Anavex Life Sciences : Phase IIb/III Trial of Blarcamesine in Early Alzheimer Disease Demonstrates Pre-specified Clinical Efficacy Through Upstream SIGMAR1 Activation

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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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Forward Looking Statements

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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.