ANAVEX®3-71 treatment prevents cognitive impairment, reduces amyloid, and neuroinflammation even after a long drug washout
ANAVEX®3-71 halts neurodegeneration and prevents cognitive decline in a transgenic Alzheimer’s disease model
Confirmation of Anavex’s upstream SIGMAR1 oral small molecule drug platform in Alzheimer’s disease
This study ascertains potential disease-modifying properties of ANAVEX®3-71 (AF710B) on Alzheimer’s disease (AD) pathology and could be a drug candidate for a once daily oral preventive strategy.
ANAVEX®3-71 activates the sigma-1 receptor (SIGMAR1) and the M1 muscarinic receptor (M1R). Data suggests that activation of SIGMAR1 results in the restoration of homeostatic function within the body and is pivotal to restoring neural cell balance and promoting neuroplasticity.2 Previous studies of ANAVEX®3-71 have demonstrated its potential to treat Alzheimer’s disease (AD)-like pathology at advanced stages of disease in animal models.3,4
ANAVEX®3-71, an orally available small molecule, has already successfully completed a Phase 1 human clinical trial demonstrating good safety and tolerability signals at all doses studied.5
In this publication, transgenic rats that develop AD-like symptoms as they age were treated with ANAVEX®3-71 for 7-months before they developed amyloid plaques, followed by a 4-week washout period. Preventative treatment with ANAVEX®3-71 reduced levels of insoluble and soluble amyloid-beta as well as plaque deposition in the aging cortex and hippocampus, areas heavily impacted by AD. Notably, the reduction in amyloid pathology was accompanied by a reduction in inflammatory glial activity which is connected to the disease cascade in AD and other dementias. ANAVEX®3-71 treatment downregulated the proinflammatory IL-1β and IL-6 cytokines, which are known to be associated with AD. Additionally, ANAVEX®3-71 treatment boosted brain derived neurotrophic factor (BDNF) which reinforces the evidence that ANAVEX®3-71 protects neurons.
Importantly, these beneficial effects were sustained after a month-long drug washout. This differentiates ANAVEX®3-71 from other therapeutic approaches and suggests long-lasting, disease-modifying effects on AD pathology. This long-lasting effect was also observed in previous animal studies of ANAVEX®3-71 at advanced stages of the disease.
The publication is consistent with previous scientific findings, including with the more advanced drug candidate ANAVEX®2-73 (blarcamesine), which successfully completed a Phase 2b/3 study in early Alzheimer’s disease, that SIGMAR1 activation acts upstream of multiple contributors to AD and other dementias including but not limited to mitochondrial dysfunction6, oxidative stress7, impaired autophagy8 and that amyloid pathology can be reduced by M1R stimulation9.
The authors of the paper (Neurobiology of Aging 132 (2023) 220–232) from the
“This publication is a confirmation of the scientific depth of Anavex’s upstream SIGMAR1 platform, which gives hope to the Alzheimer’s disease community, especially for the patients, families and caregivers who fight everyday against this devastating disease for a potential disease-modifying drug candidate with a once daily oral preventive strategy. We also look forward to presenting in an upcoming major publication the complete dataset of the Phase 2b/3 Alzheimer’s disease trial of ANAVEX®2-73 (blarcamesine), a potential next-generation precision medicine convenient once daily oral Alzheimer’s disease treatment,” said Christopher U Missling, PhD, President and Chief Executive Officer of Anavex. "We are also on track within our neurodevelopmental precision medicine Rett syndrome program to release top-line data of ANAVEX®
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1 Orciani C, Do Carmo S, Foret MK, et al. Early treatment with an M1 and sigma-1 receptor agonist prevents cognitive decline in a transgenic rat model displaying Alzheimer-like amyloid pathology [published online ahead of print, 2023 Sep 26]. Neurobiol Aging. 2023;132:220-232. doi:10.1016/j.neurobiolaging.2023.09.010
2 Advances in Experimental Medicine and Biology Volume 964 (2017) Sigma Receptors: Their Role in Disease and as Therapeutic Targets.
3 Fisher A, Bezprozvanny I, Wu L, et al. AF710B, a Novel M1/σ1 Agonist with Therapeutic Efficacy in Animal Models of Alzheimer’s Disease. Neurodegener Dis. 2016;16(1-2):95-110. doi:10.1159/000440864
4 Hall H, Iulita MF, Gubert P, et al. AF710B, an M1/sigma-1 receptor agonist with long-lasting disease-modifying properties in a transgenic rat model of Alzheimer's disease. Alzheimers Dement. 2018;14(6):811-823. doi:10.1016/j.jalz.2017.11.009
5 Fadiran EO, Hammond E, Tran J, et al. Concentration-QTc Relationship from a Single Ascending Dose Study of ANAVEX3-71, a Novel Sigma-1 Receptor and Allosteric M1 Muscarinic Receptor Agonist in Development for the Treatment of Frontotemporal Dementia, Schizophrenia, and Alzheimer's Disease. Clin Pharmacol Drug Dev. 2023;12(9):888-901. doi:10.1002/cpdd.1303
6 Lahmy, V., Long, R., Morin, D., Villard, V., Maurice, T., 2014. Mitochondrial protection by the mixed muscarinic/sigma1 ligand ANAVEX2-73, a tetrahydrofuran derivative, in Aβ25-35 peptide-injected mice, a nontransgenic Alzheimer’s disease model. Front. Cell. Neurosci. 8, 463. https://doi.org/10.3389/fncel.2014.00463
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8 Christ MG, Clement AM, Behl C. The Sigma-1 Receptor at the Crossroad of Proteostasis, Neurodegeneration, and Autophagy. Trends Neurosci. 2020;43(2):79-81. doi:10.1016/j.tins.2019.12.002
9 Zhao LX, Chen MW, Qian Y, Yang QH, Ge YH, Chen HZ, Qiu Y. M1 Muscarinic Receptor Activation Rescues β-Amyloid-Induced Cognitive Impairment through AMPA Receptor GluA1 Subunit. Neuroscience. 2019
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