Two Measures of Efficacy in Alzheimer’s Trials. Blarcamesine $AVXL $SAVA $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! And I am long $AVXL $ANVS $CRTX FYI

There are two measures by which go trials of Alzheimer’s/dementia. The most popular and the most expeditious is the average increase/decrease in MMSE or ADAS-Cog points of the dosed cohort vs. the placebo. The other is taking much more time and is probably more telling of the drugs potential. It is the number of dropouts or remaing patients in the dose cohort over time vs. the placebo. Why do I make a statement like this? It is because the average change is scores can be much easier a statistical event (fluke) during the 18 months long trial than the dropout rate during few years of study. Again, I use the information in the reference https://pubmed.ncbi.nlm.nih.gov/10404988/ to make the point. In this study 372 subjects were followed over the natural progresion of the disease from diagnosis to droping out. The event of disappearing from the study rolls was connected with severe disease or natural death, almost exclusively. There was a plot of the changes in MMSE scores in consecutive one year periods. If indeed, the change in a patient was in given year over 10 points then we can reasonably believe that he might become soon a dropout due to severe AD and find himself institutionalized. This rate of those declining 10 or more points MMSE is almost steady during the 6 years of the study. The picture of the disease I see in this graph is that of a disease which accelarates rapidly during the final year in the study leading to removal from the study. Notable is that the first year results do not confirm this phenomenon and as such are the event which confirms the phenomenon taking place later in the study, as the initail scores are still not in the domain of severe Alzheimer’s/dementia leading to dropping out. The average decline in MMSE scores for this study was -3.8 SD +/-4.3. This is visible as the line under the zero MMSE line. The average rate is almost constant. Also remember that a dot stands for score not a patinets and can represent few patients.

The overwhelming efficacy of the drug can be seen in the ability to stop or at least control this phenomenon of rapid and accelerated decline and in effect lowering drop out rate.

In this plot I normalized the 372 subject trial to 32 patients in Phase 2a of Blarcamesine. At 5 years the number of normalized 32 patients dwindle to 5.

During the latest Conference Call Q1 2021, Dr. Missling said that the number of remaing patinets in Open Label Extesion after 5 years is between 10 and 21. Parsing it a bit, any number in between is technicly true now so we were not given an answer but a clever way of confounding us. 10 patients left and we still are much better than placebo from the study. 21 patients might be equally true and we are shining. See my last few post on the possible meaning and interpretation of that data. I shall refrain from further interpratation of the Conference Call statment by Dr. Missling. Hat tip to Tom Bishop from BI Research for asking this question. Does anybody know what BI Research wrote about $AVXL if ever?

Currently not company can boast data that deep and rich as $AVXL. I am waiting for data from $SAVA and $ANVS.

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

Do not trade this blog as 4 billion years of evolution is against me and possibly even God laughs at it, He has a great sense of humor! And I am long $AVXL $ANVS $CRTX FYI

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

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

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

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

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

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Implications of Soon to Be Resealed 5 year Data on Extension of Blarcamesine Phase2a for Alzheimer’s in One Chart. $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 $ANVS $CRTX FYI

See this post first…. https://piotrpeterblog.com/2021/05/18/morbidity-and-disability-in-phase-2a-alzheimers-study-of-blarcamsine-vs-background-morbidity-in-similar-age-control-group-avxl/

Now to the Chart.

I will be on a 12 days vacations so might not post anything so I need a more beer money ….
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Who is Following Whose Success? $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! And I am long $AVXL $ANVS $CRTX FYI

