PBT-434

多系统萎缩（MSA）有医学记载可以追溯到20世纪初，彼时的医生们陆续发现并记录下了一些相关病变。由于MSA的临床表现极其多样，研究者对它的认识如同“盲人摸象”，每个人只看见了真相的一小部分。 直到1969年，英国学者J.G. Graham和D.R. Oppenheimer首次指出，以往描述的不同临床表现，实质上是神经元萎缩以不同方式重叠所呈现出的多种表现形式，并提出了统一的命名：“多系统萎缩”（Multiple System Atrophy, MSA）。 MSA可分为两种主要临床类型： ●MSA-P（帕金森型）：以帕金森综合征为主要表现，对应纹状体-黑质系统的退行性病变。 ●MSA-C（小脑型）：以小脑性共济失调为主要表现，对应延髓-脑桥-小脑系统的退行性病变。 尽管类型不同，但随着病程进展，两者的临床和病理差异会逐渐模糊。 MSA属于三大α-突触核蛋白病之一（另两种为帕金森病与路易体痴呆）。其核心病理特征在于α-突触核蛋白主要沉积于少突胶质细胞中，形成胶质细胞胞质内包涵体（GCIs），而非像帕金森病那样主要存在于神经元内。这种细胞受累的差异是MSA的重要病理基础，但其确切成因目前尚不明确。当前治疗现状与挑战 令人遗憾的是，MSA目前尚无根治方案和疾病治疗药物。所有治疗措施均以对症支持为主，旨在改善生活质量和延缓功能衰退。 ●对症治疗：包括使用升压药物治疗体位性低血压、导尿处理泌尿系统功能障碍、吞咽训练、睡眠调节药物等。 ●药物反应：左旋多巴在部分MSA-P患者中可能短暂有效，但大多患者无显著改善，且疗效通常会随疾病进展而减弱。 随着疾病恶化，许多患者在3至5年内便会丧失独立行走能力，后期可能需要胃造瘘或气管切开等生命支持措施。MSA的平均生存期在6至10年之间，进展迅速，预后较差。 尽管挑战巨大，全球科研界仍在为攻克MSA不懈努力。截至2026年3月，全球在研临床试验药物概览如下： 序号 药品名称 药物类型 针对类型 研发企业 阶段 1  Lu AF-82422 SNCA抑制剂 系统萎缩；帕金森病 灵北制药；GenmabA/S 临床二期 2  ONO-2808 S1PRs激动剂 多系统萎缩神经系统变性病 Ono PharmaceuticalCo.,Ltd. 临床二期 3  Ampreloxetine 选择性去甲肾上腺素再摄取抑制剂 多系统萎缩nOH TheravanceBiopharma 临床二期 4  ATH434 a-突触核蛋白聚集抑制剂 神经退行性疾病，多系统萎缩 Alterity Therapeutics 临床二期 5  AB-1005 基于腺相关病毒血清型2载体基因治疗 多系统萎缩-帕金森病型 AsklepiosBioPharmaceutical 临床二期帕金森病 临床一期多系统萎缩 6  Indenebart/ TAK341 a-synuclein抑制剂 多系统萎缩，帕金森 AstraZeneca PLC 临床二期 7  KM-819;KR-33493 FAF1(FAS相关因子1)抑制剂 帕金森病和多系统萎缩 Kainos Medicine Inc 临床二期 8  Movronersen a-突触核蛋白抑制剂 多系统萎缩，帕金森 lonisPharmaceuticals,Inc 渤健 临床二期 9  Anle-138b/Emrusolmin 新型寡聚体调节剂 多系统萎缩、帕金森病 Modag Gmbh、梯瓦制药工业有限公司 临床二期多系统萎缩；帕金森病一期 10  UB-312 a-突触核蛋白抑制剂 多系统萎缩，帕金森病 United NeuroscienceLtd. 临床二期 11 NouvNeu004 基因治疗 多系统萎缩 睿健毅联医药科技 临床一/三期 针对MSA的在研疗法主要集中在两大方向：一是旨在改变疾病进程的疾病修饰疗法，二是着眼于修复受损神经的细胞与基因治疗。1. 疾病修饰疗法 此类疗法旨在从源头上干预疾病的核心病理机制，如α-突触核蛋白聚集和铁代谢紊乱。 ● ATH434 (Alterity Therapeutics) ○ 一种口服的试验性小分子金属螯合剂，旨在通过重新平衡大脑中的过量铁元素，抑制α-突触核蛋白的异常聚集，从而发挥神经保护作用。 ○ 根据关键的II期ATH434-201研究（77名MSA患者，12个月，随机、双盲、安慰剂对照），其在主要终点——改良版统一MSA评估量表（mUMSARS）I部分（日常生活活动能力）上展现出显著疗效。50mg剂量组的疾病进展相对延缓达48%（p=0.02）；75mg剂量组在校正基线直立性低血压（OH）差异后，疗效信号增强至35%。 ○ 整体耐受性良好，未报告与药物相关的严重不良事件（SAE）。 ○该药已获美国FDA快速通道认定，计划于2026年推进III期临床试验，目前未在中国同步开展研究。 ● Lu AF82422 (Amlenetug) ○ 一种人源单克隆抗体，旨在结合并清除细胞外的α-突触核蛋白，阻止其在脑内的扩散和聚集。 ○尽管其全球II期临床试验未达到主要终点，但数据显示能显著减缓疾病进展约19%，并在预先设定的MSA-P亚组中观察到更具说服力的疗效信号。 ○ 基于积极数据，FDA已授予其快速通道资格。一项新的全球III期临床试验（MASCOT）已启动，计划招募约550名早期、未接受左旋多巴治疗的MSA患者（主要为MSA-P型）。 ● 其他在研项目：多个项目处于II期临床阶段，包括阿斯利康与武田制药合作的TAK-341/MEDI1341，以及梯瓦制药与MODAG合作的Emrusolmin（TEV-56286）等。2. 细胞与基因治疗 此类疗法代表了更具突破性的治疗策略，旨在修复或替换受损的神经系统功能。 ● NouvNeu004注射液 (睿健医药) ○ 全球首个进入临床阶段的MSA细胞治疗产品。它是一种基于“AI+化学诱导”技术的iPSC（诱导多能干细胞）来源的通用型神经前体细胞。采用“神经营养+神经重建”的复合策略，旨在为病灶区域提供营养支持并实现系统性神经修复。 ○ 2025年10月，获得中国NMPA的I-III期全周期临床试验许可。同时，该产品也获得了美国FDA的批准，实现了中美同步开发。 3.其他领域治疗 除了上述两大热点，全球从更多维度解构MSA的病理机制，并取得了一定进展。 在髓鞘修复领域，日本大塚制药的ONO-2808和韩国KM-819等药物也传来了积极讯息。 ONO-2808致力于促进髓鞘再生，保护神经传导功能；在2025年公布的一项2期临床试验中，展现出了积极的疗效信号。与安慰剂组相比，服用该药的MSA患者在统一MSA评分量表（UMSARS）上的病情进展速度有所减缓，且耐受性良好，安全性可控。 而KM-819是一种FAF1（Fas-associated factor 1）抑制剂。通过抑制促进细胞凋亡的FAF1蛋白，保护多巴胺能神经元。该试验于2023年2月启动II期临床研究（NCT05737563），旨在评估在早期MSA患者中的安全性及初步疗效（主要终点为mUMSARS变化）。目前正处于患者招募尾声或数据锁库分析阶段。该药物在美国和日本开展临床试验，尚未在中国开展，是目前全球极少数专门针对MSA病理机制开展的II期试验。 总结： 尽管MSA的治疗目前仍面临巨大挑战，但上述研究正在取得突破性进展，为未来可能的有效治疗带来了曙光。

