Anavex Life Sciences Reports New Publication in Medical Journal Elucidating the Mechanism of ANAVEX®2-73 (blarcamesine) and ANAVEX®3-71 (AF710B) related to the Treatment of Alzheimer's Disease
NEW YORK, June 14, 2021 (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 that ANAVEX®2-73 (blarcamesine) and ANAVEX®3-71 (AF710B) are featured in a new peer-reviewed publication in the journal of Expert Opinion on Therapeutic Targets, titled “The emerging role of the sigma-1 receptor in autophagy: Hand-in-hand targets for the treatment of Alzheimer's”.1
Scientific Paper Highlights:
- Sigma-1 receptor (SIGMAR1)’s expression increases with age, however in Alzheimer’s disease (AD) it decreases
- The decrease in SIGMAR1 expression during AD coincides with an age-related decrease in autophagy
- The SIGMAR1 may compensate for loss of receptors and autophagic machinery during healthy aging
- SIGMAR1 is activated by ANAVEX-compounds
- ANAVEX®2-73 has been shown to induce autophagy
- Activation of the SIGMAR1 can induce cytoprotective autophagic pathways
The authors of the paper point out that studies using positron emission tomography (PET) have shown that in healthy aging, there is no loss of the SIGMAR1; in fact, there is a possible increase in SIGMAR1 expression2 that coincides with the age-related loss of the M1/M4 muscarinic receptors3, D1/D2 dopamine receptors4, and serotonin (5HT2A) receptors5. The increase in SIGMAR1 expression may be a compensatory mechanism for the loss of the other receptors6.
However, PET scans of patients with a recent AD diagnosis show a reduction of SIGMAR1 expression7. SIGMAR1 also promotes autophagy and results in the degradation of amyloid-beta precursor protein (APP) thereby inhibiting Aβ production8.
The publication explains that AD is a multifactorial disease, where several pathways interlink with each other and cause cognitive impairments. The available drugs only tend to target 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 for the development of drug molecules that can target multiple pathways to halt disease progression and improve the memory function.
SIGMAR1 has emerged as one of the prominent targets in treating neurodegeneration. It is involved in the modulation of glutamate levels, maintaining endoplasmic reticulum (ER) function, and calcium regulation, promoting neurogenesis, reducing reactive oxygen species (ROS) formation, suppressing neuroinflammation and ameliorating Aβ toxicity9. Recent studies with ANAVEX®2-73 show that SIGMAR1 activation is also involved in autophagy, an intricate phenomenon that clears damaged cellular organelles and misfolded proteins10. SIGMAR1 agonists, including ANAVEX®2-73 and ANAVEX®3-71 have been reported to block toxic Aβ, tau and neuroinflammation11.
Autophagy and the cellular machinery involved are essential to homeostasis and cell survival. Autophagy has been shown to be important for axonal health and homeostasis as autophagy inhibition leads to axonal wasting12.
During the early stages of AD, it has been noted that there is an accumulation of Aβ and tau protein in the dystrophic or swollen neurites of AD patients’ brains. Furthermore, it is well known that autophagy plays a key role in the management of Aβ and tau protein levels, and that some of the key proteins involved in the autophagy mechanism disappear with age, resulting in decreased autophagy in older brains13. At the same time the SIGMAR1 is upregulated, possibly compensating for the reduction in autophagy, and reduction in other receptors, such as muscarinic receptors14, dopamine receptors15, and serotonin receptors16, in an attempt to protect the neuron cells.
Since it has been observed that a number of SIGMAR1 agonists, including ANAVEX®2-73, is able to upregulate SIGMAR1 expression in the brain, it is possible that these drugs could help the cells to compensate for the loss of other receptors and autophagy machinery.
The authors conclude, that in the future it may be the case that SIGMAR1 ligands (or drug combinations) targeting the activation of autophagy, and other SIGMAR1 related neuroprotective pathways, are prescribed prophylactically, in much the same way as with statins for the prevention of heart disease today in an effort to prevent the loss of the SIGMAR1 receptor seen during AD.
“This independent paper highlights the understanding of the relevance of utilizing sigma-1 receptor activation as compensatory mechanism to chronic CNS diseases, currently tested in late-stage placebo-controlled ANAVEX®2-73 Phase 2b/3 clinical Alzheimer's disease study, which recently completed enrollment, as well as in Parkinson’s disease dementia (ANAVEX2-73-PDD-001) and ongoing Rett syndrome program (ANAVEX2-73-RS-001/002/003)”, said Christopher U Missling, PhD, President and Chief Executive Officer of Anavex.
