Anavex Life Sciences Corp (AVXL)

[TempePhil]

Interpretation of the Parkinson PR good news:

The relevant paragraphs of the PR are quoted at the bottom of this post.

The first paragraph (ANAVEX®2-73 activates the sigma-1...)lays out proof that the there is good correlation between biomarkers and clinical efficacy. This is presented as the biomarker increase of SIGMAR1 activation and the resulting efficacy data. This appears to be strengthening the case for approval, given the Biogen approval for Adu, which was strongly based on biomarkers. It appears pharma is taking that approval as a signal from the FDA, that biomarkers have increased importance as far as approval.

The second paragraph (Parkinson's Disease-related Scores) presents amazing results for the high dose arm for the Unified Parkinson’s Disease Rating Scale test. This MDS-UPDRS test is a standardized test for measuring Parkinsons disease. The high dose arm improved 18.9 % over the 14 week trial. This is twice as much needed to be a meaningful clinical change. This is a great improvement, similar to the increase in memory presented at CTAD. Next Anavex suggests A2-73 is capable of slowing and reversing symptoms, and that is an urgent unmet medical need. Using this wording "unmet medical need" means that they will be pursuing FDA Fast Track Designation. By stating there are also improvements seen over SOC levodopa, Anavex can pursue FDA Breakthrough Therapy Designation!

The third paragraph (Dementia-related Scores), reviews the data presented at CTAD. Note the trial used the standard CDR system Episodic Memory test, but Anavex converted these test results to standard Alzheimer Disease test (ADAS-COG) scores. Some on ihub have suggested that test score conversion is not possible, unlike shown by the PR.

The PR ends with this great quote by Dr.Missling, “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.”
The PR supports his statement, and continues to make the case that A2-73 is a cross-platform CNS drug!

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.[1] Recent independent findings strengthen the understanding of the beneficial effect of SIGMAR1 activation as compensatory mechanism to chronic CNS diseases.[2]
Parkinson’s disease (PD) is a chronic CNS disease and the second largest age-related disorder after Alzheimer’s disease.[3] This study demonstrates for the first-time that a drug-specific biomarker correlates with clinical efficacy endpoints in Parkinson’s disease.
ANAVEX®2-73 treatment resulted in significant (p = 0.035) mRNA expression increase of SIGMAR1, the gene encoding for the receptor targeted by ANAVEX®2-73, which correlated with clinical efficacy as measured by primary cognitive efficacy endpoints, CDR system Continuity of Attention (CoA) (p = 0.029) and CDR system Power of Attention (PoA) (p = 0.015), and secondary Parkinson’s efficacy endpoints Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS)[4], MDS-UPDRS Part III (p = 0.024) and MDS-UPDRS Total (p = 0.038).

Parkinson’s Disease-related Scores
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.

Dementia-related Scores
Previously reported cognitive outcome measures from this study relevant to Alzheimer’s disease presented at CTAD 2020 observed statistically significant improvement of CDR system Episodic Memory of +42.22 between ANAVEX®2-73 high dose and placebo, which was dose-dependent (p = 0.003).[7] CDR system Episodic Memory has been shown to be highly correlated (70%) with the ADAS-Cog score (r = 0.7).[8] The calculated corresponding ADAS-Cog mean change from baseline score is -1.9 (improvement) for patients in the high dose group, an 8% mean improvement from baseline to 14 weeks. The difference between the ANAVEX®2-73 group and the placebo group in the change from baseline at 14 weeks was a 4.0-point improvement of calculated corresponding ADAS-Cog score (p = 0.015).[9]
ANAVEX®2-73 is currently being tested in late-stage placebo-controlled ANAVEX®2-73 Phase 2b/3 clinical Alzheimer’s disease study, which recently completed enrollment, and is utilizing the same dosing regimen as in the above-described completed Parkinson’s disease dementia (ANAVEX®2-73-PDD-001) study with differentiated patient selection criteria.[10]