beclin-1

Fosgonimeton counteracts mechanisms of amyloid-beta (Aβ)-driven toxicity and demonstrates neuroprotection in preclinical models of Alzheimer’s disease BOTHELL, Wash., April 11, 2024 (GLOBE NEWSWIRE) -- Athira Pharma, Inc. (NASDAQ: ATHA), a late clinical-stage biopharmaceutical company focused on developing small molecules to restore neuronal health and slow neurodegeneration, today announced the publication of preclinical data supporting the therapeutic potential of fosgonimeton in Alzheimer’s disease. The original research article, “Fosgonimeton Attenuates Amyloid-Beta Toxicity in Preclinical Models of Alzheimer’s Disease,” authored by Reda, S., et al., was published in the peer-reviewed journal, Neurotherapeutics. Fosgonimeton is a potentially first-in-class, once daily, subcutaneously administered small molecule drug candidate designed to enhance the neurotrophic hepatocyte growth factor (HGF) system, and is in development for neurodegenerative disorders, including Alzheimer’s disease. “These data continue to highlight the potential of fosgonimeton as a novel therapeutic approach for Alzheimer's disease targeting multiple facets of its complex pathophysiology,” said Kevin Church, Ph.D., Chief Scientific Officer of Athira. “By positively modulating the HGF signaling system, fosgonimeton demonstrated neuroprotective and neurotrophic effects, countering mechanisms of amyloid-beta (Aβ)-induced toxicity both in vitro and in vivo. Our preclinical findings describe several mechanisms by which fosgonimeton may disrupt the neurodegenerative cascade of Alzheimer’s disease downstream of Aβ toxicity, including reduction of mitochondrial oxidative stress and excitotoxicity, improvement of autophagic pathway function, and attenuation of tau hyperphosphorylation.” Key findings reported in the study publication regarding fosgonimeton in preclinical models of Alzheimer’s disease include: In primary rat cortical neurons challenged with Aβ, fosgonimeton treatment improved neuronal survival, protected neurite networks, and reduced tau hyperphosphorylation following Aβ injury. Fosgonimeton attenuated Aβ-induced mitochondrial stress and apoptotic signaling. Fosgonimeton enhanced activation of pro-survival effectors extracellular signal-regulated kinase (ERK) and protein kinase B (AKT). It also reduced activity of glycogen synthase kinase 3 beta (GSK3β), one of the main kinases involved in tau hyperphosphorylation. Fosgonimeton mitigated Aβ-induced deficits in Unc-like kinase 1 (ULK1) and Beclin-1 expression, suggesting a potential effect on autophagy. Fosgonimeton improved cognitive performance in an Aβ rat model of Alzheimer’s disease. “There is an urgent need for new treatments that tackle the multifactorial pathologies of Alzheimer’s disease (AD), especially for people with mild-to-moderate AD, an advanced stage of the disease,” said Mark Litton, Ph.D., President and Chief Executive Officer of Athira. “These preclinical data published in a peer-reviewed journal suggest that fosgonimeton counteracts aspects of AD pathology that lead to neurodegeneration. These findings bolster our confidence in the Phase 2/3 LIFT-AD trial evaluating fosgonimeton in mild-to-moderate AD, with data anticipated in the second half of 2024.” The article is available on the Neurotherapeutics website and from the Scientific Publications & Presentations page of the company’s website at . About Fosgonimeton Fosgonimeton is a potentially first-in-class, once daily, subcutaneously administered small molecule drug candidate. Targeting the protection and repair of neuronal networks, fosgonimeton has disease-modifying potential to address a broad range of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and dementia with Lewy bodies. About Athira Pharma, Inc. Athira Pharma, Inc., headquartered in the Seattle, Washington area, is a late clinical-stage biopharmaceutical company focused on developing small molecules to restore neuronal health and slow neurodegeneration. Athira aims to alter the course of neurological diseases by advancing its pipeline of therapeutic candidates that modulate the neurotrophic HGF system, including fosgonimeton, which is being evaluated for the potential treatment of mild-to-moderate Alzheimer’s disease in the Phase 2/3 LIFT-AD trial that is expected to report topline data in the second half of 2024. For more information, visit . You can also follow Athira on Facebook, LinkedIn, X (formerly known as Twitter) and Instagram. Forward-Looking Statements This communication contains “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933, Section 21E of the Securities Exchange Act of 1934 and the Private Securities Litigation Reform Act of 1995. These forward-looking statements are not based on historical fact and include statements regarding: product candidates as a potential treatment for Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, and other neurodegenerative diseases; future development plans; the anticipated reporting of data; expectations regarding the potential efficacy and commercial potential of Athira’s product candidates; and Athira’s ability to advance its product candidates into later stages of development. Forward-looking statements generally include statements that are predictive in nature and depend upon or refer to future events or conditions, and include words such as “may,” “will,” “should,” “on track,” “would,” “expect,” “plan,” “believe,” “intend,” “pursue,” “continue,” “suggest,” “potential,” and similar expressions. Any forward-looking statements are based on management’s current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to, the data from preclinical and clinical trials may not support the safety, efficacy and tolerability of Athira’s product candidates; development of product candidates may cease or be delayed; regulatory authorities could object to protocols, amendments and other submissions; future potential regulatory milestones for product candidates, including those related to current and planned clinical studies, may be insufficient to support regulatory submissions or approval; Athira may not be able to recruit sufficient patients for its clinical trials; the outcome of legal proceedings that have been or may in the future be instituted against Athira, its directors and officers; possible negative interactions of Athira's product candidates with other treatments; Athira’s assumptions regarding its financial condition and the sufficiency of its cash, cash equivalents and investments to fund its planned operations may be incorrect; adverse conditions in the general domestic and global economic markets; the impact of competition; regulatory agencies may be delayed in reviewing, commenting on or approving any of Athira’s clinical development plans as a result of pandemics or health epidemics, which could further delay development timelines; the impact of expanded product development and clinical activities on operating expenses; the impact of new or changing laws and regulations; as well as the other risks detailed in Athira’s filings with the Securities and Exchange Commission from time to time. These forward-looking statements speak only as of the date hereof and Athira undertakes no obligation to update forward-looking statements. Athira may not actually achieve the plans, intentions, or expectations disclosed in its forward-looking statements, and you should not place undue reliance on the forward-looking statements. Investor Contact Anne Marie Fields Stern Investor Relations annemarie.fields@sternir.com 332-213-1956 Media Contact Janine Bogris Inizio Evoke Comms Janine.bogris@inizioevoke.com 201-245-6838

