SIGMAR1 Agonists – Therapeutic Swiss Army Knives $AVXL, Prilenia Therapeutics, $ATHA, $ALKS, $SAVA

SIGMAR1 Agonists – Therapeutic Swiss Army Knives

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

My intention is to call on a paper which unravels the mystery of mechanism of action of the SIGMAR1 receptor agonists, among them is Blarcamesine ($AVXL) and Pridopidine from Prilenia Therapeutics Development LTD.

The paper in question is titled

[1] Sigma-1 Receptor (S1R) Interaction with Cholesterol: Mechanisms of S1R Activation and Its Role in Neurodegenerative Diseases

Vladimir Zhemkov 1, Michal Geva 2, Michael R. Hayden 2,3 and Ilya Bezprozvanny 1,4

Link https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071319/

The abstruct reads..

Abstract: The sigma-1 receptor (S1R) is a 223 amino acid-long transmembrane endoplasmic reticulum

(ER) protein. The S1R modulates the activity of multiple effector proteins, but its signaling

functions are poorly understood. S1R is associated with cholesterol, and in our recent studies we

demonstrated that S1R association with cholesterol induces the formation of S1R clusters. We propose

that these S1R-cholesterol interactions enable the formation of cholesterol-enriched microdomains in

the ER membrane. We hypothesize that a number of secreted and signaling proteins are recruited

and retained in these microdomains. This hypothesis is consistent with the results of an unbiased

screen for S1R-interacting partners, which we performed using the engineered ascorbate peroxidase

2 (APEX2) technology. We further propose that S1R agonists enable the disassembly of these

cholesterol-enriched microdomains and the release of accumulated proteins such as ion channels,

signaling receptors, and trophic factors from the ER. This hypothesis may explain the pleiotropic

signaling functions of the S1R, consistent with previously observed effects of S1R agonists in various

experimental systems.

The SIGMAR1 receptors are in this paper associated with parts of Endoplasmic Reticulum which contain the ER/Mitochondria-Associated Membrane (MAM). Yet these are not the only places which hold SIGMAR1 receptors, to present evidence that SIGMAR1 receptors are also involved with the Nucleus Envelope, I am going to quote the abstruct from another paper.

The sigma-1 receptor (Sig-1R) chaperone at the endoplasmic reticulum

(ER) plays important roles in cellular regulation. Here we

found a new function of Sig-1R, in that it translocates from the ER to

the nuclear envelope (NE) to recruit chromatin-remodeling molecules

and regulate the gene transcription thereof. Sig-1Rs mainly reside at

the ER–mitochondrion interface. However, on stimulation by agonists

such as cocaine, Sig-1Rs translocate from ER to the NE, where Sig-1Rs

bind NE protein emerin and recruit chromatin-remodeling molecules,

including lamin A/C, barrier-to-autointegration factor (BAF), and histone

deacetylase (HDAC), to form a complex with the gene repressor

specific protein 3 (Sp3). Knockdown of Sig-1Rs attenuates the complex

formation. Cocaine was found to suppress the gene expression

of monoamine oxidase B (MAOB) in the brain of wild-type but not

Sig-1R knockout mouse. A single dose of cocaine (20 mg/kg) in rats

suppresses the level of MAOB at nuclear accumbens without affecting

the level of dopamine transporter. Daily injections of cocaine in

rats caused behavioral sensitization. Withdrawal from cocaine in

cocaine-sensitized rats induced an apparent time-dependent rebound

of theMAOB protein level to about 200% over control on day 14 after

withdrawal. Treatment of cocaine-withdrawn rats with the MAOB

inhibitor deprenyl completely alleviated the behavioral sensitization

to cocaine. Our results demonstrate a role of Sig-1R in transcriptional

regulation and suggest cocaine may work through this newly discovered

genomic action to achieve its addictive action. Results also

suggest theMAOB inhibitor deprenyl as a therapeutic agent to block

certain actions of cocaine during withdrawal.

Title of the paper:

[2] Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatinremodeling factors at the nuclear envelope

Shang-Yi A. Tsaia,1, Jian-Ying Chuanga,b,1, Meng-Shan Tsaia, Xiao-fei Wangc, Zheng-Xiong Xic, Jan-Jong Hungd,

Wen-Chang Change, Antonello Boncif,g,h, and Tsung-Ping Sua,2

LINK: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4664336/ kjinm

SIGMAR1 Agonists and ER/MAM Microdomains

To have a better look at these papers is to recognize that different neurodegenerative diseases have been traced to the terms of health of SIGMAR1 receptors. Since it is impossible for me to read that many papers, and it would require to posses tremendous amount of knowledge and high level of analysis so instead I rely here on [1]. The paper has two officers of Prilenia Therapeutics LTD as co-authors.

This is further supported by human genetic studies, showing that complete loss of function (LOF) mutations in the S1R are associated with a juvenile form of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD), while partial LOF mutations cause late onset ALS [11–14]. Thus, there is a gene dosage relationship between S1R activity and the age of onset of ALS with the complete loss of S1R associated with the earliest age of onset. Additional LOF mutations in the S1R cause distal hereditary motor neuropathies (dHMN) [15–19]. Furthermore, S1R expression levels are reduced in sporadic ALS [20], Parkinson’s disease (PD), and Alzheimer’s disease (AD) patients [21,22].

This connection is very important since the health of SIGMAR1 would be then bestowing a natural resistance against these ailments as I intepret the implcations correcetly, here. When talking SIGMAR1 health we can as well talk quality and quantity. Quality can be traced to mutation in the SIGMAR1 gene and quantity into relative amount of trascribed protein. I believe that at this point both of these can be measured for truely precision medicine. SIGMAR1 agonist release into CNS tissues proteins which shortage can be blamed on the SIGMAR1 condition or lack of in quantitative sense. This pictutre might be partialy true or might be very strong, but the true strength will be revealed in number of trials where SIGMAR1 agonist will be given to the patients. If indeed SIGMAR1 gene expression can be linked to neurodengenerative diseases then a genetic tests can be administered to assess the probability of an individual to succumb to any of these ailments, at least in the very general terms. Nevertheless, if such connection can be drawn then purely “natural” way has been found to ameliorated conditions leading to these diseases. I listened to presentation by Prilenia officer, available on Prilenia’s website, and again I heard a notion implying that the drug is more of a preventative so that it should be given and is most effective in patient at the earliest onset of the symptoms and the disease than at the more advanced stages. As notion has been expresed by both, $AVXL and Prilenia, it seems to confirm what I wrote above.