– Company is advancing ATH434 in late-stage clinical development for Multiple System Atrophy, a rapidly progressive neurodegenerative disease with no approved therapies – MELBOURNE, Australia and SAN FRANCISCO, March 02, 2026 (GLOBE NEWSWIRE) -- Alterity Therapeutics (ASX: ATH, NASDAQ: ATHE) (“Alterity” or “the Company”), a biotechnology company dedicated to developing disease modifying treatments for neurodegenerative diseases, recognizes Multiple System Atrophy (MSA) Awareness Month this March and the importance of raising awareness for a devastating and often misunderstood rare neurological disorder with no approved treatment options. MSA is a progressive neurodegenerative disease characterized by a combination of motor impairment, autonomic dysfunction, and rapid loss of independence. Symptoms can include problems with balance, coordination, movement, and blood pressure regulation, and the disease typically progresses quickly following diagnosis. Because early symptoms can resemble Parkinson’s disease, MSA is often difficult to diagnose in its initial stages, contributing to delays in care. Currently, treatment options only address symptom management, as there are no approved disease-modifying therapies available. “MSA Awareness Month is an important opportunity to recognize the resilience of patients and care partners living with this devastating condition and to highlight the urgent need for therapies that can change the course of disease,” said David Stamler, M.D., Chief Executive Officer of Alterity Therapeutics. “At Alterity, we are committed to advancing research that targets the underlying pathology of MSA and are very encouraged by our data that demonstrate the potential of ATH434 as a disease-modifying therapy. We are grateful to the patients, families, and clinical investigators who make this work possible, and we remain focused on developing treatments that may offer hope for slowing disease progression and improving quality of life.” Alterity is advancing ATH434, an investigational oral therapy designed to redistribute excess iron in the brain, which contributes to the aggregation, or clumping, of the α-synuclein protein and the progression of neurodegeneration in MSA. The Company has reported data from its Phase 2 clinical development program evaluating ATH434 in individuals with MSA, demonstrating meaningful clinical benefit alongside favorable safety and tolerability pro The Company’s clinical program has featured the incorporation of biomarkers and advanced neuroimaging to better characterize disease progression and assess therapeutic impact. These efforts are intended to support the development of disease-modifying approaches and contribute to a deeper understanding of this complex and devastating condition. Throughout MSA Awareness Month, Alterity will share educational information about the disease on its social media accounts, highlight the experiences of the MSA community, and underscore the importance of continued research to address the significant unmet need for effective treatments. Alterity is committed to supporting patient advocacy efforts and organizations working to raise awareness and improve outcomes for the MSA community. About ATH434 Alterity’s lead candidate, ATH434, is an oral agent designed to reduce iron accumulation and inhibit abnormal protein aggregation associated with neurodegeneration. ATH434 has been shown to reduce α-synuclein pathology and preserve neuronal function by restoring normal iron balance in the brain in preclinical models. As an iron chaperone, it has excellent potential to treat Parkinson’s disease as well as various Parkinsonian disorders such as Multiple System Atrophy (MSA). Positive results from the randomized, double-blind, placebo-controlled Phase 2 clinical trial in patients with MSA demonstrated robust clinical efficacy, target engagement as indicated by key biomarkers, and a favorable safety profile. Positive data from a second Phase 2 open-label biomarker