$SAVA Success Wave Lifting All Boats

The released $SAVA data brought about a wave of investment and renewed vigour to investing into smaller Alzheimer’s narratives. When most of the news is just shadowing the declines and any number above the initail score is reason for hope. A couple of things are transpiring among the companies searching for Alzheimer’s drugs. One, and the most impoortant is that most of them focused on MCI (Mild Cognitive Impairment) patients with MMSE scores 25 or ADAS-Cog11 15. This is a big departure from looking into average score of 21 MMSE points as it was done by $AVXL 5 years ago. It was learned the hard way that Mild to Moderate Alzheimer’s patient (16-25 MMSE) do not respond readily to experimental drugs as it was expected. For $AVXL drug Blarcamesine the cut-off MMSE score is 20. In the words of Dr Missling $AVXL “can rescue anybody over 20 MMSE”. That is now lowest the MMSE score that responds to an experimental drug. All late comers are treating those with average scores of MMSE scores 25 or ADAS-Cog11 15. As Alzheimer’s is neurodegenerative disease the relatively advanced disease can preclude a successful rescue of a patient or even possibility of stabilizing him. The other thing happening is massive outpouring of half-baked efficay data.

Here, we will strive to compare results from 3 companies $SAVA, $ANVS and $AVXL. Sometimes these are akin to oranges and sometimes apples and oranges.

The most fair comparision might be between $SAVA and $ANVS. Both treated MCI patients, the former up to 6 months the latter just 25 days. The narratives used by the companies differ but ultimatetly they are derived from the Amyloid plaque theory of AD. In my conviction both aim for limiting neuroinflammation notwithstanding their narratives. Though more widly touted, $SAVA presented less of improvement than the rapid results of $ANVS ANVS401. $SAVA over 6 months improved the patients cognition just by -1.6 ADAS-Cog11 points (negative values on this scale indicates improvement). Starting from similar conditions ANVS401 lowered the ADAS-Cog11 score by -3.3 in just 25 days (adjusted for placebo). In such short period of time the problem becomes the dispersion of the test data due to “statistical events” or chances of scoring higher even if the cognition objectively moves in any possible direction. The difference from initial condition was -4.4 ADAS-Cog11. The p-value went from p=.04 for initial scores to p=.13 indicating that some results could have been no different than the dispersion about placebo mean.

Let’s See How The Biomarkers Look for Both of Our Contenders

We can only directely compare A-beta42, Tau, p-Tau and YKL-40. If all those are undesirable then the winner hands down is $ANVS. ANVS401 pratically removes those from the brain. YKL-40 level indicates that neuroinflammation is practically gone. ANVS401 is supposed to lower the production of A-beta precursor APP by 60%. The mechanism of action has not been expained by $ANVS sufficiently well to come to definitive conclusions what the drug really does. Nevertheless is astoundingly effective in putting down neuroinflammation during the short span of time. I thought that all those drugs putting down inflammation will have middling results but ANVS401 does the real job on this front. This is compatible with the experiments conducted by one doctor who injected anti-inflammatory drug into neck portion of spine and the lowered the patients head down to have the drug migrate into the brain. The results were in just hours, with “fog lifting” as described by patients. Unfortunatelly, he was censured by FDA and videos were removed.

Looking into $AVXL and $ANVS as Synergistic Apples and Oranges

It is very hard to compare the above companies to $AVXL as it dosed the Middle and Moderate Alzheimer’s patients and not just MCI only. Nevertheless $AVXL scored great success with those who were on average MMSE = 23 or ADAS-Cog11 = 17. These aptients in just 5 weeks (35days) scored improvement of 1.2 MMSE or ADAS-Cogs11 -2.8, in 57 weeks this was 2 MMSE or ADAS-Cog11 -4.7 and finaly in 70 weeks 3 MMSE or ADAS-Cog11 -7.0.

ANVS401 shuts down neuroinflammation and Blarcamesine does on one hand the same but on the other hand it rejuvenates ( post [1] ) the neurons with possibly reversing the neurodegeneration described in post [2]. ANVS401 will probably have a quick action with a plateau whereas Blarcamesine will deliver consistent increases of cognition scores over longer period of time. These two drugs and will work in synergy.

$SAVA is no longer therapeutically relevant!