In paper [1] the ER/MAM microdomains are involved in “processing” post transciption proteins into fully folded functional ones, but these microdomain are used also as “storage facilities’ for those protein. The scientist involved just advanced this hypothesis in this paper. The number of the protein has been “captured” and their connections to various physiological mechanism vaugely given. They range from Ca+2 channel regulating to extracellular matrix protein. The spread in function between those protein covers many of those therapeutic targets advanced by various companies. In few cases, these companies have been mentioned on this blog. For example, $ATHA Athira has been talked about in terms of the merits of its terapeutic target which is a neural growth factor not unsimilar to brain derived neurotrophic factor (BDNF) released by SIGMAR1 agonists. If indeed the SIGMAR1 agonist action releases plethora of vital to neural (and not only neural) health factors then most of these companies are concentrating on a single factor in the CNS health puzzle of tens if not hundreds of factors. The CNS diseases are then attacked on the perifery leading to limited results vs. serendipitously hitting the jackpot.

The above paper also stated that the action of the agonists releases the SIGMAR1 protein into the endoplasm. The seccond of the papers [2] places the next position where the SIGMAR1 protein ends up after this process as the Nuclear Envelope. The paper [2] contains a text box titled Significance.

That is only part of the story. a company called Alkermes $ALKS works on compound bringing about increased trascription of genes connected with the creation of synapses. The macropicture of that interaction can be presented with the slide from the corporate presentation 2021.

The genetic mechanism involved includes following genes and proteins.
Here comes a slide witht he basic information on conveying the therapeutic target at the basic level. It is also a very good illustration of way the DNA helix is package and the trascription is controlled.
The SIGMAR1 agonists afect the same Histone Deacetylases HDAC as it was elucidated in the paper [2]. Just as I try to point out that the present effort to tackle CNS diseases becomes multi-prong, outside the field of SIGMAR1 it usualy involves a single agent at a time. Following quote from [2] should bring the point home.

Cocaine apparently increased the levels of Sig-1R, lamin A/C, and emerin (Fig. 2H). Those binding to HDAC3 (24). To clarify whether emerin also binds with other class I HDACs, we performed co-IP assays for emerin, HDAC1, and HDAC2. Anti-emerin antibody pulled down both HDAC1 and HDAC2 (SI Appendix, Fig. S5A). Conversely, the HDAC2 antibody pulled down emerin and HDAC1 (SI Appendix, Fig. S5B). Those results indicated that emerin interacts with HDAC1 and HDAC2, as well as with the recently reported HDAC3. Cocaine dose-dependently increased the interaction of emerin with both HDAC1 (SI Appendix, Fig. S5C) and HDAC2 (SI Appendix, Fig. S5D).

The interacting proteins are the same but the resulting changes are different. Cocain blocks the production MAOB protein which is plays a role in controlling the quantity of Dopamine the feel good neurotransmitter. The user of cocaine have elevated levels of Dopamine. Upon break in usage he feels withdrawal symptoms as MAOB surges to 2-5 fold greater amount cutting the available Dopanime. The mechanism involves the same proteins but the inner workings are still a mystery. Each SIGMAR1 agonist will have smoehow different pattern of action, at least what the current knowledge suggests. Ultimately, there will be a race between all those pictured on the opening illustration. $AVXL and Prilenia are at the best runners at this moment. Their piplines are not conflicted at this moment as Prilenia pursuits ALS and Huntington Disease, but soon will try its drug on Rett Syndrome, in few years time. At this point Prilenia is private.

Paper [1] ishas been written as an extesion of Prilenia Theurapeutics LTD study. As far I know at this moment both Blarcamesine and Pridopidine are the most advanced in clinical studies SIGMAR1 agonist. Paper [1] makes a mention of it.

Recent clinical studies have shown the potential efficacy of the selective S1R agonist

pridopidine in HD patients, demonstrating maintenance or slowing the decline of

the patient’s functional capacity [127,128]. The non-selective S1R/Muscarinic (M1R) agonist

blarcamesine shows a potential beneficial effect in AD [129]. Clinical pivotal studies

with pridopidine are currently ongoing for HD and ALS (NCT04556656, NCT04297683).

Blarcamesine is currently being evaluated for AD, Rett syndrome, and PD dementia patients

(NCT04314934, NCT04304482, NCT04575259). Results of completed clinical trials

of S1R agonists in variety of disorders have been comprehensively summarized in recent

reviews [4,130].

Number of voices has been clamoring to speed up the development of Blarcamesine. Prilenia has targeted as its first dieases to tackle Huntington Disease. It phase 2 has interestigly stretched into 5 years of data in OLE study, not unsimilar to Blarcamesine AD phase 2 OLE.

The scale TFC (Total Functional Capacity) starts with 13 as fully functional and decends to zero for total loss of function. I believe that the mean TFC score for all patients has been around 9 points. There are no bars suggesting standard deviations so Effect Size can not be calculated. What is interesting here is that it is a first drug for HD which makes for hope of any efficacy in HD. Again, Prilenia makes the point that those who were in the earlier stages of the disease responded much more vigorously than those with older diagnosis. SIGMAR1 agonists make for natural way of defence against CNS degenerative diseases and are very interesting from evolutionary biology point of view.
Prilenia just like $AVXL with AD has acumulated 5 years of data on Huntington Disease. There is a quip going in biotech stocks world that one should never invest in the first company with new type or MOA drug as FDA needs so much data on safety and efficacy that it becomes a challenge to investors patients. Once the path is blazed through the FDA wilderness second and third companies with the same MOA are a better investments. We shall see whether this becomes also true in the case of $AVXL and Prilenia.

Before I wraped up this post I would like to call on a third paper

[3] Stimulation of astrocytic sigma-1 receptor is sufficient to ameliorate inflammation- induced depression

Author links open overlay panelLinGuoab1TianyuGaoa1CeGaoaXiaoxiaJiaaJingNiaChaojunHancYunWanga

Quoting the abstruct from the paer [3]

Astrocytes play important roles in the development of depression. As a promising target for antidepressant development, sigma-1 receptor (Sig-1R) is reported to promote activation of astrocyte in chronic stress-induced depression in our previous study. However, astrocytes are hyper-activated in inflammation-induced depression, raising concerns of whether stimulation of astrocytic Sig-1R would exert antidepressant-like effect in inflammation-induced depression. Here we reported that specific stimulation of astrocytic Sig-1R using adeno-associated virus (AAV) significantly attenuated lipopolysaccharide (LPS)- induced depressive-like behavior in the forced swim test (FST), tail suspension test (TST), sucrose preference test, and improved the memory function in novel object recognition test. Besides, specific stimulation of astrocytic Sig-1R decreased the activation of astrocyte and microglia, as well as increased brain-derived neurotrophic factor (BDNF) in LPS-induced depression. In primary cultured astrocytes, overexpression of Sig-1R also reduced the expression of IL-1β, TNF-α, iNOS during inflammation-treated astrocyte. Taken together, the results suggest that specific stimulation of astrocytic Sig-1R ameliorates inflammation-induced depressive-like behavior, providing the evidence that astrocytic Sig-1R could represent a reliable therapeutic target for depression.

