An Analysis of More Than 33,000 Genes Identified Variants That May Enable a Precision Medicine Approach to Alzheimer’s Disease Research and Treatment
The Study Identified 80 Percent of Participants as ANAVEX®2-73 Responders Resulting in Improved Cognition (MMSE) and Activities of Daily Living (ADCS-ADL) Scores
Data Will Inform Recruitment for ANAVEX®2-73 Late-Stage Clinical Trials
NEW YORK – July 25, 2018
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 diseases including Alzheimer’s disease, Rett syndrome and other central nervous system (CNS) diseases, today reported results of the entire genome DNA and RNA evaluation of study participants in a 57-week Phase 2a Alzheimer’s disease study investigating ANAVEX®2-73, a selective sigma-1 receptor agonist, resulting in the analysis of 33,311 genes and 860 pathways. Additionally, direct target occupancy of ANAVEX®2-73 at the sigma-1 receptor using quantitative Positron emission tomography (PET) scanning was presented.
Several genetic variants that impacted response to ANAVEX®2-73 were identified in the study analysis including the Sigma-1 receptor (SIGMAR1), the target for ANAVEX®2-73, and the Catechol-O-methyltransferase (COMT) gene, produced by nerve cells and involved in memory function. Results showed that study participants with SIGMAR1 (rs1800866) or COMT (rs113895332/rs61143203) variants were less likely to benefit from treatment with ANAVEX®2-73. In the study population, when participants with these variants (approximately 20 percent) were excluded, the remaining study participants (approximately 80 percent) showed improved scores on gold-standard tests of cognition (MMSE) and activities of daily living (ADCS-ADL) (p<0.05).
Including participants with milder disease (baseline MMSE ≥20) and excluding those with a SIGMAR1 variant resulted in an average improvement of +1.7 MMSE and +3.9 ADCS-ADL at week 57 compared to baseline.
The additional exclusion of participants with the COMT variant resulted in a score improvement of +2.0 MMSE and +4.9 ADCS-ADL at week 57 compared to baseline.
“This is the first full genomic analysis of ANAVEX®2-73 in Alzheimer’s disease which resulted in the identification of actionable genetic variants, bringing us one step closer to realizing the full potential of a precision medicine and precision pharmacology approach to treating this devastating disease,” said Professor Harald Hampel, M.D., Ph.D., MA, MSc, AXA Research Fund & Sorbonne University Excellence Chair, Department of Neurology, Sorbonne University, Paris. He is the speaker of the Alzheimer Precision Medicine Initiative (APMI). Professor Hampel continues that “We look forward to advancing the ANAVEX®2-73 program and believe that a biomarker-guided approach to targeted drug development that allows to select those patients who will respond best to treatment will result in improved clinical results.”
The presentations at AAIC 2018:
Sigma-1 Receptor Target Occupancy Study with Dynamic PET Scan Analysis of ANAVEX®2-73, a Clinical Candidate for Neurodegenerative and Neurodevelopmental Diseases (P4-262)
Full Genomic Analysis of ANAVEX®2-73 Phase 2a Alzheimer’s Disease Study Identifies Biomarkers Enabling Targeted Therapy and a Precision Medicine Approach (P4-206)
Systematic Processing of Full Genomic Analysis of ANAVEX®2-73 Phase 2a Alzheimer’s Disease Study Identifies Biomarkers Enabling a Precision Medicine Approach (DT-01-05)
“The innovative study findings based on ANAVEX®2-73 moves precision medicine and pharmacology a step closer in Alzheimer’s therapy trials,” said Christopher U. Missling, Ph.D., President and Chief Executive Officer of Anavex. “We continue to focus on the effect of ANAVEX®2-73 leveraging this approach to drug development to provide intelligent solutions beyond many traditional neurology trials to disease areas with high unmet needs.”
