Announcement PDF September 2026 Corporate Presentation Forward looking statements 2 This presentation should be read in conjunction with the risk factors disclosed in Alterity Therapeutics Limited’s most recent filings with the Australian Securities Exchange and the United States Securities and Exchange Commission, including the Company’s most recent Annual Report on Form 20-F and subsequent reports on Form 6-K. This presentation may contain forward-looking statements, including within the meaning of the United States Private Securities Litigation Reform Act of 1995, section 27A of the United States Securities Act of 1933 and section 21E of the United States Securities Exchange Act of 1934. Forward-looking statements relate to anticipated future events, results, performance, plans, strategies or business developments. 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In the context of the Company’s business, forward-looking statements may include, but are not limited to, statements regarding: the initiation, timing, progress, completion and results of the Company’s preclinical and clinical trials and research and development programs; the Company’s ability to advance ATH434 into, enroll and successfully complete clinical trials, including multinational clinical trials; the timing and likelihood of regulatory filings, regulatory interactions and regulatory approvals; the safety, efficacy and potential therapeutic or commercial benefits of ATH434; manufacturing, supply and product development activities; the protection, duration and enforcement of the Company’s intellectual property rights and its freedom to operate; the Company’s future funding requirements and its ability to obtain additional financing; and potential commercialization, licensing, collaboration or partnership activities. These forward-looking statements are subject to risks and uncertainties associated with drug development, clinical trial recruitment and conduct, clinical outcomes, regulatory review and approval, manufacturing and supply, intellectual property, competition, future funding and commercialization. Unexpected safety findings or inadequate therapeutic efficacy could delay or prevent the development or commercialization of ATH434. The Company’s actual results, performance or achievements may differ materially from those expressed or implied by the forward-looking statements. Accordingly, readers should not place undue reliance on forward-looking statements. Forward-looking statements speak only as of the date of this presentation. Except as required by applicable law, the ASX Listing Rules or Nasdaq rules, the Company undertakes no obligation to publicly update or revise any forward-looking statement as a result of new information, future developments, changes in expectations or otherwise. Alterity is a late clinical stage biopharmaceutical company dedicated to developing treatments for neurodegenerative diseases Our goal is to slow the course of disease progression We strive to create an alternate future and improve patient quality of life Alterity means the state of being different Redefining Neurodegenerative Disease Therapy 4 1 Compelling Phase 2 Efficacy on FDA-Endorsed Endpoint – Up to 46% slowing of disease progression v. placebo (p<0.05) on FDA-endorsed endpoint* – Favorable safety profile with no drug-related serious adverse events 2 Unmet Need with Significant Commercial Potential – MSA is a rare, rapidly progressive disease (up to 50,000 U.S. patients) – ~$US2.4B global peak sales opportunity in MSA with patent protection to 2045 3 Differentiated, Disease-Modifying Approach for MSA – Oral iron chaperone ATH434 targets excess reactive iron and α-synucleinopathies – Blood brain barrier penetrant small molecule 4 Pivotal Advancement in 2026 with Clear Regulatory Path – Successful End-of-Phase 2 FDA meeting obtained alignment on Phase 3 design – Veteran development team with 3 FDA approvals in Neurology area *11-item Unified MSA Rating Scale Part 1 (mUMSARS) A Potential First-in-Class, Disease-Modifying Therapy for Multiple System Atrophy (MSA) Program: Discovery / Pre-clinical Phase 1 Natural History Phase 2 Phase 3 Collaboration Multiple system atrophy Double blind study Multiple system atrophy Open label study in advanced MSA Multiple system atrophy Natural history study Parkinson’s disease Friedreich’s