Bibliography

[1] SIGMAR1 Agonists – Therapeutic Swiss Army Knives $AVXL, Prilenia Therapeutics, $ATHA, $ALKS, $SAVA https://piotrpeterblog.com/2021/05/13/1372/

[2] 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/

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The Alzheimer’s Etiology Wars! $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! And I am long $AVXL $ANVS $CRTX FYI

A Battle in Etiology Wars!

The most prevalent hypothesis of the etiologies of Alzheimer’s disease is the A-Beta Amyloid deposits theory.  The theory has been evolving into few branches.  One of them states that there is production of A-beta in the axions of neurons in response to stress and the toxicity of A-beta works its way from axions to the whole neurons.  This evokes the problems of axonal transport with all its complexity, involving among others the A-beta deposits interference with the process of transport, autophagy and mitochondrial health.  Just to mention the most prominent ones, without talking in detail on the mechanism.  I refering here to paper titled

[1] Axonal generation of amyloid-b from palmitoylated APP in mitochondria-associated endoplasmic reticulum membranes link: https://www.cell.com/cell-reports/fulltext/S2211-1247(21)00473-3


The precursor protein to production of A-beta is called APP. In the case of axion production of A-beta this compound gets palmitoylated that is another chain of a compound is attached to APP, since then it is referred as palAPP.  This is done to differentiate it from the A-beta produced from APP by the center body of the neuron, that is without being palmitoylated.  The researchers asks how they can control the production of A-beta by axions, as in their view that is what precedes axion swelling, indicating the onset of Alzheimer’s disease in vitro, and implied to be connected with axonal transport interference. Interrupting the production palAPP becomes in their eyes a therapeutic target. In a further explanation, palAPP is attached to the lipid rich outer cell membrane where the Mitochondria Associated Membrane (MAM) of Endoplasmic Reticulum comes into contact with the former.  As it can be seen in the illustration, the sheer number of MAM’s is connected with the increased occurrence of palAPP sticking from the cel membrane where the A-beta is cleaved off the palAPP chain by Beta-secretase to create the A-beta deposits in the extracellular  space.  These deposits of A-beta are blamed for toxicity which ultimately kills neurons starting with axions swelling. 

Literature provided few observations. First, that intra axonal A-beta is generated ahead of extracellular A-beta when axions are under stress. Would it mean that axions are the first under stress? The genetic degeneration which was described in the post (link: [2] 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/ [2]) starts with the lack of trascription of the protein neccesary for the axions to function and atrophy of axions sets in. Nevertheless, the quantity of palAPP is just 20% of APP total created in the model of FAD (mutation) Human Neural Progenitor Cell. FAD stands here for familial AD. In healthy neurons ~40% of A-beta comes from axions so the 20% in FAD model of Alzheimer’s disease seems like changing the nature of the ratio. In grand picture of the disease this should not stand as the most importan source of A-beta. Should we think that the placement of pal APP in the axions matters? Again, the question of axonal trasport.

 If we connect this fact with turning on the cellular stress response mechanism and so increased transcription of the SIGMAR1 gene into the protein so that MAM’s population increases with the associated increase in palAPP on the cell walls then we have an explanation tying A-Beta etiology with function of SIGMAR1. I am only speculating here, all in the light of the information from the paper. In this scenario A-beta is part of the stress copying mechanism of axons and neurons.  Also another observation is that, Amyloid deposits decrease when A-beta generation moves from axions to body of the cell, and 70% of palAPP is concentrated in MAM’s. So if you fault the axions for production of palAPP and connected it with the occurrence in axions of MAM’s then if can you control the quantity of MAM’s you can lower the production of A-beta. This reasoning is only valid if you fault A-beta alone for the damage.  Here, enter our friend SIGMAR1 protein, which is associated with the creation of MAM’s on the surface of Endoplasmic Reticulum.  The researchers silenced the production of SIGMAR1 protein and after 48 hours halved the production of SIGMAR1 protein.  But what is more interesting for us, in 72 hours of  silencing SIGMAR1 production to the level of 10% remaining cells became none-responding to viability tests, they became zombies.   Further on, researchers used agonist/antagonist pair to double or halved the number of MAM’s with resulting production of palAPP.   SIGMAR1 is not yet here, a therapeutic target per se, but rather a tool to control palAPP through MAM population. Nevertheless, agonist to SIGMAR1 increased production of axonal A-beta40 vs. none made when antagonist where used, but that was in vitro so systemwide assessment is missing. How relevant this is?  We will give a tentaive answer at thee end of this post.