trial in patients with more advanced MSA reinforced these results. ATH434 has been granted Fast Track Designation by the U.S. Food and Drug Administration (FDA), and Orphan Drug Designation by the FDA and the European Commission for the treatment of MSA. About ATH434-201 Phase 2 Clinical Trial The ATH434-201 Phase 2 clinical trial was a randomized, double-blind, placebo-controlled investigation of 12 months treatment with ATH434 in patients with MSA. The study evaluated the efficacy, safety and pharmacokinetics of ATH434 and assessed neuroimaging measures of brain volume and iron-related parameters, together with protein biomarkers. Wearable sensors were employed to evaluate motor activities outside of the clinic. The study enrolled 77 adults who were randomly assigned to receive ATH434 50 mg or 75 mg twice daily or matching placebo. The data showed that, compared to placebo, ATH434 produced clinically and statistically significant improvement on the modified Unified Multiple System Atrophy Rating Scale (UMSARS) Part I, a functional rating scale that assesses disability on activities of daily living affected in MSA. Additional efficacy assessments demonstrated improvement consistent with the positive UMSARS Part I findings including trends in improved motor performance on the Parkinson’s Plus rating scale, the Clinical Global Impression of Severity Scale, and the Orthostatic Hypotension Symptom Assessment (a patient reported outcome). Wearable sensor data used to assess outpatient activity levels indicated that patients receiving ATH434 also experienced less decline compared with placebo. Biomarkers were used to evaluate potential drug effect and target engagement relative to placebo. Both dose levels reduced iron accumulation in MSA affected brain regions with trends in preservation of brain volume. ATH434 was well tolerated with similar adverse event rates compared to placebo and no serious adverse events attributed to ATH434. Additional information on the Phase 2 trial can be found at ClinicalTrials.gov Identifier: NCT05109091 . About Multiple System Atrophy Multiple System Atrophy (MSA) is a rare, neurodegenerative disease characterized by failure of the autonomic nervous system and impaired movement. The symptoms reflect the progressive loss of function and death of different types of nerve cells in the brain and spinal cord. It is a rapidly progressive disease that causes profound disability. MSA is a Parkinsonian disorder characterized by a variable combination of slowed movement and/or rigidity, autonomic dysfunction affecting involuntary functions such as blood pressure maintenance and bladder control, and impaired balance and/or coordination that predispose patients to falls. A pathological hallmark of MSA is the accumulation of abnormal clumping of the protein α-synuclein within oligodendrocytes, the myelin-producing support cells of the central nervous system, along with progressive neuronal loss in multiple brain regions. MSA affects up to 50,000 individuals in the U.S., and while some of the symptoms of MSA can be treated with medications, currently there are no drugs that are able to slow disease progression and there is no cure. 1 1 Multiple System Atrophy | National Institute of Neurological Disorders and Stroke (nih.gov) About Alterity Therapeutics Limited Alterity Therapeutics is a clinical stage biotechnology company dedicated to creating an alternate future for people living with neurodegenerative diseases. The Company is focused on developing disease