Anavex Life Sciences Corp (AVXL)

[sokol]

The PDD trial in Spain, and the exposure of PDD trial patients to Covid-19.

This is a two part discussion. In the first part, I include my rough analysis that indicates that the PDD trial may have substanitally progressed before Covid-19 was recognized as a problem. In the second part, I discuss Covid-19, the "cytokine storm" (the deadly Covid-19 event), and exposure of PDD patients to the virus.

1. PDD trial in Spain:

The Anavex PDD trial is a 120 patient, 14 week study in Spain (Europe) along with 3 sites in Australia.

1. First PDD patient enrolled patient - October 30, 2018. https://www.anavex.com/first-patient-enrolled-in-anavex-life-sciences-phase-2-clinical-trial-of-anavex2-73-for-the-treatment-of-parkinsons-disease-dementia-pdd/
2. Trial recruitment reaches half way mark - March 13, 2019. https://parkinsonsnewstoday.com/2019/03/13/anavex-life-sciences-reaches-50-enrollment-threshold-in-anavex2-73-parkinsons-disease-dementia-pdd-phase-2-study-ahead-of-schedule/
3. Achievement of full enrollment - Jan 27, 2020. https://www.biospace.com/article/releases/anavex-life-sciences-announces-achievement-of-enrollment-target-for-the-anavex-2-73-blarcamesine-phase-2-parkinson-s-disease-dementia-pdd-clinical-trial/
4. "To offer eligible participants of the Phase 2 PDD study access to ANAVEX®2-73 (blarcamesine), participants completing the trial may enroll in a voluntary 48-week open-label extension study." (Same reference as #3 above.)

I estimate that 75% or more enrollment was achieved as of August 2019 based on March 2019 50% enrollment achievement within a little less than 5 months after the first patient was dosed. In other words, 5 months and 1/2 after 50% was achieved, I am estimating that 75% enrollment was achieved by the end of August 2019. Therefore, by the end of December 2019, 14 weeks after 75% enrollment, the vast majority of patients 75% (90) or more patients should have completed 14 weeks of dosing of either AVXL 2-73 or the placebo. By sometime in May of this year, all patients in the PDD trial will complete the 14 week trial. However, more than 75% have now, as of April 2020, completed this trial. 100% may complete the trial by the end of May, assuming no interference from the C-virus.

It does seem that the Anavex PDD trial was and is far enough along so that any complications to this trial caused by the C-virus are likely not significant enough to invalidate the trial.

Some number of patients, probably at least 60, PDD clinical trial participants will complete dosing of AVXL 2-73, assuming 50% of the PDD patients receive AVXL 2-73 and 50% receive the placebo. More that 60 from the PDD trial will be AVXL 3-73 dosed, assuming some PDD placebo patients were switched to the real thing once they completed their 14 week regimen of the placebo. Additionally, I assume that a number of AD patients, at the very least those patients in the initial AD trials, continue to receive the drug. "Interim 2-Year (104)-Week) data from the Phase 2a ANAVEX®2-73 (blarcamesine) extension study, with Alzheimer’s disease patients followed for up to five years, will be presented at the 12th Clinical Trials On Alzheimer’s Disease (CTAD) 2019 Conference in San Diego, CA (December 4-7, 2019)." https://www.anavex.com/anavex-life-sciences-presents-anavex2-73-blarcamesine-data-at-12th-clinical-trials-on-alzheimers-disease-ctad-2019-conference/.

Seemingly, all of the 120 PDD clinical trial patients that complete the PDD trial, will have an opportunity to receive AVXL 2-73, Therefore, using only the PDD numbers and the number from the previous AD trials, unless we have a high drop out rate, we should have more than 100 or so PDD patients (potentially most of the PDD patients will receive AVXL 2-73 with voluntary enrollment in the extension study) during this year from which we may evaluate AVXL 2-73. The number is higher if we consider all patients in all AVXL 2-73 trials.

We all know what will happen if the PDD trial fails. We may have mixed results that leaves us uncertain, which would set us back. Hopefully, we will see a high percentage of success rate among PDD patients in this precision trial, but I am sure that arguments may be made that it is unrealistic, even if this is a trial for an unmet need, to expect approval of AVXL for PDD or any other disease based on this number alone. Even so, if the PDD trial is successful, this will be an attention grabber.

2. EXPOSURE OF PDD TRIAL PATIENTS TO COVID-19

Potentially, patients in Anavex's clinical trials have been exposed to Covid -19. My question is: How have Covid-19 infected clinical trial patients fared? I ask this question because it has been intimated that AVXL 2-73 has a beneficial impact on neurological inflammation.

Inflammation is the major problem causing deaths in Covid -19 patients. It is sometimes referred to as the "cytokine storm". This virus adversely impacts the central nervous system and organs throughout the body. Here is a list of articles about the "cytokine storm'', inflammation caused by the C-virus, and the adverse impact of the virus on the central nervous system.