ataxia Drug discovery Broad opportunity for ATH434 in neurodegenerative disease 5 Planning Multiple System Atrophy (MSA): Parkinsonian disorder with no approved treatment 0 Years: 3 6 9 7.5 years median survival after symptom onset Over 50% require wheelchair in 5 years Rapidly progressive Highly debilitating Up to 50,000 patients in U.S. Disease characteristics: • Motor: Parkinsonism, uncoordinated movements, balance problems, falls • Autonomic dysfunction: blood pressure maintenance, bladder control, bowel function • Atrophy and α-synuclein accumulation in multiple brain regions Premotor MSA Clinically probable MSA Death can occur Clinically established MSA Urinary dysfunction REM sleep behavior disorder Orthostatic hypotension Multidomain autonomic failure Pyramidal signs Parkinsonism Cerebellar features Recurrent falls Indwelling catheter Frontal executive dysfunction Tracheostomy Bronchopneumonia Urosepsis Unintelligible speech Gastrostomy 6 Sources: Fanciulli, Wenning. NEJM 2015 | Wenning, et al. Mov Disorders 2022 | Coon, et al. Brain 2015 | Multiple System Atrophy: National Institute of Neurological Disorders and Stroke (nih.gov) Sudden death Targeting the pathology in Parkinsonian disorders 8 Targeting key players in MSA pathology Alpha-synuclein and iron balance in health and disease Two forms of iron required for cellular function • Neurotransmitter synthesis (e.g., dopamine) • Myelin synthesis (allows fast signal transmission) α-Synuclein protein • Present in all neurons • Enables neuronal communication Fe2+ Fe3+ Fe2+ Reactive Fe3+ Stable In disease: α-Synuclein aggregates in neurons in MSA impairing communication and leading to dysfunction In disease: Excess reactive iron drives α-synuclein aggregation and oxidative injury Pathology of Parkinsonian disorders 9 Parkinson’s disease n = 24 n = 13 n = 9 n = 7 * n = 3 n = 8 * 0 10000 20000 30000 S. nigra (T) S. nigra (pc) Cerebellum nmol iron/g of human brain n = 8 n = 8 n = 9 n = 8 n = 11 n = 8 * n = 9 n = 6 * n = 10 n = 8 * 0 10000 20000 30000 nmol iron/g of human brain Putamen (M) Putamen (L) Globus pallidus (M) Globus pallidus (L) S. nigra (T) Increased Brain Iron in Areas of Pathology Patients Healthy controls Multiple System Atrophy Parkinson’s disease Dexter et al. Brain.1991 Excess labile iron is a key driver of pathology causing α-synuclein aggregation and oxidative injury 10 Iron imbalance Excess labile iron Fe2+ Fe2+ Fe2+ Fe2+ Fe2+ Fe3+ PCBP Fe2+ Neuron death and impaired oligodendrocyte function monomer or normal oligomers fibrils α-syn fibrils toxic to neurons α-syn fibrils impair oligodendrocyte myelination α-Synuclein aggregation Mitochondrial dysfunction ROS damage to cellular components. Lipid peroxidation/ferroptosis Increased ROS ROS Fe2+ PCBP PCBP: Poly(rC)-binding proteins, endogenous iron chaperone Lee. S, et al. Neurobiology of Disease 197 (2024) https://doi.org/10.1016/j.nbd.2024.106535 Dusek, P, et al. Cerebral Iron Deposition in Neurodegeneration. (2022), 12, 714. https://doi.org/ 10.3390/biom12050714 Benarroch, E. Ferroptosis in Neurodegeneration 2023;101:312-319. doi:10.1212/WNL.0000000000207730 Fe3+ Stable Fe3+ Fe2+ Reactive Fe2+ ATH434 mechanism of action: Iron chaperone ATH434 chaperones excess labile (reactive) iron to reduce neuronal injury Efflux iron from cell (ferroportin) Increase iron storage (ferritin) Buffering Fe2+ in labile iron pool PCBP: Poly(rC)-binding proteins, endogenous iron chaperones 1 2 Fe3+ Fe2+ ZIP8 ZIP14 Transferrin receptor Labile iron Fe2+ Fe2+ Fe2+ Fe2+ Fe2+ Fe2+ Fe2+ Fe2+ Fe2+ Fe2+ Fe2+ Fe2+ Fe2+ ATH434 ATH434 PCBP PCBP 1 Fe2+ PCBP 2 Fe 3+ Tf Fe 3+ PCBP Enzyme PCBP ATH434 ROS Fe2+ Fe2+ Fe2+ 3 11 Chaperone mechanisms: 3 Sources: Adapted from Yanatori et al., BBA 2020 and Philpott et al., Frontiers Mol Bio. 2023 | Pall, et al. Metallomics, 2024. ATH434 treatment approach addresses underlying pathology 12 Based on mechanism of action, ATH434 is a potential disease modifying therapy Preserve neurons and oligodendrocyte cell function Reduce α-synuclein aggregation and oxidative injury Chaperone excess labile iron in the CNS Stabilize function or slow decline ATH434: Small molecule drug candidate 13 Broad treatment potential Potential to treat many neurodegenerative diseases (e.g., Parkinson’s, Friedreich Ataxia) Orphan & Fast Track designations US FDA Fast Track Designation