I want to quote here the paper.

The degree of dementia in AD is primarily correlated with loss of synapses. Synaptic dysfunction, preceded by reduced syn- aptic transmission and loss of dendritic spines, is largely driven by neurotoxic Ab42-oligomers (Cleary et al., 2005; Haass and Selkoe, 2007). Physiological levels of Ab42-oligomers have also been shown to suppress long-term potentiation (LTP) in hippocampal slices (Mango et al., 2019). In contrast, Ab in the picomolar range has also been shown to be required for LTP in- duction (Koppensteiner et al., 2016). 

I would like to stress here that the last sentence in this quotation bring the chickens to roost home.   Mostly in medicine, total removal of any compound can be detrimental so does the same applies to A-beta?  A-beta has its function in spite the fact that its currently blamed for the onset of the disease. It sure, is not toxic in small concentrations as the quote suggests. Well, your long term memory needs it. Besides the produced A-beta was A-beta40 not the most toxic A-beta42.  The other fact is that the interruption in axonal production of A-beta did not lower the total APP and A-Beta production in the 3D in-vitro model of Alzheimer’s disease. 

Scientific papers are not written in an objective manner.  From the onset they presuppose some approach that is tested in the papers.  In biology where the vastness of sheer number of connections overwhelms human cognition one has to go one step at a time.  There is number of competing views on Alzheimer’s and not all of them can be correct.  There, lies the root of the cause of 10 drugs out of 11 tried failing.  Papers can be convincing but the final word is with the clinical trials and the progress the patients make.  

Researchers face a dilemma, they can lower palAPP at the cost of silencing SIGMAR1 that ultimately makes cells not viable, in vitro.  If the cost of therapy is so defined as endangering the cells viability, they restore to hinting at “MAM deregulation” as a probable cause of axonal A-beta production leading to axon swelling. In the context of the paper I postulate that the as the axons become under stress they turn on their stress fighting mechanism and the increased transcription of SIGMAR1 gene leads to among others heightened production of palAPP as part of the copying mechanism.  Yet, few fold production of A-beta might interfere with axonal transport for example. This scenario makes sense in the face of few voices claiming that A-beta’s toxicity is part of infection fighting mechanism of the brain.  It  even turned out be toxic to brain tumors cells, but overproduced can be toxic to the whole brain.

From the years long results of dosing Blarcamesine, the stress fighting and neurotrophic factors released from MAM’s by the action of the agonist (see my previous post link: https://piotrpeterblog.com/2021/05/13/1372/   ) ultimately restore neuronal health. 

Search of Drugs to Lower palAPP Production

Though the researches make a point that SIGMAR1 antagonist could be used to control palAPP and axonal A-beta other target gets their attention, and I can directly quote them.


We and others have previously shown that the loss or inhibition of the MAM-resident enzyme acyl-co-enzyme A:ACAT reduces cell surface localization of APP and Ab genera- tion (Huttunen et al., 2009; Bhattacharyya and Kovacs, 2010; Murphy et al., 2013). More recently, we showed that inhibition of ACAT reduces palAPP in lipid-rafts by ~76%, in vitro (Bhatta- charyya et al., 2013). Palmitoylation inhibitors 2-bromopalmitate and cerulenin also reduced palAPP level and Ab generation in vitro (Bhattacharyya et al., 20 .  

The inhibitors for A:ACAT  already exist and are  being involved in treating atherosclerosis  due to their connection to cholesterol theory.  From short search I think that these drugs have been tested in animal models for  a decade, and as far as I searched it did not yield a drug which phase 3 onto market in both atherosclerosis and AD.  It seems to be a dead end. 