Though, the paper [3] deals with inflammation caused depression it references the lowering of inflammation biomarkers among astrocytes. These cells nurture the neuron and inflammation is mentioned as a cause of neurodegeneration by few companies in their narratives of providing therapeutic action. To mind comes here $SAVA. here, again we are looking at very broad therapeutic action of SIGMAR1 agonists vs. single or double target from its competitors. The middling results from $SAVA, between total losers like $BIIB Aducanumab and promissing high fliers like $AVXL, are proof that $SAVA laboring under the single or double therapeutic target syndrome.

The scientific evidence is piling up when it comes to MOA of SIGMAR1 agonists. FDA does not like MOA missing from the clear picture but this is quickly changing as researchers have taken their interest to SIGMAR1 receptors. This field is vast and barely scratched so chances for seminal papers are great and I hope that money will not only flow from companies pursuing drugs but government grants on basic research.

CRISPIR has all the attension but as CRISPIR can cure those who have genetic mutations, it can not affect the kind CNS degeneration described in my post ( 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/ . The number of people with genetic disorders can be large so does the number of people with CNS degenerative diseases who carry no genetic mutation but succumb to age related degeneration. In public eye the amyloid plaque is the main actor behind Alzheimer’s degeneration. Yet, the cure can come from the proverbial left field on which we can find SIGMAR1 receptors. But unfortunaletly, this is not yet the case with the public. Patience is advised.

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Vivoryon and Others: Neuroinflammation or Epigenetics; Risk and Reward Today $LLY $SAVA $CRTX $AVXL $ALKS

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

There is Nothing like a Good Slideshow….

I looked at Vivoryon, a Dutch company with German address, or the other way around. I stole some slides from the presentation as they make great visual aids so that I don’t have to type so much. LOL.

From Vivoryon presentation being available on its website. I would advise to go to the website and view the presentation.

Nicely put, three waves of Alazheimer’s drugs. In the third way we finally have nueuroinflammation, synaptic function and protein stabilization. $SAVA, $CRTX $ALKS and Vivoryon fit the former two, $AVXL I would place in all. This is very imperfect description of the therapetic target classification but it might in some limited way contain the gist of the situation at this moment.

Varoglutamastat with respect of its MOA would be described as aiming to lower neuroinflammation by removing pGlu-ABeta which is best described in the next slide.

This makes a great presentation from the company as the target is well defined and what is more it is present only in the diseased individuals. On the face of it removing pGLU-Abeta should improve the patients.

The trial Phase 2a has 16 weeks duration, recuited patients with MMSE scores 21-30 who exhibited Mild Cognitive Impairment and are treatment naive. The latter is important as in many trial patients are on Standard of Care Drugs.

Here again, we see that it is much easier to cure AD patients on biomarkers than on measures of cognition. Nevertheless, in 16 weeks some measures of working memory are reaching the efficacy of Donezepil without having anybody on Donepezil or any other SOC drug. Working memory is the most important mark of cognition. Mr Dauer makes a point that Vivoryon chose the same therapeutic target as $LLY. I think I have mistaken Donanemab as pure Amyloid play. Actually, as I learn more about Amyloid/Tau physiology the connection starts being established between those two biomarkers and the neuroinflammation. The question of the day is; is it possible to stop Alzheimer’s progress by only controlling the neuroinflammation due to AmyloidBeta or any other cause?

So, let’s see what targeting pGlu-Abeta has done for Eli Lilly’s Donanemab.

see Eli Lilly website for the full presentation.

Let’s compare it with Donezepil (Aricept) (copied from the label).

Anybody who ever invested in Alzheimer’s drug company knows how after just 6 months the Donezepil effect ebbs, and the decline resumes. Donanemab isn’t even beating Donepezil in the first six months but shows limited improvement by lagging the progress of the disease by six months. From the viewpoint of an epidemiologist, this does not provide any value.

For anybody investing in these companies of primary concern is the therapeutic target because it seems that for many years drug discovery has been barking up the wrong tree. There are three distinct options now. The plaque as the therapeutic target, both Amyloid and Tau, in its classical sense you stick with the narrative; “let’s get rid of it and cure the patients”. To that effect, Big Pharma wants to even use antisense RNA silencing technics to interdict its synthesis in the cells, besides the antibodies like Donanemab marking it for destruction by the immune system. This is the narrative of “direct assault”. This mutates right now, as more is known about the plaque/tau physiology, to focus the assault onto the most toxic components in views of failures of “direct assault”. The narratives are morphing now into the tale of fighting neuroinflammation itself. I think that a bit further and neuroinflammation will emancipate itself from the amyloid/tau cause/sign narrative. This is inevitable in the prospects of marginal effects on the conditions of the patients. The companies following the scenario described above, that is from getting rid of the plaque to moving against neuroinflammation are $BIIB, $LLY, then Vivoyron crossing the rubicon to neuroinflammation/plaque combined narrative, as well as $SAVA and $CRTX.

$SAVA transforms itself into this perfect vehicle for neuroinflammation but still calls on the plaque in its narrative. $CRTX created its own narrative of neuroinflammation with the gingivitis bacterium being the sole cause of the Alzheimer’s destruction wrecked on the brain.

The second option is “synaptic health”. Here, we see the neurotransmitters as the “fuel” to run those “neural-switches”. Our good friend Donepezil and most Standard of Care drugs have mostly something to do with neurotransmitter quantity or receptors of neurotransmitters. They fail in the same predictable manner as they address not the disease but temporarily boost the performance of the still prevailing healthy neurons. $ALKS wants, by the way of HDAC inhibitor (ALKS 1140), to make neurons sprout new synapses on dendrites hoping that this will help to restore the synaptic health (in numbers synapses but not their individual health?). HDAC Inhibitors affect the transcription from the DNA-Chromatin complex in this way making the neuron create more synapses. In my mind questions abound on this attempt to rectify the basic observation of vanishing synaptic quality and quantity but the way it is done seems to be very interesting. Let’s leave this aside for now.

The third option is right now $AVXL with the mechanism of action having nothing to do with a single neurotransmitter or gene but it setting in motion some basic physiological mechanism with broad reach. I came across a paper outlining the effect of an agonist of the SIGMAR1 receptor on cellular physiology. We can expect that there will be many papers written about SIGMAR1 receptors as the mystery of the SIGMAR1 mechanism of action starts being thoroughly researched and revealed. My next post will be on that paper and its content.

