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."