Possible Scenarios Implied by Paper [1]

  • In response to cellular stress SIGMAR1 gene is transcribed in larger amounts
  • The increased SIGMAR1 protein leads to more MAM microdomains
  • This leads to increased production palAPP in axions and larger amounts of A-beta is created
  • A-beta toxicity affects axonal transport affecting viability of neurons, and or lead to axonal swelling
  • Enter Blarcamesine: a SIGMAR1 agonists releases stored in MAM neurotrophic and cellular health compound
  • The consequenses of A-beta toxicity are reversed by these compounds
  • Patients score higher on congnition test and maintain their scores

Possible Scenarios Implied by Papers [1] and [2]

  • Epigenetic change deprives axions of the neccesery protein to build viable synapses and stresses them
  • SIGMAR1 transcription increases in stressed axons especially increasing production of palAPP
  • Overproduction of A-beta beccomes toxic to neurons in synergy with epigenetic degeneration
  • Enter Blarcamesine: a SIGMAR1 agonist releasing stored in MAM neurotropic and cellular health compounds
  • The consequenses of A-beta toxicity are reversed by these compounds
  • Patients score higher on congnition test and maintain their scores

Possible Synergy with ANNOVIS $ANVS Pophisen ANVS401?

Not much is known about the Mechanism of Action of the ANVS401. The only metric released was that 60% of production of APP total is taken out of the line, so to speak. The drug does not affect the RNA for synthesis but somewhere breaks the chain of events leading to the fully folded APP. The narrative touted by ANNOVIS is improved axonal transport. Alzheimer’s disease has number of scenarios where some aspect of cellular physiology can be visibly disrupted. Reseachers “marry” certain faults and spend years pursuing them in hopes of finding the underlying cause of the disease. Hat tip to their tedious and arduous work. Nevertheless, for investors what carrier the water is a good narrative limiting the scope of the disease to single fault being fixed with particular drug.

The link to the press release is here. https://irpages2.eqs.com/websites/annovis/English/431010/us-press-release.html?airportNewsID=364451b1-06a7-4b96-a389-016f3ef3e6e3

The information on https://clinicaltrials.gov/ # NCT04524351

First let us consider the average MMSE and ADAS-Cog11 of the 14 early Alzheimer’s and Parkinson’s patients. 30% improvement with delta=-4.4 ADAS-Cog11 and 22% improvement with delta=-3.3 ADAS-Cog11 gives consistent reading of 15 ADAS-Cog11 points average starting score. On more familiar MMSE scale, that is equivalent of 25 points. All that is inspite the eligibility criteria of MMSE 18-28 points on clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT04524351?term=ANNOVIS&draw=2&rank=1

I have noticed that very consequently new trials in AD and PD sphere are enrolling subjects with earlier disease as it is easier to get a response from them. And no wonder, since hundreds of trials produced unremerkable results when the inclusion criteria are really MMSE 18-25. The down side of this trend will be visible in just few lines of text.

Patients improving -4.4 points on ADAS-Cog11 scale when compared to initial positions are achieving p-values p=.04. So measured against itself there is 4% chance that the data is result of statistical event and not workings of the drug in just 25 days. Isn’t p=.04 asking for some measure of randomness when measured against itself?

But when we compare these results to the placebo arm then this chance becomes 13%. The explanation of this discrepancy lies in the fact that dispersions about the average for the placebo and the dosed are a bit more indistinguishable. So versus placebo, there is the loss of the “statistically significant”.

Though the MMSE scores were collected, as well as ADAS-Cog11, by their nature they are less sensitive in this range and the company might be less prone to release them. Don’t get me wrong. Many companies recently have been releasing data from early phase2’s with just a handful of patients and after 30 days of dosing produces impressive numbers in some less known measure. I am being a bit facetious. ANVS401 is the first drug following A-beta deposit etiology and scoring high improvement rates in a short period of time.

