A precision medicine framework using artificial intelligence for the identification and confirmation of genomic biomarkers of response to an Alzheimer's disease therapy: Analysis of the blarcamesine (ANAVEX2‐73) Phase 2a clinical study
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Introduction: The search for drugs to treat Alzheimer's disease (AD) has failed to yield effective therapies. Here we report the first genome‐wide search for biomarkers associated with therapeutic response in AD. Blarcamesine (ANAVEX2‐73), a selective sigma‐1 receptor (SIGMAR1) agonist, was studied in a 57‐week Phase 2a trial (NCT02244541). The study was extended for a further 208 weeks (NCT02756858) after meeting its primary safety endpoint. Methods: Safety, clinical features, pharmacokinetic, and efficacy, measured by changes in the Mini‐Mental State Examination (MMSE) and the Alzheimer's Disease Cooperative Study‐Activities of Daily Living scale (ADCS‐ADL), were recorded. Whole exome and transcriptome sequences were obtained for 21 patients. The relationship between all available patient data and efficacy outcome measures was analyzed with unsupervised formal concept analysis (FCA), integrated in the Knowledge Extraction and Management (KEM) environment. Results: Biomarkers with a significant impact on clinical outcomes were identified at week 57: mean plasma concentration of blarcamesine (slope MMSE: P < .041), genomic variants SIGMAR1 p.Gln2Pro (ΔMMSE: P < .039; ΔADCS‐ADL: P < .063) and COMT p.Leu146fs (ΔMMSE: P < .039; ΔADCS‐ADL: P < .063), and baseline MMSE score (slope MMSE: P < .015). Their combined impact on drug response was confirmed at week 148 with linear mixed effect models. Discussion: Confirmatory Phase 2b/3 clinical studies of these patient selection markers are ongoing. This FCA/KEM analysis is a template for the identification of patient selection markers in early therapeutic development for neurologic disorders.
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AV2-73 has beneficial effects in neurodegenerative disorders because of improvement in proteostasis, autophagy, oxidative stress, prevention of protein aggregates, and improvement in mitochondrial function leading to benefits in Alzheimer's disease and Parkinson's disease dementia.
“AV2-73 also has beneficial effects in neurodegenerative disorders because of improvement in proteostasis, autophagy, oxidative stress, prevention of protein aggregates, and improvement in mitochondrial function leading to benefits in Alzheimer’ disease and Parkinson’s disease dementia [146–148].”
From An Update on Psychopharmacological Treatment of Autism Spectrum Disorder (2022) · cites this paper as [146]
Blarcamesine combines agonist activities at the muscarinic M1 receptor, NMDA receptor, and sigma-1 receptor, targets tau protein, and reduces Alzheimer's disease neurodegeneration.
“Blarcamesine, combining agonist activities at the muscarinic M1 receptor, the NMDA receptor, and the sigma-1 receptor, targets protein tau and reduces AD neurodegeneration [29].”
From Current therapeutics for Alzheimer’s disease and clinical trials (2024) · cites this paper as [29]
ANAVEX2-73 (Blarcamesine) targets sigma-1 and M1 muscarinic receptors and demonstrated disease-modifying activity in AD transgenic mice (3xTg-AD), including reducing amyloid and tau pathologies and improving cognitive deficits.
“ANAVEX®2-73 (Blarcamesine), which targets sigma-1 and M1 muscarinic receptors, has also demonstrated its disease-modifying activity in AD transgenic mice (3xTg-AD), including reducing amyloid and tau pathologies as well as improving cognitive deficits.51,52”
From Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future (2023) · cites this paper as [52]
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References 64 · Cited by 84
Research works printed but not linked: 3
- [48]Broadhouse KM, Suo C, Singh MAF, et al. What happens to the hippocampus 12‐months after training? Longitudinal linear mixed effects model analysis of mild cognitive impairment in the smart trial. Alzheimers Dement J Alzheimers Assoc. 2017; 13(7): P260.
- [59]Swanson C. Clinical and Biomarker Updates from BAN2401 Study 201 in Early AD: Pre‐specified Subgroup Analysis in BAN2401 Study 201. Presented at the: October 24, 2018; 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference. Barcelona, Spain. https://www.eisai.com/ir/library/presentations/pdf/e4523_181025.pdf. Accessed: February, 2020.
- [60]Cummings J. Clinical and Biomarker Updates from BAN2401 Study 201 in Early AD: BAN2401 Study 201 Design and Topline Results. Presented at the: 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference; October 24, 2018; Barcelona, Spain. https://www.eisai.com/ir/library/presentations/pdf/e4523_181025.pdf. Accessed: February, 2020.
- Authors
- Hampel, H., Williams, C., Etcheto, A., Goodsaid, F., Parmentier, F., Sallantin, J., Kaufmann, W. E., Missling, C. U., & Afshar, M.
- Affiliations
- Sorbonne Université (FR)
- Ariana Pharmaceuticals Paris France
- Regulatory Pathfinders LLC San Juan Puerto Rico USA
- Centre National de la Recherche Scientifique (FR)
- Emory University (US)
- Anavex Life Sciences Corp. (United States) (US)
- Corresponding author
- Hampel, Harald
- Kaufmann, Walter E.
- Afshar, Mohammad
- ORCID
- Venue
- Alzheimer's & Dementia: Translational Research & Clinical Interventions
- Publisher
- Wiley
- Published
- 2020-01
- Volume
- 6
- Issue
- 1
- Pages
- e12013-e12013
- ISSN
- 2352-8737 (ISSN-L)
- PMC
- PMC7167374
- OpenAlex
- W3017335992
- Cited by
- 84
- References
- 64
- Citations by year
- 2026: 10 · 2025: 9 · 2024: 19 · 2023: 13 · 2022: 17 · 2021: 8 · 2020: 7
- FWCI
- 6.77
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Alzheimer s & Dementia Translational Research & Clinical Interventions (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- AXA Research Fund
- Eisai
- Sorbonne Université
- Fondation pour la Recherche sur Alzheimer
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pharmacological Receptor Mechanisms and Effects
- Keywords
- Alzheimer's disease, sigma-1 receptor agonist, genomic biomarkers, treatment response prediction, precision medicine, formal concept analysis, exome sequencing, transcriptome, plasma drug concentration, cognitive decline
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