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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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 $ANVS $CRTX 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 $ANVS $CRTX 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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