ANAVEX®2-73 activates the Sigma-1 receptor (S1R) protein, which serves as a molecular chaperone and functional modulator involved in restoring homeostasis. S1R activation has demonstrated the ability to reduce key pathophysiological signs of Alzheimer’s disease: beta amyloid, hyperphosphorylated tau, and inflammation. In a previous Phase 2a Alzheimer’s disease study, ANAVEX®2-73 showed dose dependent improvements in exploratory endpoints of cognition (MMSE) and function (ADCS-ADL). A full genomic analysis of those Phase 2a Alzheimer’s disease patients was also performed. In addition, the initiation of a 48-week Phase 2b/3 study of ANAVEX®2-73 in early Alzheimer’s disease and a 14-week Phase 2 study of ANAVEX®2-73 in Parkinson’s disease dementia have just been approved. Both studies will incorporate the biomarkers presented at AAIC 2018.
Professor Harald Hampel, MD, PhD, MA, MSc
Professor Harald Hampel is Full Professor and AXA research fund and Sorbonne University Excellence Chair at Sorbonne University, Departments of Neurology and Neuroscience, Paris, France.
He is principal investigator and speaker of the Alzheimer Precision Medicine Initiative and of the Cholinergic Systems Working Group and Senior Associate Editor of the journal of the Alzheimer Association, “Alzheimer’s & Dementia”.
He published more than 700 peer-reviewed research papers and edited 8 books, won multiple awards for his research focusing on brain health & disease, biomarker and therapy discovery in Alzheimer’s disease. He holds international research grants and is principal investigator of research consortia.
About the Alzheimer’s Disease Precision Medicine Initiative (APMI)
The Alzheimer’s Disease Precision Medicine Initiative (APMI), established in 2016, is an international consortium of scientists aimed to facilitate reforms in the conceptualization of Neurological diseases, such as Alzheimer’s, away from a traditional one-size fits all approach to drug development towards individualized biomarker-guided targeted therapy for the right patient at the right time.
About Anavex Life Sciences Corp.
Anavex Life Sciences Corp. (Nasdaq: AVXL) is a publicly traded biopharmaceutical company dedicated to the development of differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental diseases including Alzheimer’s disease, other central nervous system (CNS) diseases, pain and various types of cancer. Anavex’s lead drug candidate, ANAVEX®2-73, recently completed a successful Phase 2a clinical trial for Alzheimer’s disease. 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 M1 muscarinic receptors, is a promising preclinical 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 neuroinflammation and mitochondrial dysfunction. Further information is available at www.anavex.com. You can also connect with the company on Twitter, Facebook and LinkedIn.
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 Samantha T. Reyes1, Scarlett G. Guo1, Jessa B. Castillo1, Berend van der Wildt1, Aimara P. Morales1, Jun Hyung Park1, Nell Rebowe2, Jeffrey Sprouse2, Christopher U. Missling2, Frederick T. Chin1; 1Department of Radiology, Stanford University School of Medicine, Stanford, CA, 2Anavex Life Sciences Corp., New York, NY
 Harald Hampel, MD1, Mohammad Afshar, MD, PhD2, Frédéric Parmentier, PhD2, Coralie Williams, MSc2, Adrien Etcheto, MSc2, Federico Goodsaid, PhD3, Emmanuel O Fadiran, PhD4, Christopher U Missling, PhD4; 1AXA Research Fund & UPMC Chair, Paris, France; Sorbonne Universites Pierre et Marie Curie (UPMC), Paris, France, 2Ariana Pharma, Paris, France, 3Regulatory Pathfinders LLC, San Francisco, CA, 4Anavex Life Sciences Corp., New York, NY
 Harald Hampel, MD1, Mohammad Afshar, MD, PhD2, Frédéric Parmentier, PhD2, Coralie Williams, MSc2, Adrien Etcheto, MSc2, Federico Goodsaid, PhD3, Emmanuel O Fadiran, PhD4, Christopher U Missling, PhD4; 1AXA Research Fund & UPMC Chair, Paris, France; Sorbonne Universities Pierre et Marie Curie (UPMC), Paris, France, 2Ariana Pharma, Paris, France, 3Regulatory Pathfinders LLC, San Francisco, CA, 4Anavex Life Sciences Corp., New York, NY