Exposure to air pollution while in the womb is linked to alterations in proteins that can be detected after a baby is born, and which affect cell processes such as autophagy, the 'self-eating' of damaged cells that occurs in response to stress. Exposure to air pollution while in the womb is linked to alterations in proteins that can be detected after a baby is born, and which affect cell processes such as autophagy, the "self-eating" of damaged cells that occurs in response to stress. Dr Olga Gorlanova, a research physician at the University Children's Hospital, University of Basel, Switzerland, told the European Respiratory Society International Congress in Milan, Italy, that her study also showed that healthy, new-born babies had individual and different responses to their mothers' exposure to air pollution during pregnancy. This might mean that some babies were more vulnerable to it than others. This was the case even if they were born into households in areas with relatively low levels of pollution. Earlier work by Dr Gorlanova and her colleagues had shown that exposure to air pollution during pregnancy could affect lung function and the immune system in new-borns. In the current study, they looked at proteins involved in autophagy, ageing and cell remodelling to see how prenatal exposure to air pollution could affect them. The researchers measured 11 proteins found in the cord blood of 449 healthy new-born babies from the Bern Basel Infant Lung Development (BILD) cohort study. The BILD study, started in 1999 in Bern, aims to recruit 1000 babies by 2025. It is investigating the effects of genetics and the environment (particularly air pollution) on lung development in babies and children. Dr Gorlanova and colleagues measured the mothers' exposure to nitrogen dioxide (NO2) and tiny particles called PM10,which areparticulate matter measuring 10 microns or less in diameter. Vehicle emissions, tyre and brake wear, and smoke are some of the sources of these pollutants. They found that NO2 and PM10 were both linked to changes in proteins involved in autophagy. Exposure to NO2 was linked to a decrease in the activity of the proteins SIRT1 and IL-8, and an increase in levels of the Beclin-1 protein. "Our results indicate that NO2, a pollutant formed mainly from traffic emissions, is associated with increased levels of Beclin-1 protein, which is central to initiating autophagy. Exposure to higher NO2 was also linked to decreased levels of SIRT1, which is a protein that plays a protective role in stress resistance, inflammation and aging. IL-8 is a protein active in certain inflammatory cells," said Dr Gorlanova. "We grouped the babies into four distinct clusters according to the levels of air pollution they were exposed to while in the womb. The four clusters all had similar concentrations of the proteins being studied but had differences their exposure to NO2 and PM10 air pollution. One cluster had low concentrations of nine proteins, while another cluster, consisting of seven percent of all the babies, had higher levels of proteins that are involved in inflammatory and remodelling processes: IL-8 and IL-1B. Both these groups of new-borns had been exposed to lower, although differing, levels of prenatal air pollution than the other two groups. Our findings suggest that healthy new-borns have an individual response pattern to air pollution. We think that this may be an indication that some babies are more vulnerable to it than others. "Additionally, our work adds to the growing body of evidence that autophagy-related mechanisms may be involved in how human cells react to air pollution. The findings are consistent with evidence from tissue and animal research. Further exploration of these mechanisms may help to better understand the deleterious effects of pollution on infants." The researchers plan to examine whether babies with distinct protein response patterns to air pollution will suffer from more breathing problems during infancy and childhood compared to those that do not show the same protein responses. Professor Marielle Pijnenburg, associate professor of pediatric pulmonology and head of the Department of Pediatric Respiratory Medicine and Allergology at Erasmus Medical Center, Rotterdam, The Netherlands, is head of the ERS group on paediatrics and was not involved with the research. She commented: "This study adds to the growing body of evidence that air pollution can affect the health of children before and after they are born. It contributes to other research showing that autophagy-related mechanisms may be involved in how human cells react to air pollution. We need to know more about how these mechanisms can affect the health of lungs, and we need to understand why some new-borns seem to be more susceptible to air pollution than others. "However, we already have enough evidence from this and other studies, to be sending a message loud and clear to governments and policy-makers: air pollution damages people's health, and the effects can be seen from before birth. We should all be re-doubling our efforts to reduce air pollution as quickly and as far as possible. This will not only improve the health of populations and reduce costs associated with treating diseases caused by air pollution, but will also help the environment at a time when the climate emergency is becoming more and more apparent as every day passes."

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: 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 . 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. 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.18 ; Alzheimer's Disease International. World Alzheimer Report 2019. AARP. 2020 Report: Caregiving in the U.S. .