Anavex Life Sciences Corp (AVXL)

[sokol]

A couple of important past developments to keep in mind as we wait, patiently and impatiently, for updates on Anavex's clinical trials.

Parkinson’s Disease-related Scores (June 28, 2021 announcement):

ANAVEX®2-73 high dose demonstrated statistically significant improvements compared to placebo (ITT population) for MDS-UPDRS Total score (p = 0.034). From baseline to end of trial at 14 weeks, MDS-UPDRS Total score improved by -10.98 points in the ANAVEX®2-73 high dose group and worsened by 3.53 points in the placebo group, an adjusted mean difference of -14.51 points (p = 0.034). This corresponds to a relative improvement of 18.9 % over 14 weeks.
This far exceeds an empirically established cutoff score of -7.1 for detecting meaningful clinical change.[5] For reference, the observed worsening of MDS-UPDRS Total score in patients with Parkinson’s disease in the literature is estimated in the range of 3.99 to 7.45 points per year.[6]

Treatment with ANAVEX®2-73 not only slows the progression of motor and non-motor symptoms in moderately advanced patients with Parkinson’s. ANAVEX®2-73 also resulted in clinically meaningful improvements as measured by the global composite score of Parkinson’s disease symptom severity, MDS-UPDRS Total score on top of standard of care including dopaminergic therapy, levodopa and other anti-PD medications after 14 weeks of treatment, suggesting ANAVEX®2-73’s global capability of slowing and reversing symptoms that progress in Parkinson’s disease, an urgent unmet medical need.
Sleep was a tracked variable both subjectively and objectively including sleep continuity or incidence of sleep disorders symptoms. ANAVEX®2-73 does not impair sleep and has a positive effect on REM sleep behavior disorder.
.....

This is now the second independent placebo-controlled clinical ANAVEX®2-73 Phase 2 study to confirm the predictive biomarker of response established with SIGMAR1 mRNA expression. Both ANAVEX®2-73-PDD-001 Parkinson’s disease dementia study and the recently reported ANAVEX®2-73-RS-001 U.S. Rett syndrome study are persuasively consistent with the proposed mechanism for ANAVEX®2-73,” said Christopher U. Missling, PhD, President & Chief Executive Officer of Anavex. “We believe that the easily accessible predictive biomarker combined with the observed efficacy is a consistent explanation of the efficacy in this second largest CNS indication with unmet medical need. This data further strengthens the foundation of ANAVEX®2-73 as a cross-platform CNS drug.”

https://www.anavex.com/anavex-life-sciences-announces-anavex2-73-blarcamesine-improved-both-primary-cognitive-and-secondary-mds-updrs-efficacy-endpoints-with-significant-biomarker-correlation-in-placebo-controlled-p/

So, we have had two independent placebo-controlled clinical trials that confirm predictive biomarker response and show improvement in cognitive scores versus declines in cognitive scores in patients.

Plus, the Alzheimer's clinical trials that have been completed so far have indicated improvement in cognitive scores although these trials were small and not placebo-controlled. Some patients in these early trials responded better than others. As a result, we hired Ariana and we discovered that the majority (80%) of patients is expected to benefit from Anavex. See this.

• Patients with a wild-type SIGMAR1 gene were found to have an improved benefit from ANAVEX®2-73. Patients with a variant of the SIGMAR1 gene (rs1800866) were found to have a limited benefit from ANAVEX®2-73. Same for COMT variant (rs113895332/rs61143203)
• Including patients with milder disease stage (baseline MMSE ≥20) and the exclusion of AD patients carrying SIGMAR1 variants results in a score improvement of +1.7 MMSE and +3.9 ADCS-ADL, respectively at week 57. The additional exclusion of the COMT variant results in a score improvement of +2 MMSE and +4.9 ADCS-ADL, respectively for the same period. Both effects would be clinically meaningful
• The minority of the population (about 20%) has the variant SIGMAR1 gene, hence the majority of patients (about 80%) is expected to benefit from ANAVEX®2-73
https://www.anavex.com/wp-content/uploads/2019/03/AAIC_Anavex_Gene_poster_2018_Final.pdf

And, keep in mind authophagy and homeostasis:

See the book "Ageless'' by Andrew Steele

“The logical endpoint of the process will be to gradually retire the idea of treating “aging” and begin to see all human dysfunction and disease as a “loss of homeostasis.” Homeostasis is the collective term for the myriad processes which keep aspects of our physiology, from temperature and blood sugar to levels of proteins and numbers of a particular kind of cell, within the astonishingly narrow parameters needed to keep us alive. A 20- or 30-something human is in a state of very nearly perfect homeostasis, with odds of their system falling so far out of balance that they die less than one in 1,000 annually. If we could just return our physiological parameters to where they are in young adulthood, we’d be able to rely on our bodies’ existing homeostatic systems to keep us alive.

The processes we currently label aging are a very gradual loss of homeostasis ..... The best treatments for aging would gently nudge the network of processes causing us to gradually lose homeostasis back toward a stable state, keeping us safe and healthy for decades longer than we enjoy today. Intervening in clever ways to restore order to the whole system is surely the eventual future of medicine.” Excerpt From Ageless by Andrew Steele.

"Ageless" does not mention Anavex, but we know that Anavex is pursuing treatments to nudge the body back to a stable state of homeostasis. By way of only one of many announcements about this:

"ANAVEX®2-73 activates the sigma-1 receptor (SIGMAR1). Data suggests that activation of SIGMAR1 results in the restoration of complete housekeeping function within the body and is pivotal to restoring neural cell homeostasis and promoting neuroplasticity." Reference: Advances in Experimental Medicine and Biology Volume 964 (2017) Sigma Receptors: Their Role in Disease and as Therapeutic Targets. https://www.anavex.com/anavex-life-sciences-reports-new-publication-in-medical-journal-elucidating-the-mechanism-of-anavex2-73-blarcamesine-and-anavex3-71-af710b-related-to-the-treatment-of-alzheimers-dise/#_ftn17