Expression levels of pathological dysregulated neurodegenerative genes of both Alzheimer’s and Parkinson’s disease were significantly restored by the therapeutic effect of ANAVEX®2-73 (p<0.005)
These findings will facilitate contextualization of upcoming readout of ANAVEX®2-73 Phase 2b/3 Alzheimer’s disease clinical trial
NEW YORK – July 31, 2022
Anavex Life Sciences Corp. (“Anavex” or the “Company”) (Nasdaq: AVXL), a clinical-stage biopharmaceutical company developing differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders including Alzheimer’s disease, Parkinson’s disease, Rett syndrome and other central nervous system (CNS) diseases, today announced the first entire clinical gene pathway data from the ANAVEX®2-73-PDD-001 Parkinson’s Disease Dementia (PDD) study at the Alzheimer’s Association International Conference (AAIC), taking place in San Diego, CA and virtually on July 31 – August 4, 2022.
The poster presentation titled, “Study of the mechanism of action of Blarcamesine (ANAVEX®2-73): Whole blood transcriptomics analysis (RNAseq) identifies treatment impact on compensatory pathways by restoring key neurodegenerative pathways functionality, including Alzheimer’s and Parkinson’s disease pathways” is being presented by the principal author, Dr. Mohammad Afshar, MD, PhD, Ariana Pharma, Paris, France and Cambridge, US.
Randomized, placebo-controlled clinical trial in 132 patients with Parkinson’s disease dementia (PDD) included prespecified biomarkers of response as well as Whole Exome Sequencing DNA data and full RNA exome expression data collection.
ANAVEX®2-73 transcriptomics analysis (RNAseq) identified a gene network that is differentially expressed in Parkinson’s disease dementia (PDD) patients treated with ANAVEX®2-73 compared to placebo after 14 weeks of treatment. The expression of 14,150 genes were analyzed from both placebo and ANAVEX®2-73 treated patients. Biological relevance of this gene network was assessed through pathway analysis and confirmed the impact of ANAVEX®2-73 treatment on pathways involved in neurodegenerative diseases, especially Alzheimer’s disease and Parkinson’s disease.
While genes are known to be down-regulated in Alzheimer’s disease  and Parkinson’s disease , representing pathology for these diseases, ANAVEX®2-73 singularly impacted expression levels of these genes in multiple pathways by countering the pathological down-regulation of genes in both Alzheimer’s (p<0.005) and Parkinson’s disease (p<0.005) and other degenerative diseases (p<0.005).
The scope of these detected gene expressions identified through ANAVEX®2-73 effect may represent additional potential biomarkers of disease pathology and response.
Previously, this study demonstrated dose-dependent, statistically significant improvement of dementia assessment, Quality of Episodic Memory with ANAVEX®2-73 (p=0.003) as well as significant improvement of Parkinson’s assessment, MDS-UPDRS Total score (p=0.034), in patients treated with ANAVEX®2-73 high oral dose once daily during the 14-week trial. SIGMAR1 mRNA expression significantly increased in ANAVEX®2-73-treated patients vs placebo (p=0.035) over the course of treatment and was significantly associated with improvements of MDS-UPDRS scores and cognitive efficacy endpoints CDR system. 
Dr. Jaime Kulisevsky, MD, PhD, Principal Investigator of the trial, commented, "To my knowledge, this represents the first extensive transcriptomics analysis (RNAseq) of a therapeutic agent in patients with Parkinson’s disease dementia (PDD). It is very intriguing to confirm this robust correlation of the clinical improvements of motor impairment (MDS-UPDRS) and cognition (CDR system) with compensation of expression levels of dysregulated neurodegenerative genes, especially Alzheimer’s disease and Parkinson’s disease, through the therapeutic effect of ANAVEX®2-73. PDD is a debilitating disorder with significant co-morbidities and there has not been a mechanistically novel medication approved for PDD in over 20 years. Hence, new therapies are urgently needed to alleviate this suffering and disability.”
Christopher U Missling, PhD, President & Chief Executive Officer of Anavex, stated, "It is exciting to witness ANAVEX®2-73’s (blarcamesine) demonstration of its platform Precision Medicine potential for both Alzheimer’s disease and Parkinson’s disease, and likely other neurodegenerative diseases. We believe these results will facilitate contextualization of upcoming readout of ANAVEX®2-73 Phase 2b/3 Alzheimer’s disease clinical trial and further supports pivotal studies in Parkinson’s disease and Parkinson’s disease dementia. We would like to thank all the patients and participating families as well the investigators and clinical site coordinators for their dedication to this study."
About ANAVEX®2-73-PDD-001 Clinical Study
The ANAVEX®2-73-PDD-001 study was an international, double-blind, multicenter, placebo-controlled proof of concept Phase 2 clinical study that randomized 132 patients with Parkinson’s disease dementia (PDD) equally (ratio of 1:1:1) to target doses of 30 mg, 50 mg ANAVEX®2-73 or placebo, respectively. As previously reported, in addition to prespecified ANAVEX®2-73-related biomarker of response, SIGMAR1, safety and cognitive efficacy, MDS-UPDRS, actigraphy and sleep function was assessed during the study duration of 14 weeks.
Study inclusion required diagnosis of idiopathic Parkinson's disease (PD) consistent with the UK Parkinson's Disease Society Brain Bank diagnostic criteria and diagnosis of probable PD dementia (PDD) according to the Movement Disorder Society Task Force clinical diagnostic criteria as well as Montreal Cognitive Assessment (MoCA) score of 13 to 23. DNA and RNA from blood samples were analyzed using NGS.
