Mechanism of Action of ANAVEX®2-73 (blarcamesine) and ANAVEX®3-71 (AF710B) is the activation of SIGMAR1
Endogenous increase in SIGMAR1 activation as a compensatory mechanism against early Alzheimer's disease
Top line results of randomized, placebo-controlled Phase 2b/3 study ANAVEX®2-73-AD-004 for the treatment of early Alzheimer's disease are expected in the fall of 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 therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders, including Alzheimer's disease, Parkinson's disease, Rett syndrome, and other central nervous system (CNS) diseases, today reported a relevant new peer-reviewed publication in the journal Science Translational Medicine, titled "Widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimer's disease."1
ANAVEX®2-73 activates the sigma-1 receptor (SIGMAR1). Data suggest 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
In this publication, position emission tomography (PET) and magnetic resonance imaging (MRI) markers were utilized to show that impaired mitochondrial oxidative phosphorylation and synaptic loss are central to neurodegeneration in the cellular pathology of Alzheimer's disease (AD).
One of the featured observations was an increase in SIGMAR1 expression in the early stages of AD. Increased SIGMAR1 expression may be an endogenous, compensatory mechanism for the loss of other receptors and proteostasis.3 However, PET scans of patients with more advanced AD diagnoses show a reduction of SIGMAR1 expression.4
The publication is consistent with previous scientific findings that AD is a multifactorial disease, where several pathways interlink and cause cognitive impairments.5 Currently available drugs tend to target only a single pathway and mitigate the symptoms of AD without slowing the disease progression. Combinatorial therapy has been suggested as a treatment strategy; however, the existence of drug-drug interaction is a concern. Hence, there is a need to develop drug molecules that can target multiple pathways to halt disease progression and improve memory function.
SIGMAR1 has emerged as one of the prominent targets in treating neurodegeneration. It is involved in modulating glutamate levels, maintaining endoplasmic reticulum (ER) function, and regulating calcium. SIGMAR1 activation promotes neurogenesis, reduces reactive oxygen species (ROS) formation, suppresses neuroinflammation, and ameliorates Aβ toxicity.6 SIGMAR1 also promotes autophagy and results in the degradation of amyloid-beta precursor protein (APP), thereby normalizing Aβ production.7
Recent studies with ANAVEX®2-73 and ANAVEX®3-71 show that SIGMAR1 activation also involves mitochondrial performance, an intricate 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 of the relevance of sigma-1 receptor activation as a compensatory mechanism to chronic CNS diseases, which is currently being tested in a late-stage placebo-controlled ANAVEX®2-73 Phase 2b/3 clinical Alzheimer's disease study with expected read-out this fall 2022," said Christopher U Missling, PhD, President and Chief Executive Officer of Anavex.
Anavex Life Sciences' precision medicine platform includes small molecule drug lead candidate ANAVEX®2-73 for the treatment of Alzheimer's disease, Parkinson's disease, and Rett syndrome and ANAVEX®3-71 for schizophrenia, frontotemporal dementia, and Alzheimer's disease.
Economic Burden of Alzheimer's Disease10
Alzheimer's disease is the most common cause of dementia and the fifth leading cause of death in adults older than 65 years. The estimated total healthcare costs for the treatment of Alzheimer's disease in 2020 were estimated at $305 billion, with the cost expected to increase to more than $1 trillion as the population ages. Most of the direct costs of care for Alzheimer's disease are attributed to skilled nursing care, home healthcare, and hospice care. 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 the development of novel therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders, including Alzheimer's disease, Parkinson's disease, Rett syndrome, and other central nervous system (CNS) diseases, pain, and various types of cancer. Anavex's lead drug candidate, ANAVEX®2-73 (blarcamesine), has successfully completed a Phase 2a clinical trial for Alzheimer's disease, a Phase 2 proof-of-concept study in Parkinson's disease dementia, and both a Phase 2 and a Phase 3 study 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 demonstrated its potential to halt and/or reverse the course of Alzheimer's disease. ANAVEX®2-73 also exhibited anticonvulsant, anti-amnesic, neuroprotective, and anti-depressant properties in animal models, indicating its potential to treat additional CNS disorders, including epilepsy. The Michael J. Fox Foundation for Parkinson's 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 sigma-1 and M1 muscarinic receptors, is a promising clinical stage drug candidate demonstrating disease-modifying activity against the major hallmarks of Alzheimer's disease in transgenic (3xTg-AD) mice, 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 such statements due to various 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. undertakes no obligation to revise or update this press release to reflect events or circumstances after the date hereof.
For Further Information:
Anavex Life Sciences Corp.
Research & Business Development
Andrew J. Barwicki
1 Venkataraman, A. V., Mansur, A., Rizzo, G., Bishop, C., Lewis, Y., Kocagoncu, E., Lingford-Hughes, A., Huiban, M., Passchier, J., Rowe, J. B., Tsukada, H., Brooks, D. J., Martarello, L., Comley, R. A., Chen, L., Schwarz, A. J., Hargreaves, R., Gunn, R. N., Rabiner, E. A., & Matthews, P. M. (2022). Widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimer's disease. Science 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 multireceptor approach to target diseases of the brain. Expert opinion on therapeutic targets. 2020; Wallace DR, Mactutus CF, Booze RM. Sigma binding sites identified by [3H] DTG 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. 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 enhances synaptic efficacy and neurogenesis in the hippocampal dentate gyrus of olfactory bulbectomized mice. PloS one. 2013;8(4):e60863-e60863; Rosen DA, Seki SM, Fernández-Castañeda A, et al. Modulation of the sigma-1 receptor–IRE1 pathway is beneficial in preclinical models of inflammation and sepsis. Science Translational Medicine. 2019;11(478):eaau5266; Maurice T, Volle J-N, 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.
7 Jaeger PA, Pickford F, Sun C-H, 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., & Maurice, T. (2019). Sigma-1 Receptor Agonists Induce Oxidative Stress in Mitochondria and Enhance Complex I Activity in Physiological Condition 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 nontransgenic 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. Neurodegener Dis. 2016;16(1-2):95-110.
10 W Wong Economic Burden of Alzheimer Disease and Managed Care Considerations Am J Manag Care. 2020;26:S177-S183.