Novel Etiology of Alzheimer’s 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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Many neurodegenerative and neurodevelopmental diseases might have a similar mechanism. These might be Parkinson’s, Rett syndrome, Fragile X syndrome, and Autism.

The Amyloid and Tau plaque theory has been superseded but will die slowly. ($SAVA $BIIB)

New types of drugs will emerge to address this paradigm change.

AVXL already has drugs to address the new etiology. Large Effect Size proves that it is on the right track.

On November 13, 2020, a paper has been published in Science Advances magazine presenting a novel etiology of Alzheimer’s Disease. The link to the PDF of the paper is here Dedifferentiation and neuronal repression define familial Alzheimer’s disease

Before we delve into the article content we should first acquaint ourselves with few concepts and their implications.

The acronym EOFAD stands for Early-Onset Familial Alzheimer’s Disease. This is the form of AD (Alzheimer’s Disease) caused by inherited genetic mutations, which run in families. A number of those families were researched and gene mutations were identified. Further confirmation of the genetic etiology of EOFAD can be found in transgenic murine models engineered with the above mutations and following the pattern of EOFAD in humans with such fidelity that the early onset corresponds to the same age in mice years as in humans. In one such model named 3xTg, at 4 months of mice life (35-40 years in humans years) first signs of mental deterioration appear, and at 6 months (50 years in humans) telltale sign of AD amyloid plaque appears in the brains of mice. The model suggests that mental deterioration predates the Amyloid plaque occurrence and the plaque is a secondary effect that has synergy with mental deterioration, but it is not the primary cause of AD.

Most of AD sufferers (95%) succumb to LOAD (Late-Onset AD). There has not been found overwhelming evidence to connect its etiology in this population to a specific genetic mutation. APOEe4 mutation can be connected to the severity of the disease progression but it is unnecessary for a patient to carry the mutation in order to develop the disease. At this point in time LOAD has been vaguely connected to environmental causes.

The researchers have collected cells from EOFAD subjects and healthy control group, then by turning certain genes on they matured them into adult neurons. This technic is named Human Induced Pluripotent Stem Cells. During embryonic development single fertilized cell containing the new DNA divides repeatedly and the resulting cells differentiate selectively by expressing specific genes to mature among others into neurons. This is what is called cellular fate. The process of maturation follows the evolutionary tree of life where not all stages are present or have a function in the fully developed organism.

The presence of mutated genes at one point in time caused the mature neurons to devolved partially to an earlier stage in cellular differentiation creating a kind of Franken cells. These cells have lost all synaptic function as they can’t synthesize protein to “build” synapses and operate them. It can be expected that for a living organism this would mean onset of mental deterioration, just like in transgenic murine model 3xTg at 4 months of mouse’s life. The experiment was conducted in vitro so this is only speculation on my part. The devolved neuron cells produced signals inducing inflammation response from the microglia, marking themselves for destruction by the immune system. The inflammation is so destructive in AD and it is an intrinsic part of the disease that few therapies have been proposed to use agents controlling it. A graphic representation of the state of neurons in EOFAD can be seen in Fig 6 of the above-mentioned paper.

Both amyloid and tau proteins are part of healthy working neuron physiology. I can speculate that the loss of function by devolved neurons can trigger the disturbance in the physiology and precipitate accumulation of the aforementioned plaque. This is confirmed by the reported changes in Amyloid and Tau physiology of the devolved neurons, with this the Amyloid and Tau plaque theory has to be if not altogether abandoned then at least modified.

By running an experiment versus the healthy controls researchers have documented the interaction between genes ultimately leading to changes in Chromatin.

The sole purpose of Chromatin is to provide structural support and package the DNA double helix for reading by the cellular transcription machinery to synthesize proteins. In other words, the Chromatin complex is the gatekeeper of the information contained in the DNA. Chemical changes to its structure determine which genes can be read and which can be inaccessible to the cell at its particular cellular fate.

Those chemical changes can be either due to the expression of specific genes, their fate or can be due to environmental causes which are called epigenetic.

