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.

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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