modifying therapies in Multiple System Atrophy (MSA) and related Parkinsonian disorders. Alterity is preparing to initiate a Phase 3 pivotal trial in MSA, a rare and rapidly progressive disease. ATH434, the Company’s lead asset, has demonstrated clinically meaningful efficacy in a randomized, double-blind, placebo-controlled Phase 2 clinical trial in participants with MSA. Alterity has further reported positive data in its open label Phase 2 clinical trial in participants with advanced MSA. In addition, Alterity has a broad drug discovery platform generating patentable chemical compounds to treat the underlying pathology of neurological diseases. The Company is based in Melbourne, Australia, and San Francisco, California, USA. For further information please visit the Company’s website at Authorization & Additional information This announcement was authorized by David Stamler, CEO of Alterity Therapeutics Limited. Contacts: Investors Tara Speranza Head of Investor Relations and Communications tsperanza@alteritytx.com Remy Bernarda Investor Relations Advisory Solutions ir@alteritytx.com +1 (415) 203-6386 Media Casey McDonald Tiberend Strategic Advisors, Inc. cmcdonald@tiberend.com +1 (646) 577-8520 Forward Looking Statements This press release contains "forward-looking statements" within the meaning of section 27A of the Securities Act of 1933 and section 21E of the Securities Exchange Act of 1934. The Company has tried to identify such forward-looking statements by use of such words as "expects," "intends," "hopes," "anticipates," "believes," "could," "may," "evidences" and "estimates," and other similar expressions, but these words are not the exclusive means of identifying such statements. Important factors that could cause actual results to differ materially from those indicated by such forward-looking statements are described in the sections titled “Risk Factors” in the Company’s filings with the SEC, including its most recent Annual Report on Form 20-F as well as reports on Form 6-K, including, but not limited to the following: statements relating to the Company's drug development program, including, but not limited to the initiation, progress and outcomes of clinical trials of the Company's drug development program, including, but not limited to, ATH434, and any other statements that are not historical facts. Such statements involve risks and uncertainties, including, but not limited to, those risks and uncertainties relating to the difficulties or delays in financing, development, testing, regulatory approval, production and marketing of the Company’s drug components, including, but not limited to, ATH434, the ability of the Company to procure additional future sources of financing, unexpected adverse side effects or inadequate therapeutic efficacy of the Company's drug compounds, including, but not limited to, ATH434, that could slow or prevent products coming to market, the uncertainty of obtaining patent protection for the Company's intellectual property or trade secrets, the uncertainty of successfully enforcing the Company’s patent rights and the uncertainty of the Company freedom to operate. Any forward-looking statement made by us in this press release is based only on information currently available to us and speaks only as of the date on which it is made. We undertake no obligation to publicly update any forward-looking statement, whether written or oral, that may be made from time to time, whether as a result of new information, future developments or otherwise.