Anavex Life Sciences announces a new publication in Medical
Mechanism of action of ANAVEX®2-73 (blarcamesin) and ANAVEX®3-71 (AF710B) is SIGMAR1 activation
Endogenous increase in SIGMAR1 activation as a compensatory mechanism against early Alzheimer’s disease
First results of the phase 2b/3 randomized and placebo-controlled study ANAVEX®2-73-AD-004 for the treatment of early Alzheimer’s disease are expected in fall 2022
NEW YORK, Aug. 23, 2022 (GLOBE NEWSWIRE) — Anavex Life Sciences Corp. (“Anavex” or the “Company”) (Nasdaq: AVXL), a clinical-stage biopharmaceutical company developing differentiated therapies for the treatment of neurodegenerative diseases and neurodevelopmental disorders, including Alzheimer’s disease, Parkinson’s disease, Rett syndrome and other diseases of the central nervous system (CNS), today announced a relevant new peer-reviewed publication in the journal Science Translational Medicine, titled “Generalized cellular stress and mitochondrial dysfunction occur in patients with early-stage Alzheimer’s disease.”1
ANAVEX®2-73 activates the sigma-1 receptor (SIGMAR1). The data suggest that activation of SIGMAR1 results in the restoration of homeostatic function in the body and is essential for restoring neural cell balance and promoting neuroplasticity.2
In this publication, positional emission tomography (PET) and magnetic resonance imaging (MRI) markers were used to show that impaired mitochondrial oxidative phosphorylation and synaptic loss are central to neurodegeneration in cellular pathology. of Alzheimer’s disease (AD).
One of the observations presented was an increase in the expression of SIGMAR1 in the early stages of AD. Increased SIGMAR1 expression may be an endogenous compensatory mechanism for loss of other receptors and proteostasis.3 However, PET scans from patients with more advanced AD diagnoses show reduced SIGMAR1 expression.4
The publication is in line with previous scientific findings that AD is a multifactorial disease, where multiple pathways intertwine and cause cognitive impairment.5 Currently available drugs tend to target a single pathway and alleviate AD symptoms without slowing disease progression. Combination therapy has been suggested as a treatment strategy; however, the existence of drug interactions is of concern. Therefore, there is a need to develop drug molecules capable of targeting multiple pathways to arrest disease progression and improve memory function.
SIGMAR1 has become one of the main targets for the treatment of neurodegeneration. It is involved in modulating glutamate levels, maintaining endoplasmic reticulum (ER) function, and regulating calcium. Activation of SIGMAR1 promotes neurogenesis, reduces reactive oxygen species (ROS) formation, suppresses neuroinflammation, and improves Aβ toxicity.6 SIGMAR1 also promotes autophagy and drives the degradation of amyloid-beta precursor protein (APP), thereby normalizing Aβ production.seven
Recent studies with ANAVEX®2-73 and ANAVEX®3-71 show that SIGMAR1 activation also involves mitochondrial performance, a complex phenomenon that provides energy for cellular functions.8 SIGMAR1 agonists, including ANAVEX®2-73 and ANAVEX®3-71, have been reported to reduce toxic Aβ, tau and neuroinflammation.9
“This independent paper provides further evidence for the relevance of sigma-1 receptor activation as a compensatory mechanism for chronic CNS diseases, which is currently being tested in a placebo-controlled late-stage ANAVEX.®2-73 Phase 2b/3 clinical study in Alzheimer’s disease scheduled to read this fall 2022,” said Christopher U Missling, PhD, President and CEO of Anavex.
Anavex Life Sciences Precision Medicine Platform Includes Small Molecule Drug Candidate ANAVEX®2-73 for the treatment of Alzheimer’s disease, Parkinson’s disease and Rett’s syndrome and ANAVEX®3-71 for schizophrenia, frontotemporal dementia and Alzheimer’s disease.
Economic burden of Alzheimer’s diseaseten
Alzheimer’s disease is the most common cause of dementia and the fifth leading cause of death in adults over the age of 65. Total estimated health care costs for treating Alzheimer’s disease in 2020 have been estimated at $305 billion, and the cost is expected to increase to over $1 trillion as the population ages. Most of the direct care costs for Alzheimer’s disease are attributed to skilled nursing, home care and palliative care. The indirect costs of care, including quality of life and informal caregiving, are likely underestimated and are associated with significant negative societal and personal burdens.
About Anavex Life Sciences Corp.
Anavex Life Sciences Corp. (Nasdaq: AVXL) is a publicly traded biopharmaceutical company dedicated to developing novel therapies for the treatment of neurodegenerative and neurodevelopmental disorders, including Alzheimer’s disease, Parkinson’s disease, Rett syndrome and other diseases central nervous system (CNS) diseases, pain and various types of cancer. Anavex’s lead drug candidate, ANAVEX®2-73 (blarcamesine), successfully completed a Phase 2a clinical trial in Alzheimer’s disease, a Phase 2 proof-of-concept study in Parkinson’s disease dementia, and a Phase 2 and Phase 3 in adult patients with Rett syndrome. ANAVEX®2-73 is an orally available drug candidate that restores cellular homeostasis by targeting sigma-1 and muscarinic receptors. Preclinical studies have demonstrated its potential to halt and/or reverse the progression of Alzheimer’s disease. ANAVEX®2-73 has also shown anticonvulsant, anti-amnesic, neuroprotective, and antidepressant properties in animal models, indicating its potential to treat other CNS disorders, including epilepsy. The Michael J. Fox Foundation for Parkinson’s Disease 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 muscarinic sigma-1 and M1 receptors, is a promising clinical-stage drug candidate demonstrating disease-modifying activity against key hallmarks of Alzheimer’s disease in transgenic mice (3xTg-AD) , including cognitive deficits, amyloid and tau pathologies. In preclinical trials, ANAVEX®3-71 has shown beneficial effects on mitochondrial dysfunction and neuroinflammation. Further information is available at www.anavex.com. You can also connect with the company on Twitter, Facebook, Instagram and LinkedIn.