ANAVEX®2-73 activates the sigma-1 receptor (SIGMAR1). Data suggests that activation of SIGMAR1 results in the restoration of complete housekeeping function within the body and is pivotal to restoring neural cell homeostasis and promoting neuroplasticity.17
Anavex Life Sciences’ product portfolio 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 frontotemporal dementia.
About Alzheimer’s Disease
Alzheimer’s disease is a progressive degenerative brain disorder that gradually destroys a person's memory and ability to learn, reason, make judgments, communicate and carry out daily activities. An estimated 5.7 million Americans have currently Alzheimer's dementia. Alzheimer’s is the most common cause of dementia among older adults and is estimated to rank as the third leading cause of death for older people in the United States, just behind heart disease and cancer. In 2020, Alzheimer's and other dementias cost the nation approximately $305 billion. By 2050, these costs could rise as high as $1.1 trillion.18 There are currently over 50 million people living with dementia around the world, with numbers expected to increase to nearly 152 million by 2050.19 Almost 10 million new cases of dementia are diagnosed each year worldwide, implying one new case every 3 seconds, and a significant increase in the caregiving burden placed on society and families.20
About Anavex Life Sciences Corp.
Anavex Life Sciences Corp. (Nasdaq: AVXL) is a publicly traded biopharmaceutical company dedicated to the development of 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, pain and various types of cancer. Anavex’s lead drug candidate, ANAVEX®2-73 (blarcamesine), successfully completed a Phase 2a clinical trial for Alzheimer’s disease and recently a Phase 2 proof-of-concept study in Parkinson’s disease dementia and a Phase 2 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 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.
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Research & Business Development
Andrew J. Barwicki
1 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. Epub ahead of print. PMID: 34110944.
2 Kawamura K, Kimura Y, Tsukada H, et al. An increase of sigma1 receptors in the aged monkey brain. Neurobiology of aging. 2003;24(5):745-752; 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; Horsager J, Fedorova TD, Berge NV, et al. Cardiac 11C-Donepezil Binding Increases With Age in Healthy Humans: Potentially Signifying Sigma-1 Receptor Upregulation. Journal of Cardiovascular Pharmacology and Therapeutics. 2019;24(4):365-370.
3 Norbury R, Travis MJ, Erlandsson K, et al. In vivo imaging of muscarinic receptors in the aging female brain with (R, R)[123I]-I-QNB and single photon emission tomography. Experimental gerontology. 2005;40(3):137-145.
4 Inoue M, Suhara T, Sudo Y, et al. Age-related reduction of extrastriatal dopamine D2 receptor measured by PET. Life sciences. 2001;69(9):1079-1084.
5 Sheline YI, Mintun MA, Moerlein SM, et al. Greater loss of 5-HT2A receptors in midlife than in late life. American Journal of Psychiatry. 2002;159(3):430-435.
6 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.
7 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.
8 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.
9 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.
10 Christ MG, Huesmann H, Nagel H, et al. Sigma-1 receptor activation induces autophagy and increases proteostasis capacity in vitro and in vivo. Cells. 2019;8(3):211-211.
11 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.
12 Komatsu M, Wang QJ, Holstein GR, et al. Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. Proceedings of the National Academy of Sciences. 2007;104(36):14489-14494.
13 Rubinsztein David C, Mariño G, Kroemer G. Autophagy and Aging. Cell. 2011 2011/09/02/;146(5):682-695.
14 Norbury R, Travis MJ, Erlandsson K, et al. In vivo imaging of muscarinic receptors in the aging female brain with (R, R)[123I]-I-QNB and single photon emission tomography. Experimental gerontology. 2005;40(3):137-145.
15 Inoue M, Suhara T, Sudo Y, et al. Age-related reduction of extrastriatal dopamine D2 receptor measured by PET. Life sciences. 2001;69(9):1079-1084.
16 Sheline YI, Mintun MA, Moerlein SM, et al. Greater loss of 5-HT2A receptors in midlife than in late life. American Journal of Psychiatry. 2002;159(3):430-435.
17 Advances in Experimental Medicine and Biology Volume 964 (2017) Sigma Receptors: Their Role in Disease and as Therapeutic Targets.
19 Alzheimer's Disease International. World Alzheimer Report 2019. https://www.alz.co.uk/research/WorldAlzheimerReport2019.pdf.
20 AARP. 2020 Report: Caregiving in the U.S. https://www.aarp.org/content/dam/aarp/ppi/2020/05/full-report-caregiving-in-the-united-states.doi.10.26419-2Fppi.00103.001.pdf.