I have been writing that the etiology of A-beta deposits is transitioning to inflammation narrative. The same etiology here lives under the narrative of axonal transportation. Would that be the more appropriate narrative for A-beta etiology?

I have also written that 30% patients diseased with Alzheimer’s diagnosis have no deposits of A-beta plaque (amyloid). Would Alzhimer’s be a syndrome, not a disease? We live in exiting times….

Writing is hard work, reward it with a beer…

Yet, for those who believe, could you just put a short parayer for me…….

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Morbidity and Disability in Phase 2a Alzheimer’s Study of Blarcamsine vs. Background Morbidity in Similar Age Control Group $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 $ANVS $CRTX FYI

I would like to add some additional information to the previously presented analysis on the dropout rate after 5 years. Though the number of remaing subjects in the Phase2a OLE and Humanitarian Extension is rather imprecise as Dr. Missling put it between 21 and 10, I used as reference paper titled

Variability in Annual Mini-Mental State Examination Score in Patients With Probable Alzheimer DiseaseA Clinical Perspective of Data From the Consortium to Establish a Registry for Alzheimer’s Disease

Christopher M. Clark, MDLianne Sheppard, PhDGerda G. Fillenbaum, PhDet alDouglas Galasko, MDJohn C. Morris, MDElizabeth Koss, PhDRichard Mohs, PhDAlbert Heyman, MD; and the CERAD Investigators

link: https://pubmed.ncbi.nlm.nih.gov/10404988/

Complex Picture of Age, Comorbidity, MMSE Test Sensitivity and Dispersion of Test Results

The paper contains an interesting graph as it represents the MMSE scores difference for patients at the end of the last year of given patient in the study. The line through the distribution of scores is the average decline per year.

What conclutions I draw from this graph?

First Year: The dispersion is the highest, most are scoring well below the initial scores and minority showing miraclously improvement. This was confirmed on the patients map for Phase2a as low to medium concentration cohorts followed this pattern of dispersion and the average rate of decline.

On subsequent years the dispersion tightens as well as the rate of average decline approaches with years = -3.4 +/-2.8. Also the frequency of miraculous test scores above initial scores falls precipitously. By year 5 there is nobody who scores above the initial score. There is also dying out of the patients as median age is 71 years old and average MMSE initial score was ~ 20. So the least healthy, both cognitevely and physically either die out or drop out. Age had a definitive influence on the average decline for given starting age. Quotation from the paper:

The MMSE score declined by an average of 3.41 points per year (P<.001) at age 71 years. Age had a statistically significant impact, with a 0.06-point-per-year (P<.001) additional decline for every year greater than 71 or a corresponding reduction in the rate of decline for every year less than 71. Sex had no significant effect (P=.43).

So on average if subject is 55 of age the anual decline is =-2.4, but at age 85 it is = -4.2. It seems as the older subjects die out the younger stay in the study.

I have been thinking how to measure the performance of Blarcamesine in this complex situation, where age, inital score, dropouts due to comorbidity and dropouts due to low MMSE scores can not be fully untangled or separated from the picture painted by the given data. Add to that a small sample size and you have gotten more than you can chew. I think that I found an alternative measure.

The paper had two cohorts. One was the people with probable Alzheimer’s diagnosis and the other was a control group of the same composition but cognitively healthy. Figure 1 shows the dwindling number of both groups over time.

Nothing is perfect in this picture, but it seems that by that measure Blarcamesine brings the morbidity very close to the background morbidity and disability experienced by the healthy controls. This is in some sense comparable as the study in the paper had recruited people from age 50 and up and average age being 71. Anavex recruited from ages 55 to 85, and used score from 14 to 24, if I am correct. The above study scored ranged from 10 to 24 MMSE.

Due to the advanced age of the subjects this comparison makes more sence than just looking at absolute numbers of survivors. In the study we can not separate death from disability due to very low MMSE scores, as both produced droping out of the study. I hope that similar situation was present in the Phase2a trial.

I do not know wwhether my analysis has any validity. The voices which want the dosing to be moved toward less progressed patients might indeed bring the morbidity of those who succumb to Alzheimer’s near those experienced by the cognitively healthy.