Years ago I stipulated that Alzheimer’s starts with some yet unexplained fault in homeostasis leading to plaque/tau deposits and ultimately ending in neuroinflammation doing its destructive job. I called that the Unified Theory of Alzheimer’s. Just recently, a paper on the novel etiology of Alzheimer’s has changed in my mind the narrative that to epigenetic changes leading to what I called in layman terms “frankencells” cascading into plaque and neuroinflammation making the disease progress even if plaque and inflammation are controlled, theoretically. See my post 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/

The most essential difference between those two etiologies/progressions of the disease is the narrative of the role of neuroinflammation. In the Unified Theory of Alzheimer’s neuroinflammation is the final and massive force behind the destruction of neurons. In the Novel Etiology, the destruction of neurons happens early on and snowballs during the course of the disease with neuroinflammation (and AmyloidBeta and Tau too) being secondary. This is a radical change in the lay of the land of Alzheimer’s disease. Nevertheless, we should not dismiss entirely the devastation wrecked on brain by massive neuroinflammation.

Drugs like $LLY Donanemab, $SAVA Simufilam, or $CRTX Atuzaginstat claim to lower the neuroinflammation. We have to dismiss $LLY Donanemab as it presents us with the least of performance even at Phase 3 level. It brings no improvement to patients, just delays decline by six months, similar to Donepezil. Conclusions that we can draw from this trial are that toxicity of AmyloidBeta plaque might be “peripheral” to the disease. $SAVA Simufilam data on 28 days or 4 weeks of dosing improved the 21 patients per cohort (3 in all, placebo and two dosed). This was exploratory phase 2b with cognition as a secondary measure and biomarkers primary. Since different measures have been used by companies and the phase 2 trials are usually explorative it is hard to compare them to each other. Due to the varying sensitivities of different measures of cognition, even the Effect Size Cohen’s d can be influenced by the measures used, and for sure by the duration of the trial as the placebo arms keep deteriorating. Public companies live and die on the perception of the efficacy of their drug so that companies release only the data which makes them look most promising. By biomarkers, Simufilam has again “cured” Alzheimer’s but by Effect Size Cohen’s d it somehow moved over Donepezil. This situation can drastically change during the phase 3 trials as they can provide the duration necessary to make the least viable comparison with $AVXL Blarcamesine having already 3 years of dosing. There are simply too many factors at play to definitively say something beyond the short-term data itself. $CRTX Atuzaginstat make even more difficult case to unravel when it comes to cognition due to using computerized language test for cognition to claim strong efficacy but the sensitivity of the language measure might be of completely different class and nature. The number of patients in the phase 2 trial can be counted with fingers of both hands (9 altogether, 6 dosed 3 placeboes (LOL)) so I would refrain from any conclusions. The duration here was about 30 days. Here, again biomarkers play a larger role in reporting results than the more relevant cognitive measures. Press release by $CRTX, link: https://www.cortexyme.com/cortexymes-phase-2-3-gain-trial-of-atuzaginstat-cor388-in-patients-with-alzheimers-disease-successfully-advances-past-interim-analysis/ . As the above document states the p values are lower than .005 after 300 subjects finished 6 months of dosing. As “statistical significance is not practical significance”, (https://support.minitab.com/en-us/minitab/18/help-and-how-to/statistics/basic-statistics/supporting-topics/basics/statistical-and-practical-significance/ ) these results can not raise my expectation to a feverish level, especially that p-values are heavily influenced by a large number of participants. However the speculative juices can be made flowing at this moment, the only company having any data relevant to the progress of the disease is $AVXL. From an epidemiologist’s viewpoint, the only truly game-changing drug is the one that can prevent the decline over the longer term. We have already a number of drugs improving the patient’s scores at first and then disappointing patients and caregivers with just a delay of few months on the way to severe dementia. At this moment in time, the coming results from these few drugs shall break the disease or just practically leave it unchanged. If neuroinflammation is the sole destroyer of neurons then $SAVA, $CRTX, and $AVXL can cure the disease. I included $AVXL here because it has a proven record contrary to the others. Yet, if neuroinflammation is just a sideshow and the Novel Etiology is true and is the sole cause of the disease then $AVXL and yet undiscovered drugs (like those tried by $ALKS) will overtake the field.

This 148 data from Open Label Extension of Phase 2a Blarcamesine Alzheimer’s study. Part of recent Corporate presentation.

ES stands for Effect Size Cohen’s d. The ideal Alzheimer’s drug should keep the patients in decent ADCS-ADL scores up to a decade and as well should prevent age-related deterioration. Blarcamesien is how close we got to this ideal drug. The market here is enormous as it would cover most, if not all, 65 years old and beyond the population.

In this post, I created the image of two sets of outcomes in the Alzheimer’s drug discovery arena. Those two sets have a common member in both, $AVXL. Whatever is your view on the prospects of these companies and risk appetite $AVXL makes for the most of reward and the least of risk.

In my next post, I will write about the new discoveries in the mechanism of action of SIGMAR1 agonist. Blarcamesine is a SIGMAR1 agonist. I will continue with the thread of two etiologies through the prism of that information. So stay tuned, it is getting very exciting.

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EIP Pharma, Alzheimer’s and Lewy Body Dementia as Seen by $AVXL Investor

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

Discovery Brings About the Therapetic Taget of the Day and Damned be the Complexity.

Thousands of researchers study and write papers on number of different physiological processes. Some compounds discovered at one place are used to do quite different job somewhere else in the matrix of physiological maze. A layman like me reading the papers recognizes at first that in this maze of connections the possible cross-referencing points to number of connections beyond the ability to be grasped by a mind of a single human being. Human mind likes to simplify this multitude of connections with some ordering thought. In search of therapeutic targets the modern medicine man has to place his hopes on one compound at the moment to carry him to point at which he can claim that he succeeded in bringing benefit to the sick. Any new discovery is viewed with this hope in mind. Complexity of these connections can defeat him by bringing about crushing side effects, or the irrelevence of the compound to the over all health can dash the hopes.

EIP Pharma (private) hopes to address CNS system diseases with targeting p38 Alpha (MAPK14(gene)). This gene expression is connected to “programed cell death through network of signaling molecules and trascription factors” [1]. Also p38 alpha was identified to play role in “proliferation, differentiation and trascription” [1]. The picture which emerges in my mind is that of molecule mediated through trascription of MAPK14 gene to bring about cascade of changes, all entailed by occurance of some form of prior cellular stress. This should lead to apoptosis (cellular suicide) of cells stressed beyond the recovery and starting mechanism of replacing the dead cells with new ones through “proliferation, differatiation and trascription”. This mechanism can cope with mild stress introduced to the cells but when overwhelmed by it, it adds fuel to the fire. Would p38 alpha downregulation (inhibitor) stop the apoptosis and lower the resulting neuronal death and inflammation? Or would it stop the “prior cellular stress” which theoretically might be found upstream?

