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.
Forward-Looking Statements
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 DevelopmentToll-free: 1-844-689-3939Email:
info@anavex.com
Investors:Andrew J.
BarwickiInvestor RelationsTel: 516-662-9461Email:
andrew@barwicki.com
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.
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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
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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.18
https://www.nia.nih.gov/health/alzheimers;
https://www.alz.org/alzheimers-dementia/facts-figures;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.
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