In the case of the EOFAD cells, the devolution was caused by mutations in the key genes. The progress of the disease in the familial EOFAD type and LOAD type does not differ with the exception of the onset of the disease. A next step in the scientific pursuit of AD etiology might be to seek the epigenetic nexus between the two forms of the disease.

Since the end of the nineteenth-century plaque has been connected to dementia, by the early science of histopathology. In 1985, the chemical structure of the plaque has been identified and it became later the primary therapeutic target. As in any field, new tools open new horizons and new insights into the etiology of previously unsolved mystery diseases. Once a while, a study upends years of research in a case of scientific “creative destruction”. The insight present in the paper could not have been elucidated had it not been for HiPSC and a myriad of other methods not available in 1985. No doubt, the content of the paper is the seminal work in the field of Alzheimer’s disease, introducing a new paradigm, and entirely dismissing the Amyloid or Tau plaque as a therapeutic target. The only unanswered question is the relevance of the work on EOFAD to LOAD. Epigenetic changes in the structure of chromatin can serve as a potential conceptual bridge. Other studies point to a similar set of affected genes in LOAD patients. Reference to these studies can be found in the Discussion section of the paper.

As investors, we are much more concerned with the relevant consequences of scientific discovery to define therapeutic targets, so that effective drugs can be designed, than the science itself. Currently, I see few types of drugs ready to address this novel etiology of AD. One is growth factors, then RNA interference, finally are Sigma 1 receptor agonists. Growth factors are usually compounds coxing stem cells to divide and transform into specific types of cells. In the Alzheimer’s field, Athira Pharma ($ATHA) comes to mind. Growth factors are present in embryonic development as well as in wound healing. So-called autologous stem cells are present in all kinds of tissues and can be called on to assist in the healing process. They are undifferentiated and waiting to assume some limited cellular fates. RNA interference can mute the expression of a gene at the point of protein synthesis. Yet, the most comprehensive drugs are the sigma 1 receptor agonists. Aptly, one researcher has called the capabilities of the SIGMAR1 receptor “pluripotent”. The SIGMAR1 receptors are located in the endoplasmic reticulum where protein synthesis and protein folding takes place. Since the endoplasmic reticulum is an outgrowth of the cell nucleus it is not surprising that SIGMAR1 has been implicated in affecting the Chromatin complex and by this the expression of certain genes as is in the example of cocaine being an agonist of SIGMAR1 and its interference with the transcription of MAOB protein. Link to the paper Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope

There is no single definitive agonist for this receptor, its specificity is kind of amorphous. It can have a high affinity with different compounds but the effective agonists are few.

$AVXL has two such compounds in the pipeline. Anavex3-71 is a future development, just looking to enter clinical trials soon. Blarcamesine is currently in Alzheimer’s phase 2b/3 trials and few others.

The design of phase 2b/3 builds on the results of phase 2a, which in the High Concentration Cohort bifurcated into those who succumbed to the disease and the group in which basically the course of the disease has been reversed, the so-called Super Responders. Anavex Life Sciences is in pursuit of precision medicine and Artificial Intelligence was used in analyzing all the possible connections between the genome of the subjects and the measurable in the trial. The Super Responders tended to be the carriers of the wild type SIGMAR1 gene, roughly 80% of the general population, and certain variants of the COMT gene, with lesser benefits. Also, they tended to test on MiniMental State Examination above 20 points. MMSE test goes from 30 points for a healthy individual to zero for somebody incapacitated. The following illustration is a slide from CTAD 2017 presentation with the results of the 57-week dosing.

The numbers at the position of each patient are is the change in MMSE score from baseline after 399 days of dosing. Y-axis is the slope of the line to the 57 weeks score in MMSE points per day. The High Concentration Cohort roughly corresponds to a 50mg/kg daily dose.

The task which is set before us is to determine how likely is Anavex’s Blarcamesine to obtain approval for its Alzheimer’s drug?

When you have a drug trial you measure a variable in two populations, placebo, and the dose cohort. Both populations can be described by the mean and the distribution around the mean. The first question: Is the distribution of data on the dosed population part of the placebo population distribution? Second question: How far removed are those two distributions from each other? Both these questions are partially answered by Effect Size Cohen’s d. We will try to arrive at a somewhat objective measure of Blarcamesine performance versus other drugs via this statistical tool. In order to do so we need to make some assumptions and calculations.