I crossed referenced ref. [2] witht the list of genes p38 alpha interacts with (ref [1]). The etiology of reference [2] is tracing the Alzheimer’s disease to the genetic mutation mostly in PSEN1 gene ([2]), and by extension to some undisclosed yet epigenetic change in those with LOAD (late on-set AD). Indeed, p38 alpha interacts with two genes which are the same as in ref [2], STAT1 (inflammation) and SRF (serum responce factor-neuronal apoptosis). This implies the possibility that p38 alpha is triggered downstream of the PSEN1 etiology [2]. See link to post talking about the PSEN1 etiology. 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/

The reference [2] placed the fault in EOFAD (early on-set familial AD) on genetic changes in the trascription mechanism in the cells nucleus (chromatin DNA complex – (histone+acetyl group)). There is arising evidence that that is also the case with LOAD (late on-set AD) through egenetic changes. This might be the reason that all the means of assaulting the disease has up to this point in time where aimed at “periphery” of its etiology or even outside of it. The results presented by EIP Pharma might be proving my point, and the altest new from Dr. Missling corroborates the etiology given in referenc [2]. The results for Phase 2b for the EIP Pharma drug Neflamapimod was presented under this link on the corporate slideshow https://www.eippharma.com/wp-content/uploads/2019/12/CTAD-REVERSE-SD-Presentation-Final-5-December-2019.pdf .

Let us view the slide on recruitment for the trial. It is earily similar to the Anavex’s phase 2b/3 Ad trial (pivotal).

The same MMSe score range and the presence of amyloid and tau plaque. In case of EIP Pharma this is Celebral-Spinal Fluid bio markers but Anavex had the brain scan made in order to eliminate any doubt of the amyloid plaque deposits existance. This might explain the long recruiting period. It sems that FDA might be doubly cautious with Anavex as it leaves no possibility of so called random event skewing the results because as a lay person would say they are “unbelievably” good. (too good to be true) (beyond the range of prrevious trials).

The primary measures are total disasters. Let’s see the secondary.

The secondary ones, which are more familiar to me follow the suit. So what EIP Pharma did was to turn to Plasma Drug Concentration as covariance. (covariance is a variable of secondary importance (possibly))

At the 75th precentile 18 patients show slight improvenet. As far as I can read this plot the least suare mean of those patients is .075 (7.5%) standard deviations above the least square mean of the inintial scores for all measures combined. You indeed need a degree in biostatistics to fully understand what is going on here. Z-scores are the values for each data point in relation to the mean expressed in the multiple of Standard Deviation. The Least Square Mean is a version of mean where a covariance (or few of them) is kept constant. This mean can be different from the mean but not much different. And what the conclusion of the management was after this debacle? Need to increase the dose to 150%. Let’s compare it to plot of delta of MMSE scores vs. concentration for Anavex2-73 Blarcamesine in phase 2a at 57 weeks. This study preceded the Phase 2b/3 AD (pivotal) which is due to present top data in summer of 2022.

These are the Effect Size calculations for the same high concentration patients after 3 years for dosing. This is much more transparent to an averge Joe like me than “the least square mean of Z-scores of all the measures of 75th precentile of plasma concentration after 24 weeks of dosing”. EIP Pharma futility in Alzheimer’s Reverse-SD study is rather obvious. Nevertheless its Lewy Body Dementia study Phase2 AscenD-LB was able to produce Effet Size of above 0.50 values, theoretically sufficient for approval. You can read the Press Release at this link https://www.eippharma.com/news/eip-pharma-announces-presentation-of-positive-clinical-trial-results-with-neflamapimod-at-the-13th-clinical-trials-in-alzheimers-disease-ctad-meeting/

EIP Pharma eexpects to have Neflamapimod approved at least for Lewy Body Dementia, and in deed it just reached that point of efficacy where the approval is possible.

The etiology given to Alzheimer’s in reference [2] is becoming confirmed by further research into Sigmar1 receptors and their MOA in the cellular physiology. In this recent presentation link: https://wsw.com/webcast/needham107/avxl/2271566 (time sensitive) Dr Missling talks of new paper being review to be published and talking about the sigmar1 involvement in regulation of the chromatine-DNA complex besides autophagy and protein “uality control”. Alzheimer’s is indeed the thoughest nut to crack in the pool of CNS diseases but inevitably science has been granted the tools to look into the etiology of these diseases and new generation of drugs might mitigage the suffering and morbidity.

Bibliography

[1] Wikipedia artickle https://en.wikipedia.org/wiki/MAPK14

[2] Dedifferentiation and neuronal repression define familial Alzheimer’s disease

Andrew B. Caldwell1, Qing Liu2, Gary P. Schroth3, Douglas R. Galasko2, Shauna H. Yuan2*, Steven L. Wagner2,4, Shankar Subramaniam1,5,6,7†

https://advances.sciencemag.org/content/advances/6/46/eaba5933.full.pdf

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The Ideal Dementia Drug and Dementia Patients Population

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

I looked up a paper on the web from British reserchers who used NHS records on dementia of 1,400 patients. They used the MMSE tests administered to patients over period of quite few years to map the distribution of dementia history of these patients. [1]

The total of 1,400 patients is the 100% here, and they are spread over the range of ages when the first dementia diagnosis was given. What is interesting is that the mean MMSE score at diagnosis is 18.2 +/-6.6 which is spread significantly. We can atrribute this to the age distribution of the ages at which diagnosis is given. Almost 30% of thoses diagnose are between 85 and 89 years old. The diagnosis of dementia is skewed toward those with little education. They also score the lowest for their age group on MMSE tests.

I copied from the web this distribution of MMSE score of those with no dementia divided into brackets of education level and age, mean values. I am sorry but I did not recorde the source.

The other metric given is the mean time between diagnosis and death (1.9 +/-1.7 years). This is not suprising as the advanced age of the diagnosed points to high probability of death.

It seems that dementia strikes people with advanced age and lesser amount of education. The mean duration is just a couple of years but the decline can be substantially incapacitating patients. The range of mean MMSE scores at death can be read off the next illustration copied directely from [1].

The conclusions I can reach is that most people affected by dementia die after about couple of years never reaching severe dementia. About 1/3 deteriorate to sever dementia and these are the most likely with earlier onset of dementia. Those who passed away at zero MMSE scores are just 3.2% of the total 1,400 patients.

The study did not only looked at Alzheimer’s. It included the diagnosis of few types of dementia which is documented in the blue box on the upper left corner.

There is no way we can separate the Alzheimer’s component from the rest of dementias. Most likely the unspecified dementias can be also Alzheimer’s as Alzheimer’s is thought to contribute about 70% to all dementia deaths.

What would be the ideal dementia drug?

I can only conclude that there are three separate “diseases” here.

  1. Earlier Onset Dementia with prolonged (5-10 years) disease duration resulting in death with severe dementia. Hypothetically this is a patient with initial diagnosis mostely in 60-75 years of life with MMSE score above 20 points. I would mark him/her as 20% of the population.
  2. There is the decline connected with age progression and its sign is the “initial” onset of symptoms of the final stage of the disease mostly for ages 80 years and up with MMSE scores of below 20 MMSE points. This condition would affect about 50% of those succumbing to dementia.
  3. Finally, we have the dementia as comorbidity with decline in the last days of life resulting in the drop of quality of life at best or would range to more severe form of disability. These patients would make about 80% of the population.