1. WSJ article "Haywire Immune Response Eyed in Coronavirus Deaths, Treatment - Researchers are looking at treatments to suppress ‘cytokine storm,’ increasingly linked to the most severe Covid-19 cases"

Haywire Immune Reaction Linked to Most Severe Cases


2. Pro-inflammatory cytokines in Alzheimer's disease].


Stamouli EC1, Politis AM1.
Author information
Abstract
Alzheimer's disease (AD), the most common progressive neurodegenerative disorder in the elderly, is clinically characterized by progressive impairment of cognitive functions, including reduced critical capacity, weakness of decision-making and problem orientation, while in the more advanced stages it is accompanied by behavioral disorders and impaired verbal ability. Neuropathological characteristics of the disease are the neurofibrillary tangles (NFT), the neuritic plaques (NP), the prominent synaptic loss and eventually the neuronal loss. The presence of inflammatory process seems to be playing important role in the progression of the disease. This process is directed by the activated glial cells and it leads to the overproduction of acute phase proteins, complement factors activation and induction of inflammatory enzyme systems. These inflammatory factors can contribute to neuronal dysfunction and cell death. Cytokines belong to the acute phase proteins, which are secreted from glial cells. They can either strengthen the inflammatory reaction or suppress it, adjusting the intensity and duration of the immune response. In the category of cytokines belong several interleukins (ILs) and various factors (TNF-a, TGF-ß). Interleukins are involved in complex intercellular interactions among neurons, microglia and astrocytes, as well as intracellular signal transduction events, which are necessary to promote the inflammatory cascade characteristic of AD neuropathology. It has been observed that increased levels of pro- inflammatory cytokines, including tumor necrosis factor (TNF), interleukin 1ß (IL-1ß), interleukin 6 (IL-6) and interferon ? (IFN-?), may suspend phagocytosis of amyloid Aß in brains of patients with AD. Thus, it may interfere with the effective removal of plaque from microglia, promote astrogliosis and neural death. Normally, during immune surveillance, a balance is maintained between pro- and antiinflammatory influences. Yet, during AD, the abnormal accumulation of soluble amyloid oligomers triggers excessive release of pro inflammatory factors, such as cytokines and other acute-phase reactants, out of proportion to the regulatory components, such as IL-4, IL-10, receptor antagonists, interleukin inhibitors and others, ultimately leading to neuronal and synaptic injury and loss and cognitive decline. These changes in the brain parenchyma are often accompanied by changes in levels of these inflammatory proteins in peripheral blood. Even though literature is presenting conflicting studies, efforts are being made for the detection of cytokines in peripheral blood and association of their levels with the progression of AD. Inflammatory pathways, involving the signaling of cytokines, could be potential targets for the prevention of AD and the development of new therapies. The aim of the present work is to review studies indicating a correlation between these inflammatory agents and AD pathogenesis.

https://www.ncbi.nlm.nih.gov/pubmed/28114090


3. These slides were used at the Anavex July 2019 presentation:

http://www.arianapharma.com/wp-content/uploads/2019/07/Anavex-Microbiota-Presentation-AAIC-July-2019-FINAL-1.pdf

See specifically the slide entitled: SIGMAR1 Restores Homeostasis Caused by Neuro-inflammation

https://www.anavex.com/wp-content/uploads/2019/12/CTAD2019_ANAVEX2-73_P84_Microbiota_.pdf

4. These articles touch how the C-virus may invade and effect the central nervous system:

A. "Lost Smell and Taste Hint COVID-19 Can Target the Nervous System"

https://www.the-scientist.com/news-opinion/lost-smell-and-taste-hint-covid-19-can-target-the-nervous-system-67312

B. "The Surprising Neuroscience of COVID-19
Effects on the central nervous system might contribute to respiratory failure."

https://www.psychologytoday.com/us/blog/long-fuse-big-bang/202003/the-surprising-neuroscience-covid-19

It is reported that recovered C-virus patients have lingering effects from the virus and potential damage to their bodies, including the central nervous system. We have a long way to go before we know about any of this, but there is a need for treatments for complications in recovered C-virus patients. What those drugs may be is anyone's guess, and I do not wish to give anyone the impression that AVXL 2-72 may be one of those drugs. AVXL 2-72 has not yet been approved for any use, it has not been studied for Covid-19 treatment or prevention, and it is unrealistic to speculate about whether it will ever be available for or of any use in treating recovered C-virus patients.

Lastly, I raise the question of why it is that Covid-19 is more deadly among the elderly population? Is it because of underlying diseases that come with age? Is it due to degeneration of the body and its ability to maintain internal stability (homeostasis)? Why do some young people that otherwise appear healthy die from Covid-19? If we have a drug or drugs that helps to restore homeostasis of the central nervous system, may it be of use (not now for Covid because there is not enough time to test for that) prophylactically in the future to prevent diseases and infections from developing?

We have a long way to go, and we have many interesting things to explore.