Phase 2b/3 pivotal Alzheimer’s trial #NCT03790709 recruits subjects inclusive MMSE scores 20-28 but with proven Alzheimer’s hallmark of Amyloid deposits. Patients are not selected on the basis of carrying the genes tending to cause a better response. They represent the general population, where about 16 to 20% carry the mutation lowering response.

Let us now make the assumptions.

1. From calculations of phase 2a data, we got the mean and SD deviation for the Super Responders annual change in MMSE scores +3.5+/- 2.6. Let us disregard the small sample size.
2. We assume that the trial responders will follow this performance metric. 80% percent of the dosed population to be Super Responders, 20% placebo equivalent responders.
3. We assume that the combined dosed cohort will have an average change in MMSE scores +2.4+/-3.2
4. The baseline score will be MMSE 23.
5. As the trial uses ADAS-Cog11 as a primary cognitive measure we assume that the calculations are equally valid for MMSE scores.
6. We assume that the placebo arm will follow loosely the synthetic placebo arrived by the ADNI industry consortium for the purpose of eliminating the placebo arm in Alzheimer’s trials with MMSE annual change of -2.2 +/-1.2. We prefer to set the SD to 1.2 instead of 0.31 as it seems to be more realistic and in line with the experience from phase 2a.
7. We assume that patients in phase 2b/3 will respond to Blarcamesine just like the few in phase 2a, disregarding the sample size. `

The formulas for calculating Effect Size Cohen’s d are available on many pages on the web. No adjustments are taken into considerations as the trial sample size is above 50 subjects. We need to compare the Effect Size numbers for Donezepil, Cassava Science Simufilam and for Blarcamesine (projected) to give the insight into possible therapeutic effect which might be reached in phase 2b/3.

The clear winner is Blarcamesine with an Effect Size of 1.89, which is qualitatively given as “very large” versus Simufilam’s .37 or “small”. Donezepil has been approved with ES=.28, so the hurdles are set low. A similar range of Effect Size metrics has been achieved by Blarcamesine in Parkinson’s Disease Phase 2 (ES~1.20) and Rett Syndrome phase 2 (ES~1.20 with only 5mg/kg daily dose as of now).

The Rett Syndrome has been linked to a similar mechanism of cellular degeneration but involving a mutation in the gene MECP2 which among others regulates the expression of genes during neural maturation and development. Link to paper MeCP2 as a genome-wide modulator: the renewal of an old story The success with Rett Syndrome confirms the moniker of “pluripotency” in regards to Blarcamesine, which at least partially is restoring function where the transcription mechanism is at fault. Similar mechanisms are being identified in other degenerative diseases of the central nervous system.

Just like Rett Syndrome Autism Spectrum Disorders (ASD) are neurodevelopment diseases. The aforementioned “pluripotency” of Blarcamesine might be proven true in the next market by entering with Fragile X Syndrome the field of ASD. Visit anavex.com to see the pipeline of its drugs.

There is a concept to refer to the almost miraculous self-regulations of life in spite of the prevailing entropy, it is called homeostasis. The phrase of “restoring homeostasis” has been often used in reference to SIGMAR1 receptors therapeutic action.

The rapid progress the drug is making in Rett Syndrome and the lack of effective medication in this rare disease bodes well for timely approval of the drug to hit the market in early 2022. The company already is talking fo developing its own marketing of Blarcamesine for Rett syndrome as other companies have done with rare diseases drugs.

Anavex has been dosing, through the vehicle of Open-Label Extension, patients with Alzheimer’s for the last 3 years without any serious adverse effects. Currently, Phase 2b/3 is 86% enrolled and randomized and the release of data is expected to take place in the first half of 2022.

To summarize, AVXL presents unsurpassed and yet unrecognized by the market opportunity with wide therapeutic reach and unparalleled efficacy of its drugs. Timing-wise Blarcamesine beats Cassava Science ($SAVA) and Athira Pharma ($ATHA) by at least 3 years.