My procentages of the disease progression are estimates and are totally “unscientific”. They are my “deep estimates” of the character of the market.

The case number 1 requires a drug which can at least retard the progress of the disease for many years to fully relieve the condition of the patients. In this respect the drugs by $BIIB and $LLY has to be dismissed as completely inadequate. $SAVA presents 0.7 MMSE (ADAS-Cog -1.6) gain over 6 months for decent 50 patients sample size with Effect Size of .37. As of yet it is more likely a better Donezepil. The data is neither a screaming buy or reason to reject $SAVAas extended testing might reveal a better outcome. It is kind of middling result. Both, $CRTX and $ATHA present high hopes on selected measures but lack any track record yet. This can change soon. The only company left with decent track record is $AVXL with 3 years of dosing keeping the small cohort of 8 patients virtually unchanged since dosing started. The difference is such that the Effect Size is in the range of 6 and the p-value in .0001. A new study, ClinicalTrials.gov Identifier: NCT03790709, should have its results in mid 2022. In short, duration of dosing 78 weeks, initial MMSE scores above 20 and all patients having Amyloid deposits. Here goes the amyloid plaque theory!

The answer to the case number 2 is “anti-aging agent”. For the above given reasons $AVXL again at this moment gives the best performance with more than 3 years of safety and minimal decline data and proven record of rescueing patients above 20 points on MMSE scale.

I wanted here to present a illustration of restorative abilities of Blarcamesine (Anavex2-73) to the electric activity of synaptic network. This slide can be found on previous company presentations. This is the improvemnt in the amplitude of the P300 wave which is much more important than the delay time itself (latency) (see the post link below). What is most interesting is the 52 weeks result breaching the healthy controls line. Of course, these measures are illustrative and vaguely connected with MMSE or ADAS-Cog scores which are the workhorses of the industry. If you are interested in knowing more about it please visit post, link https://piotrpeterblog.com/2021/03/14/athira-pharma-revisited-future-cure-for-alzheimers-or-a-dud-atha-avxl-ath-1017-blarcamesine/

In similar fashion $ATHA claims to restore the measure in latency of P300 Auditory Event Potential in short duration of just 8 days of dosing. See post on both. I have not found a source giving a correlation between these measures and MMSE or ADAS-Cog scores, but I found this (see image below). $CRTX on the other hand was discussed in this post link: https://piotrpeterblog.com/2021/03/27/cortexyme-and-the-brave-new-ideas-in-alzheimers-drugs-crtx-sava-atha-avxl/

If the ideal drug can cover the case number 2 then the case number 3 is solved by extension. The only drug which currently has enough data to lead us toward accepting it as the closest to the ideal Alzheimer’s drug is $AVXL Blarcamesine (ANVEX2-73). None of these companies release full set of data points for all the involved patients so even at the level of layman we can not say that definitely the data corroborate the claimes. The companies pick and choose what we are presented to tailor to their strategic vision or rather their claim to be the “ideal drug”. At this moment the only contender standing is $AVXL. The key to fighting this disease with success is long term performance of the drug and the ability of just holding to the MMSE scores as long as it is possible. At this point nothing can match the performance og Blarcamesine.

For the reasons presented in the previous post the next and remote contender is $CRTX but it suffered a setback as after 48 weeks of dosing patients developed transient liver problem. link: https://www.cortexyme.com/cortexyme-provides-regulatory-update-on-development-program-for-atuzaginstat-in-alzheimers-disease/ Of course, this does not disqualifies $CRTX but limits the drug to some undetermined degree.

Bibliography

[1] Dementia Severity at Death… link https://pubmed.ncbi.nlm.nih.gov/30382865/

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Measures of Dementia in Alzheimer’s and Their Distortion of Trial Results $AVXL $LLY Blarcamesine Donanemab

I have been asked about different measures of dementia and their impact on the trials. There are two basic aspects of these measures and dementia.

  • There is the innate to human cognition nature of deterioration resulting in greater or lesser progress to an observer.
  • There is the sensitivity of type and mix of measures build into a test tasks, or selected to create the composite score expressing the amount of deterioration

Mini-Mental State Examination on average has such plot for Alzheimer’s sufferes. In the pursuit of ideal measure DSRS has been created as it strives to produce straight line from MMSE 20 to 7. [3]

That is prospective decline from MMSE 17 points initial position to zero for an average patient.

Another illustration presents the respective scales relationship between 30 and 19 MMSE. [1]

Notice that MMSE scale is very insensitive at the almost healthy 30 points scale having a ceiling effect, that is early demantia, but is doing much better at 19 MMES vs. ADAS-Cog and CDR-SOB at this interval. The best to sense changes in early stages of dementia is ADAS-Cog and it is reasonable at 19 MMSE. The illustration of the relationship of these scales is in itself suspect of bias as the x-axis “Cognitive dysfunction” calls for its own criteria which is doubtful to be just entirely objective.

Some measures are questinnaires to be filled by care givers or doctors like CDR-SOB other are tests like ADAS-Cog or MMSE. At different points in patient deterioration they will have varing difficulties with relating the progress of the disease as the cognition is heterogeneous and each individual might follow a slightly differnt pattern. There are even problems with repeatibility as results taken few days apart might not be the same.

Depending on the movement of patients on these scales different values of Effect Size will be calculated. Effect Size Cohen’s d calculations need only the means and standard deviations. So it looks how the means are separated from each other and whether the distributions don’t overlap each other.

The p value in statistical parlance means that if you run the sample size experiment you have to get a p*100% chance to get it wrong, that is at least in the layman terms. Once this is below 5% chance of getting the difference between the drug and placebo as nonexistant due to random effects it is called statistically significant. The calculations take into consideration the distribution of data points and sample size.

Anavex posted the results for the 148 week OLE extension of the phase 2a trial. Assuming that the bars are standard deviations I calculated following Effect Sizes from the data.

Can these disparities between Effect Sizes be placed squarely on the shoulders of scale sensitivities? I do not know. One is certain that these things are real hard to assess as there is no completely objective measure of cognitive deterioration of people with Alzheimer’s or dementia. The large Effect Sizes are a bit concerning to me as to their authenticity but they follow the assumption of the bars being SD (standard deviations). I guess I must be doing somethig wrong or this is just insane efficacy. LOL

The trials are run against placebo. But if the sensitivity is varying along the path of progress or deterioration the picture is somewhat distorted. A solution could be to select few measures which complement each other. This can run foul of the accepted till now standards or the limited resourse a small biotech can expand on the trial. another solution could be to run all drugs on standard set of measures so that distortions are equivalent from trial to trial. But even this has it down side as different trials with cover varing parts of the scales. An example is trial by Anavex where MMSE hits ceiling effect with patients actually recovering and $LLY Donanemab trial where patients are deteriorating so close to placebo that the theory that one’s runs against placebo makes this to be the case where the distortions are equal in both arms is close to valid.