Now, give me a beer……

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Anavex Life Sciences Alzheimer’s Phase2a Dropout in Light of Info from Conference Call Q1 2021 Blarcamesine $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 $ANVS $CRTX FYI

On the 13th of May 2021, Dr Missling had conference call on the Q1 2021 results. The call was very brief but the questions from analysts were more detailed and aimed at elucidating future prospects of the company.

One was of interest to me over immediate promises. Namely, question about dropout rate in Phase2a Alzheimer’s study over the 5 years.

I have written about the dementia epdemiology and the dropout rate among Alzheimer’s patients in particular. link: https://piotrpeterblog.com/2021/04/11/the-ideal-dementia-drug-and-dementia-patients-population/ , link: https://piotrpeterblog.com/2021/03/20/can-blarcamesine-rescue-those-above-mmse-20-with-alzheimers-avxl-blarcamesine/ .

The Eligibility Criteria called for adults between 55 years and 85 years. This range covers Alzheimer’s of 85 years old patient to statistically last only 2 years to live to be cut short by comorbidity, and 55 years old otherwise healthy succumbing to Alzheimer’s dementia for the next 10 years till he dies of it. Sample with 32 patients is very sensitive to these varations so the data can be taken to be interpreted both ways. later we see that a suprising picture is emerging.

I have normalized the results of over 400 subjects study of natural run of the disease to 32 patient sample size. All this was done was to compare the amout of dropout in Phase2a Alzheimer’s and the reference link: https://pubmed.ncbi.nlm.nih.gov/10404988/ . I included the possible outcomes of 10, 15 and 21 patients left in the OLE and the Humanitarian Examption all counting on 5 years.

It is very hard to say anything specific here. We are not privy to the detailed data on all the patients. Dr. Missling has revealed that the drug works best on people who have not deteriorated below 20 MMSE points. 6 patients intially responded strongly to the drug. Later 4 responded strongly with 2 deteriorating much slower. Most of the death with dementia are due to comorbidity. Statistically, raw dropout rate give us an indication that Blarcamesine is doing better than “natural” progression of the disease but the situation is so complex that nothig can be said with any certainty. But then again, let’s look at the first year (57 weeks data for MMSE scores) results.

I made the calculations for three separate groups of patients. What is initialy visible is that;

  1. 4 patients with average MMSE score = 23 increased score by 3.5 points with narrow SD +/-0.7
  2. 4 patients with possible average MMSE score = 19 deteriorate -4.1 MMSE points/y the rate of 184% of ADNI model and wide SD of +/-3.2
  3. 15 patients detriorated even faster -5.3 +/-2.4 MMSE points/y 240% of ADNI rate -2.2 MMSE points/y. Yet the dispersion is smaller than in case of patients in point 2.

Let’s put in equaly importan piece of information. The APOE e4 gene distribution.

What puzzles me is that most of the patients are deteriorating double the rate ADNI synthetic placebo. If this continues then soon may be that many of these patients will die with very low MMSE scores. Either the large portion of Phase2a subjects were very old or deteriorated rapidly double the rate of ADNI synthetic placebo. In period of 5 years this can make a big difference. Taking into consideration APOE e4 distribution, and the double rate even the low number of 10 patients remaining after 5 years is Big Big Number.

There has been other statement from Dr. Missling who said that over time even those who do not initially respond to Blarcamesine start responding over longer time frame. The first year brings very high number of dropouts as if the population would be “very sick” then next 2 years the dropouts beat the normalized curve on slope first than on absolute number of patients still in program. This result holds for the next 2 years to total of 5 years.

My take on the Conference Call. People are concenrned about the data, but not the data itself but the timely data release. The data release might be done allright, but the research organization might drag its feet. Dr. Missling might have been very optimistic and enthusiastic over the data but the research organization might be not be keeping its inintial deadline.

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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 $ANVS $CRTX 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 $ANVS $CRTX 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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