Study participants were allowed to be on stable regimen of anti-Parkinson's disease medications (including levodopa, dopamine agonists, MAO-B inhibitors, or entacapone). Treatment with cholinesterase inhibitors, rivastigmine, donepezil and galantamine (Exelon®, Aricept®, or Reminyl®) were also permitted.
The study found that ANAVEX®2-73 was well tolerated in oral doses up to 50 mg once daily. The results showed clinically meaningful, dose-dependent, and statistically significant improvements in the Cognitive Drug Research (CDR) computerized assessment system analysis. The study validated the precision medicine approach of targeting SIGMAR1 as a genetic biomarker of response to ANAVEX®2-73, confirming that ANAVEX®2-73 acts through SIGMAR1 activation.
Broad and statistically significant improvements in CDR system Cognitive Domain of Attention assessed by Choice Reaction Time (p = 0.039) and Digital Vigilance (p = 0.008) and CDR system Episodic Memory (p = 0.047), representing complex cognitive tasks with impact on quality of life such as making a choice between similar objects and remembering daily personal experiences, which are mostly impaired in both PD and AD. 
Statistically significant dose-dependent (p = 0.003) improvement of Episodic Memory, which has been shown to be highly correlated (70%) with the Alzheimer’s Disease Assessment Scale–Cognitive score (ADAS-Cog; r = 0.7). 
ANAVEX®2-73 does not impair sleep and has a positive effect on REM sleep behavior disorder.
ANAVEX®2-73 was generally safe, well tolerated, and improved safety profile compared to dementia drugs associated with typical adverse effects.
After completing the ANAVEX®2-73-PDD-001 trial, participants were able to enroll in a voluntary 48-week open-label extension study, ANAVEX®2-73-PDD-EP-001, which continued to assess safety, long term efficacy and changes in gut microbiota. 
About Anavex Life Sciences Corp.
Anavex Life Sciences Corp. (Nasdaq: AVXL) is a publicly traded biopharmaceutical company dedicated to the development of novel therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders including Alzheimer’s disease, Parkinson’s disease, Rett syndrome and other central nervous system (CNS) diseases, pain, and various types of cancer. Anavex’s lead drug candidate, ANAVEX®2-73 (blarcamesine), has successfully completed a Phase 2a clinical trial for Alzheimer’s disease, a Phase 2 proof-of-concept study in Parkinson’s disease dementia and both a Phase 2 and a Phase 3 study in adult patients with Rett syndrome. ANAVEX®2-73 is an orally available drug candidate that restores cellular homeostasis by targeting sigma-1 and muscarinic receptors. Preclinical studies demonstrated its potential to halt and/or reverse the course of Alzheimer’s disease. ANAVEX®2-73 also exhibited anticonvulsant, anti-amnesic, neuroprotective, and anti-depressant properties in animal models, indicating its potential to treat additional CNS disorders, including epilepsy. The Michael J. Fox Foundation for Parkinson’s Research previously awarded Anavex a research grant, which fully funded a preclinical study to develop ANAVEX®2-73 for the treatment of Parkinson’s disease. ANAVEX®3-71, which targets sigma-1 and muscarinic M1 receptors, is a promising clinical stage drug candidate demonstrating disease-modifying activity against the major hallmarks of Alzheimer’s disease in transgenic (3xTg-AD) mice, including cognitive deficits, amyloid, and tau pathologies. In preclinical trials, ANAVEX®3-71 has shown beneficial effects on mitochondrial dysfunction and neuroinflammation. Further information is available at www.anavex.com. You can also connect with the company on Twitter, Facebook, Instagram and LinkedIn.
Statements in this press release that are not strictly historical in nature are forward-looking statements. These statements are only predictions based on current information and expectations and involve a number of risks and uncertainties. Actual events or results may differ materially from those projected in any of such statements due to various factors, including the risks set forth in the Company’s most recent Annual Report on Form 10-K filed with the SEC. Readers are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement and Anavex Life Sciences Corp. undertakes no obligation to revise or update this press release to reflect events or circumstances after the date hereof.
For Further Information:
Anavex Life Sciences Corp.
Research & Business Development
Andrew J. Barwicki Investor Relations Tel: 516-662-9461
 Liang WS, Reiman EM, Valla J, et al. Alzheimer's disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons. Proc Natl Acad Sci U S A. 2008;105(11):4441-4446. doi:10.1073/pnas.0709259105; Lunnon K, Keohane A, Pidsley R, et al. Mitochondrial genes are altered in blood early in Alzheimer's disease. Neurobiol Aging. 2017;53:36-47. doi:10.1016/j.neurobiolaging. 2016.12.029  Hauser MA, Li YJ, Xu H, et al. Expression profiling of substantia nigra in Parkinson disease, progressive supranuclear palsy, and frontotemporal dementia with parkinsonism. Arch Neurol. 2005;62(6):917-921. doi:10.1001/archneur.62.6.917; Hendrickx DM, Glaab E. Comparative transcriptome analysis of Parkinson's disease and Hutchinson-Gilford progeria syndrome reveals shared susceptible cellular network processes. BMC Med Genomics. 2020;13(1):114. Published 2020 Aug 18. doi:10.1186/s12920-020-00761-6
 Mahurin, R. K., & Pirozzolo, F. J. (1993). Application of Hick’s law of response speed in Alzheimer and Parkinson diseases. Perceptual and Motor Skills, 77(1), 107–113  Wesnes K, Edgar C, Andreasen N, Annas P, Basun H, Lannfelt L, et al. Computerized cognition assessment during acetylcholinesterase inhibitor treatment in Alzheimer’s disease. Acta Neurol Scand 2010; 122:270–7  ClinicalTrials.gov Identifier: NCT04575259