Statements in this press release that are not strictly historical in nature are forward-looking statements. These statements are only predictions based on current information and expectations and involve a number of risks and uncertainties. Actual events or results may differ materially from those projected in any of these statements due to a variety of factors, including the risks set forth in the company’s most recent Annual Report on Form 10-K filed with the SEC. Readers are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement and Anavex Life Sciences Corp. assumes no obligation to revise or update this press release to reflect events or circumstances after the date hereof.
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1 Venkataraman, AV, Mansur, A., Rizzo, G., Bishop, C., Lewis, Y., Kocagoncu, E., Lingford-Hughes, A., Huiban, M., Passchier, J., Rowe, JB, Tsukada, H., Brooks, DJ, Martarello, L., Comley, RA, Chen, L., Schwarz, AJ, Hargreaves, R., Gunn, RN, Rabiner, EA & Matthews, PM (2022). Generalized cellular stress and mitochondrial dysfunction occur in patients with early-stage Alzheimer’s disease. Scientific Translational Medicine, 14(658), eabk1051. https://doi.org/10.1126/scitranslmed.abk1051.
2 Advances in Experimental Medicine and Biology Volume 964 (2017) Sigma Receptors: Their Role in Disease and as Therapeutic Targets.
3 Brimson JM, Brimson S, Chomchoei C, et al. Using Sigma ligands as part of a multi-receptor approach to target brain diseases. Expert opinion on therapeutic targets. 2020; Wallace DR, Mactutus CF, Booze RM. Sigma binding sites identified by [3H] DTGs are elevated in aged Fischer_344Å~ Brown Norway (F1) rats. Synapse. 2000;35(4):311-313.
4 Mishina M, Ohyama M, Ishii K, et al. Low density of sigma 1 receptors in early Alzheimer’s disease. Annals of Nuclear Medicine. 2008;22(3):151-151.
5 Prasanth MI, Malar DS, Tencomnao T, Brimson JM. The emerging role of the sigma-1 receptor in autophagy: hand-in-hand targets for the treatment of Alzheimer’s disease. Expert Opin Ther Targets. 2021 Jun 10. doi: 10.1080/14728222.2021.1939681.
6 Nguyen L, Lucke-Wold BP, Mookerjee SA, et al. Role of sigma-1 receptors in neurodegenerative diseases. Journal of Pharmacological Sciences. 2015;127(1):17-29; Moriguchi S, Shinoda Y, Yamamoto Y, et al. Stimulation of the sigma-1 receptor by DHEA improves synaptic efficiency and neurogenesis in the dentate gyrus of the hippocampus of olfactory bulbectomized mice. PloS one. 2013;8(4):e60863-e60863; Rosen DA, Seki SM, Fernandez-Castañeda A, et al. Modulation of the sigma-1-IRE1 receptor pathway is beneficial in preclinical models of inflammation and sepsis. Science translational medicine. 2019;11(478):eaau5266; Maurice T, Volle JN, Strehaiano M, et al. Neuroprotection in non-transgenic and transgenic mouse models of Alzheimer’s disease by positive modulation of σ1 receptors. Pharmacological research. 2019;144:315-330.
seven Jaeger PA, Pickford F, Sun CH, et al. Regulation of amyloid precursor protein processing by the Beclin 1 complex. PloS one. 2010;5(6):e11102.
8 Goguadze, N., Zhuravliova, E., Morin, D., Mikeladze, D. and Maurice, T. (2019). Sigma-1 receptor agonists induce oxidative stress in mitochondria and enhance complex I activity in a physiological state, but protect against pathological oxidative stress. Neurotoxicity Research, 35(1), 1–18.
9 Lahmy V, Meunier J, Malmström S, et al. Blockade of Tau hyperphosphorylation and Aβ 1–42 generation by the aminotetrahydrofuran derivative ANAVEX2-73, a mixed muscarinic and σ 1 receptor agonist, in a non-transgenic mouse model of Alzheimer’s disease. Neuropsychopharmacology. 2013;38(9):1706-1706; Fisher A, Bezprozvanny I, Wu L, Ryskamp DA, Bar-Ner N, Natan N, Brandeis R, Elkon H, Nahum V, Gershonov E, LaFerla FM, Medeiros R. AF710B, a novel M1/σ1 agonist with therapeutic efficacy in Animal Models of Alzheimer’s Disease. Neurodegenerates Dis. 2016;16(1-2):95-110.
ten W Wong Economic Burden of Alzheimer’s Disease and Managed Care Considerations Am J Manag Care. 2020;26:S177-S183.