AVXL
Phase IIb/III Trial of Blarcamesine in Early Alzheimer Disease Demonstrates Pre-specified Clinical Efficacy Through Upstream SIGMAR1 Activation
Marwan Noel Sabbagh MD, FAAN, FANA
Moreno Family Chair for Alzheimer's Research
Vice Chairman for Research and Professor
Department of Neurology
Barrow Neurological Institute
Disclosures
Dr. Sabbagh discloses ownership interest (stock or stock options) in uMethod Health, Athira, Lighthouse Pharmaceuticals, Alzheon; consulting in Roche-Genentech, Eisai, Lilly, Synaptogenix, NeuroTherapia, Signant Health, Novo Nordisk, Prothena, Anavex, Cognito Therapeutics, GSK, AbbVie; and board of directors' membership in EIP Pharma/CervoMed.
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Blarcamesine: Mechanism of Action in
Alzheimer's Disease (AD)
AD Pathology Is Highly Heterogeneous and Complex
• … influenced by genotype, environment, cognitive reserve, and a range of demographic factors
• … multiple biologic pathways
contribute to AD presentation, including defective amyloid-beta(Aβ) and tau-clearingmechanisms
Potential solution: activation of an upstream, endogenous pathway for clearing protein aggregates
Gouveia Roque C, Phatnani H, Hengst U. The broken Alzheimer's disease genome. Cell Genom. 2024;4(5):100555.
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Blarcamesine Improves Upstream Autophagy and Clearance of Misfolded Proteins in AD
Amyloid-β
Tau
Lysosomal enzyme
SIGMAR1/sigma-1 receptor
Lysosomal dysfunction
Blarcamesine
(no fusion)
Cell stress
Accumulation of protein aggregates
Vesicle
Maturation
Protein aggregates
formation
Blarcamesine
SIGMAR1
Degradation
Autolysosome
(oral drug)
activation
Docking
Functional lysosomes
(fusion)
Schematic representation.
Christ, MG, et al. Sigma-1 receptor activation induces autophagy and increases proteostasis capacity in vitro and in vivo. Cells. 2019;8(3):211. Yang H, et al. SIGMAR1/sigma-1 receptor ablation impairs autophagosome clearance. Autophagy. 2019;15(9):1539-1557.
Lee JH, et al. Faulty autolysosome acidification in Alzheimer's disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques. Nature Neuroscience. 2022;25(6):688-701.
Neurotoxicity
Neuroprotection
Recycling
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Autophagy: An Upstream Compensatory Therapeutic Intervention in AD
Blarcamesine
SIGMAR1
(Oral drug)
activation
Autophagy
Aging
Upstream neuroprotection (remove, repair, regenerate, resilience)
Neurotoxicity
Survival of brain cells
(Aβ, tau)
Monoclonal antibodies
Microglial
Downstream removal of
(IV infusion)
phagocytosis
β-amyloid plaques
Christ, MG, et al. Sigma-1 receptor activation induces autophagy and increases proteostasis capacity in vitro and in vivo. Cells. 2019;8(3):211.
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Yang H, et al. SIGMAR1/sigma-1 receptor ablation impairs autophagosome clearance. Autophagy. 2019;15(9):1539-1557.
Lee JH, et al. Faulty autolysosome acidification in Alzheimer's disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques. Nature Neuroscience. 2022;25(6):688-701.
✓Countering neurodegeneration
✓Improving autophagy-a key clearance mechanism that removes protein aggregates and misfolded proteins
Blarcamesine MoA: Confirmation of Upstream SIGMAR1 Activation
Genetic SIGMAR1 Mutations (Variants) Linked to Suboptimal Function
SIGMAR1 is an integral membrane protein involved in activates an upstream compensatory process: autophagy through SIGMAR1 activation restoring cellular homeostasis
* Feher A et al 2012. Neurosci Lett; 517: 136-139.
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** WT = homozygous dominant (TT)
Disclaimer
Anavex Life Sciences Corp. published this content on October 31, 2024, and is solely responsible for the information contained herein. Distributed by Public, unedited and unaltered, on October 31, 2024 at 14:04:07.865.