When Anavex run the phase 2 trial of PDD (Parkinson’s Disease Dementia) it used the CDR-CA (computerized assesment). As I said we have for most no objective measure of dererioration and all we can do is to compare between them and design ever better ones more inclusive but then they become extensive. Here are some results of comparison of MMSE, ADAS-Cog and components of CDR-CA. [2]

Ss you can see for the scores of MMSE 27-30 that the ADAS-Cog can actualy show improvement which is just another way of saying that it can detect improvement where MMSE can not find any. CDR-CA is correlated to AD but mostly used for PD as it measures also time delay in psychomotor skills and memory. The shortcomings of this measure vs. MMSE is exclusion of certain languge skills. One can see that it is most sensitive between 26 to 21 MMSE points. So follows ADAS-Cog. Both ADAS-Cog and CDR-CD lose their sensitivity below MMSE 20 points. I am speaking here of sensitivity but I am not able to distinguish it from the acceleration and deceleration in deterioration as percieved by humans. Nevertheless this graph confirms the information contained in the second plot in this post.

Here is a graph representing detrioration over some period of time in group of patients dosed with different SOC Alzheimer’s drugs which in general have a similar performance. The components of CDR-CA are enclosed in a box. They probably are going to be weighted to give a final score. In a sense all these measures are very close. Nevertheless ADAS-Cog is just 70% of MMSE score on the same deterioration but if the dosed arm does not move to different regime on the scale the distortion is minimal but the point is to have the drug to do precisely this thing. In case of Anavex2-73 phase 2a trial this was introducing uncertainty as MMSE scores lacked the sensitivity to pick up changes from the 4 patients who in general seemed to beat the odds and recovered from the disease.

Bibliography

[1] link https://www.tandfonline.com/doi/abs/10.1080/13854046.2015.1119312?journalCode=ntcn20

[2] link https://europepmc.org/article/MED/20047570

[3] link https://pubmed.ncbi.nlm.nih.gov/19812470/

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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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Cassava Sciences Drug Simufilam in The Pecking Order of New Breed of Alzheimer’s Drugs. $SAVA $AVXL $BIIB $LLY

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

I have a sleepless night so……

The 3xTg (Tg for transgenic) murine model of Alzheimer’s disease uses the same gene, PSEN1 (actually, a trasngenic version of the mutation prevalent in familial AD) and two others are connected to amyloid plaque and Tau deposits. The same mutation was used in the experiments described in paper linked in this post: 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/

Having made this connection let us turn to this slide from SavaDx presentation by Cassava Sciences $SAVA:

An explanation first, PTI-125 is an old moniker for ATH-1017 called now Simufilam. I have been touting in my blog that the 3xTg mouse model at about 4 month old develops mental disability, 2 months before first signs of Amyloid plaque appear. Here, at 4 months alpha7nAChR/FLNA linking apear to rise at 4 months in the model mice but not in the Wild Type mice. 8 months old WT mice do have elevated level of the complex but in the 3xTg mice it is even higher. In 8 months 3xTg mice one would expect Amyloid plaque to be present. Just to give insight into the timeline 4 months of mice life is about 35 in human terms, 8 months is 70 years, and 6 months is about 50. In the paper referred in the post I presented link to, the degenerating neurons set off a cascade of chemicals calling on the immune systen to removed them. Inflammation is then intrinsically linked to ever increasing degeneraton of neurons under conditions described in the experiment.

What the linkage of alpha7nAChR/FLNA mean in context of Alzheimer’s. Again a slide from $SAVA presentation:

Altered FLNA binds to alpha7nAChR and Toll-like Receptor TLR4. Sumifilam reverses that action. $SAVA claims that is reducing neurodegenration and neuroinflamation. Here, you have to make a leap in conceptual thinking with me. There are papers which make the point that AlphaBeta42 act as kind of “antibiotic” fighting baterial infections and one particular paper stated that it is toxic to neuroblastoma cells. There is a growing evidence linking Amyloid plaque to defence mechanism in case of brain wide inflamation. link: https://stm.sciencemag.org/content/scitransmed/8/340/340ra72.full.pdf It seems that Amyloid plaque which comes in different peptides chain lengths and molecular weights is kind of part of inflammatory responce from the CNS, and might be only indirectly connected to the degeneration of neurons.
  • 3xTg Murine model of AD mimics familial Alzheimer’s
  • By the same mechanism by 4 months of age mice develope mild inflammation leading to mental decline all due to increasing degeneration of neurons.
  • The occurance of inflammation during this time is in line with the novel etilogy of the disease described in my previously published post (link above). Degeneration of neurons leads to inflammation.
  • Simufilam addresses just one mechanism out of many affecting the brain under this new etiology: a misfolded protein FLNA.
  • With age the brain is assaulted by inflammation but in 3xTg model it appears way sooner and is much greater in magnitude.
  • In responce to prolonged inflammation Amyloid plaque is produced as the deep brain defence mechanism.
  • Simufilam regulates the mechanism of Amyloid plaque production but does nothing to stop neurodegeneration as described in the novel ethiology paper. It acts downstream from neuronal degeneration and misfolded protein.
  • Neuroinflammation is so essential to the destructive power of AD that simufilam can improve cognition but in very limited way.
  • Simufilam can be used to rescue the Amyloid Plaque Theory of AD but for all the wrong reasons. It has to do more with inflammation than anything else!
  • Simufilam beats drugs like Donanemab and Aducanumab which just remove the Amyloid plaque but do not address inflammation.
  • Yet Simufilam is inferior to Blarcamesine ($AVXL), drug which might be affecting the degeneration of neurons and the inflammation source.
  • The evidence supporting the last point can be seen in the latest communique from Anavex Life Sciences. See the link below for my recent post.

This sums up my train of thoughts on Cassava Sciences ($SAVA). The performance of Blarcamesine can be seen in my recent post, link : https://piotrpeterblog.com/2021/03/20/can-blarcamesine-rescue-those-above-mmse-20-with-alzheimers-avxl-blarcamesine/

Indeed, there has never been a better time to be an investor in Alzheimer’s drug, or in general CNS neurodevelopmental and neurodegenrative drugs, as with the advent of genetics and the stem cell field of research, the focus now statrs to be clearly on the root causes of those diseases, leading to therapetics targets with real good prospects of success.

This blog is more energy efficient than Bitcoin mining but will mint many millionairs so please drop a coin.

