well established, and it has been proved that this activity is exerted through different mechanisms such as intracellular Ca2+ regulation, the prevention of oxidative stress, and anti‐apoptotic effects. The σ1 subtype contributes to protein homeostasis: it can stimulate neurotrophin receptor signaling and reduce protein aggregation responsible for neurodegenerative disease, and it can also ac‐ tivate autophagy as a protective mechanism against damage arisen by misfolded proteins. Recently, many studies proved the ability of σ1 receptors to directly or indirectly interact with receptors or enzymes with key roles in neurodegeneration, particularly in Alz‐ heimer’s disease (AD). Importantly, in patients with AD, a reduction of σ1 receptor density [20] has been demonstrated. Some studies attributed such reduction to the E4 variant of the apolipoprotein E gene (APOE 4) [21], although some controversies still exist [22]. All these mechanisms can promote cell survival and consolidate the role of the σ1 receptor as a target for therapies against neurodegeneration [23].

The key piece of information is that Alzheimer’s patients display reduction in SIGMAR1 incidence in CNS cells. Agonist such as Blarcamesine could stimulate release of the beneficial proteins from the MAM domains to compensate for the lower incidence on SIGMAR1 protein. The other piece of infomation is tentatively connecting this with the APOE e4 gene variant. I have “committed” a post where I stated that APOE e4 carriers were helped by Blarcamesine but I assumed that those 3 which I dentified were drop outs, but they were actually helped and stayed in the trial. We have anecdotal evidence from later data on the 3 year performance of the High Concentration Cohort, keeping 8 out of 9 in the cohort over 3 years time, and Dr. Missling saying that (praphrase) even those with bad genetics can be helped if dosed long enough.

In this particular study in late-onset Alzheimer’s (LOAD) , about 56% are APOE e4 carriers. Those with two copies of e4 are almost 14 times more likely to get AD than the general population. Those with one copy, like e3e4, are 2.33 times more likely. Compare this with 75% carriers in the High Concentration Cohort.

If I am not wrong APOE e4 is the only clear link in genetics to Late-Onset Alzheimer’s Disease. If this connection between APOE e4 and SIGMAR1 is indeed true then there is a clear connection between SIGMAR1 lower incidence and Alzheimer’s. Since the SIGMAR1 covers broad spectrum of physiology, this could be overwhelming evidence that SIGMAR1 agonist and among them Blarcamesine and Anavex3-71 are the Alzheimer’s go to drugs, and not only Alzheimer’s. Most other drugs usually interact with one or few of the compounds SIGMAR1 agonists release.

One of interesting facts, yet of little value for us, is that one of the endogenous ligands to SIGMAR1 is DMT which is a hallucinogen. YouTube is rife with stories of trips taken under the drug. One more quote on the various effects ligands to SIGMAR1 might cause:

Molecular dynamic simulations at the σ1 receptor binding pocket have shown how the diverse chemical structures to which high‐affinity σ1 receptor ligands belong may easily be accommodated producing different associations among pro‐ tomers that lead to the different activities observed.

The therapeutic search for various SIGMAR1 drugs has just started. Number of drugs which had been previously treating other disease have now been connected with SIGMAR1 interactions. A new wave of drugs are synthesized to have the ability to interact with SIGMAR1 and other receptors. Not all of them are going into the clinic but the capabilities of SIGMAR1 are now more than ever recognized as primary therapeutic target.

Both Blarcamesine and ANVEX3-71 are examples of MTDLs as they interact with SIRMAR1 and muscarinic receptors. ANAVEX3-71 has also been known to reduce beta-secretase 1 levels. This might be helpful in treating Lewy Bodies Dementia. Let me again quoote from the paper:

The effect of σ1 receptors in inflammation through microglia modulation has been reported [54,86,87], and AF710B was shown to reduce reactive astrocytes and activated microglia in the animals, as detected by the low levels of glial fibrillary acidic protein (GFAP) and ionized calcium‐binding adapter molecule 1 (Iba‐1). Notably, astrocytes and microglia are increased in number and size in AD patients.

In addition to AF710B and ANAVEX 2‐73, Anavex Life Sciences Corp portfolio com‐ prehends an isomer of ANAVEX 2‐73, named ANAVEX 1‐41 (Figure 2) that next to the activity toward σ1 and M1 receptors, also displays activity for α1, 5‐HT2, and D3 receptors [81], with an indication for the treatment of depression, stroke, and neurodegenerative diseases (anavex.com/#!/pipeline).

I have presented here information mostly pertaining to Alzheimer’s and neurodegenerative diseases. SIGMAR1 is also through the method of MTDLs implicated in creation of new drugs fighting pain and drug resistant cancer cells. Next post will be drawing on that theme from the same paper.

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