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Can Blarcamesine Rescue Those Above MMSE 20 With Alzheimer’s? $AVXL Blarcamesine

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

Please, read the latest news from $AVXL (3-16-2021), first. There is a link here: https://www.anavex.com/anavex-life-sciences-reports-anavex2-73-blarcamesine-featured-as-a-disease-modifying-small-molecule-in-phase-3-clinical-trials-in-a-new-publication-in-medical-journal-titled-future-av/

My take on this is that we are being given early insight into the result of the phase2b/3 (Alzheimer’s). The company has never kept the same group of patients to present the data or rather it kept changing many metrics as the knowledge of the benefits of the drugs has been deepening or became broader. From the wording of the newspiece my conclusion is that it references to the Super Responders as the ones who are SIGMAR1 wild type and are above 20 MMSE baseline, therefore respond readily to Blarcamesine.

There has been a change in Dr. Missling’s tight lip policy, before we had to deal with just the bland official information from the company communiques. But now Dr Missling gives to this data a lot of color with statements like this (paraphrase here) “If we give Blarcamesine, even to those who do not readily respond, for long enough time we can also rescue them” (acctually combining of mine of two statements into one). And another green shoot of hope: “We can rescue those who are above 20 MMSE points”.

Where the first statemet comes from? Maybe from this plot:

Please, read this old post link: https://piotrpeterblog.com/2018/08/18/something-about-dropout-rate-avxl/ But think about it the extension still keeps everybody on their initial dosing so it includes those on 10mg and 30 mg. Yet, I have heard voices that the dose was adjusted in the extension so the avove paraphrased sentenses from Dr. Missling might hitting the nail on the head.

And the second statement from this slide from CTAD 2017 presentation:



The comunique states that the initial average score was 22.3 for those patients (71.1 ADCS-ADL) and that they improved @57 weeks +2 MMSE and +3 MMSE @ 70 weeks. I have long ago determined that standar deviation for that group of patients was +/-2.6 and assumed that it was +/-1.2 for placebo or Donezepil. Combining these into the formula for Cohen’s d Effect Size we get 2.2 @ 57 weeks and 3.4 @70 weeks.

Just as a remainder:

It seems that with ever additional month the Cohen’s d for Blarcamesine is going to increase. The name of the game becomes to hold your patients at least steady as the placebo cohort deteriorates, which means that these people ultimately need be taken care of or institutionalized. The added bonus is that in reality Blarcamesine can raise the MMSE scores of those above 20 MMSE baseline. From all the information released I teased out the picture of a drug which can rrescue the majority with only minority still declining in slow motion respective to placebo.

Right now, the cost of Alzheimer’s drugs is higher than cancer drugs, and the later is about $65,000 per death (USA). There is 600,000 deaths due to cancer and only 120,000 deaths due to Alzheimer’s, but one fact explains this disparity best. Only 1/3 of all those afflicted by dementia, mostly Alzheimer’s, die due to its severity. 2/3 dies of other comorbidites. Maybe in next post I tackle this.

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Eli Lilly’s Donanemab And The Lack of Little Ideas Among The Big Pharma Giants $LLY Donanemab $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

I have listen to the webinar from Elli Lilly $LLY on 15th of March, 2021 about the phase 2 Donanemab results. The biotech business is fraught with failure, and spinning the results so that investors won’t lose hope and leave. In just couple of years, we have witnessed triple failures of monoclonal antybodies aimed at the amyloid and tau plaque. I have to confess, I was unable to concentrate the whole time so I would rather go over the presentation slides.

The most interesting slide in the presentation, we saw at the very beginning of the show. I shall call the slide number 4 the Illumination on the Reasons for the Reluctance to Let Go of the Amyloid/Tau plaque.

Words in purple – Cure By The Other Name …..

The other name are the biomarkers named the Amyloid and Tau. This is the case of mistaken identity. The obstinacy is amazing. The Giants complain that FDA or rather all of us pay too much attention to symptoms. Haven’t they cured the disease already by removing the plaque? This indeed is the case of making the results for the drug not the drug for the sick.

Words in blue – The Statiscally Insignificant Blues

In a trial you have two populations, placebo and dosed. Each of these are defined by the mean and most of all by the distribution around the mean. The phrase “statistically significant” references to the possibility that distribution of those dosed can’t be part of the placebo cohort distribution, when the two overlap too much hypothesis that the drug has efficacy is in question. This might be the case when the efficacy is low and patients are widly scatered.

So $LLY decided to select its own patients, ITT (Intent To Treat (population)) became large enough to justify the drug financially but lowered the dispersion of the population. However $LLY selected intermediate tau deposits patient, and it threw out all those who decline rapidly. This significantly lowers the dispersion in the subjects. Hey, they almost made it! See those p-values! Hypothesis is not null! FDA did not let $AVXL to select patients based on biomarkers. There is tendency to set the bar even lower, since researchers have realized that there is a threshold at which a patients can not be turned back or helped. The example is $AVXL Blarcamesine phase 2b/3 trial with patients between 20-28 points on MMSE scale and with proven amyloid plaque deposits, but that is because many patients above 20 points can be actually rescued form the disease by the drug. Following this thinking $LLY went for average 23.6 ppoint MMSE.

The placebo performance can affect the statistical significance but it can not make the drug perform better. I wonder how far they got with negotaiting this with FDA on Trailblazer-ALZ 2 study. Let’s see!

Seems like FDA wants those rapidly declinning in, to add to the mix. $LLY got the traditional for plaque trials thousands. Oh! Things might not be going well! Whenever I see thousands I think watch out below.

Words in green – Green Light for Profit

Let’s start with the green stuff first. In 2018 the global market for oncology drugs has been about $77 billion, half of it is the US. Since 1970’s we made some progress against cancer but very significant only in few cases, the worst ones. So 5 years survival rate for liver and interahepatic bile duct cancer is now 19% which is 6 times more than it was in 1970’s. Similarly with pancreatic cancer, the worst offender, it is now 9% or 3 times what it was in 1970’s. Most kinds of cancer the improvement has been between 1.8 and 1.3 times. The best survival is with prostate cancer 99%, used to be 66%.

The cost per death is quite high, $65,000. There is about 600,000 deaths per year due to cancer in the US. But this is not the real toll of cancer. Some doctors once having cancer decide to forgo the slash and burn therapies which destroys the quality of life of people desperately fighting for few more years of life. We, the public, only hear the stories of the happy survivors, not those who were afflicted and lost threasure, life and final quality of life in the struggle.

This is a dream scenario for drug companies, drugs for terminal diseases with efficacy slowly rising so that higher prices can be justified, but also not quickly enough to lower the deaths significantly. This summarizes the oncology analogy.

FDA is a part of government bureaucracy and is relactant to open another pandor box of tens of billions of dollars to be paid out by Medicare in new field reminiscent of oncology, but even worse, since Donanemab can only make the disease more costly and still keep it not survivable. The rest of the words are just window dressing.

In the final calculation, would Donanemab hold its own with the placebo it would only delay the disease by theoretical 6 months, but at what cost? Few thousands a month, $30,000 a year? That would double the cost of Alzheimer’s care with almost no benefit. Is this accidental lack of ideas or something programed?

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