and Orphan drug designation in U.S. and EU Blood-brain barrier penetrant Acts intracellularly to address underlying pathology Iron chaperone Moderate binding affinity, redistributes excess labile iron in CNS Oral administration Preferred by patients and doctors vs infusions (IV, intrathecal) or injections ATH434 binding to labile iron 14 ATH434 consistently improved motor performance by reducing α-synuclein aggregation and preserving neurons Target Disease Model Midbrain iron (incl. s. nigra) α-Synuclein Preserve neurons/ function Clinical observations MSA1 PLP-α-syn Improved motor performance MSA2 PLP-α-syn to Improved motor performance Parkinson’s Monkey MPTP to n/a Improved motor performance Parkinson’s Mouse MPTP Improved motor performance Parkinson’s Mouse A53T Improved motor performance Parkinson’s Mouse tau knockout Improved motor performance Multiple models of neurodegenerative disease demonstrate ATH434 efficacy Stable Sources: Bradbury et al, Am Acad. Neurol 2024; Finkelstein, Acta Neuropath Comm 2017; Beauchamp et al, Neurotherapeutics 2022; 1 Heras-Garvin et al, Mov Disord. 2021; 2 Finkelstein et al, J Park Dis 2022 ATH434 clinical development program in MSA Diligent approach to de-risk development program 16 Natural History Study bioMUSE Identified biomarkers to improve accuracy of patient selection • Observational study in 21 participants with clinically probable MSA, followed prospectively • Designed to de-risk clinical development program Phase 2 · Randomized, Double-blind ATH434-201 Clinically meaningful efficacy on MSA rating scale, orthostatic hypotension and disease severity • Randomized, double-blind, placebo-controlled trial • Favorable safety profile Phase 2 · Open Label ATH434-202 Showed improved neurological symptoms in more advanced participants • Open label trial in advanced MSA participants • Favorable safety profile *Biomarkers of progression in Multiple System Atrophy (bioMUSE).; Biomarkers: Biomarkers:; MRI, Fluid, Digital BioMUSE natural history study results 17 bioMUSE Advanced MRI methods Structural mapping Optimized patient selection in Phase 2 trials Precision biomarker assessment Differentiated MSA from Parkinson’s disease (PD) Identified ”iron signature” of early MSA Revised selection criteria in ATH434‐201 and ATH434-202 protocols to exclude PD patients Novel strategies for measuring brain iron in individual regions Improved precision of volume measurements State of the art methods enabled precise measurements of brain iron and volume with MRI α-synuclein SAA in CSF Iron content in pallidum Sources: Presentations/Posters on file, including Claassen et al, MDS Conference 2021 and 2022. ATH434-201: Randomized, double-blind, placebo-controlled study 18 N = 77 Study design: Endpoints: Patient criteria: • Clinical diagnosis of MSA • Motor symptoms ≤4 years • No severe impairment • Elevated brain iron on MRI • Elevated plasma NfL Placebo twice daily 50 mg twice daily Key clinical endpoint: MSA Rating Scale 75 mg twice daily ATH434 ATH434-201 Additional secondary endpoints: CGI-S, OHSA, Wearable Sensors, Safety ATH434 12 months treatment Key biomarker endpoint: brain iron content by MRI 1 : 1 : 1 MRI: Magnetic Resonance Imaging; UMSARS: Unified MSA Rating Scale (UMSARS) Scale– measures activities of daily living CGI-S: Clinical Global Impression-Severity scale; OHSA: Orthostatic Hypotension Symptom Assessment Importance of the Unified MSA Rating Scale Part I (UMSARS I) 19 ATH434-201 Speech Walking Swallowing Falling Handwriting Orthostatic symptoms Cutting food Urinary function Dressing Bowel function Hygiene Sexual function^ Validated rating scale to assess MSA disease severity Rates functional impairment in domains affected in MSA Rated from 0 to 48 higher scores worse UMSARS Part I Items: UMSARS is the FDA endorsed endpoint to support approval for the treatment of MSA Primary endpoint in Phase 3 ^ 11-item version of UMSARS I excludes sexual function item Placebo ATH434-201 50 mg twice daily ATH434-201 75 mg twice daily N=22 N=25 N=24 Age (y) 61.3 (6.6) 63.1 (6.1) 63.9 (6.7) Gender (% male) 63.6% 52.0% 62.5% Duration of motor symptoms (y) 2.5 (0.8) 2.6 (0.8) 2.3 (0.9) Modified UMSARS I 16.9 (3.9) 15.2 (5.4) 14.4 (4.4) Motor score of Parkinson plus scale1 57.6 (14.2) 47.8 (18.4) 48.9 (16.8) Plasma NfL (pg/mL) 34.9 (12.5) 31.1 (9.1) 32.3 (9.0) CSF aggregating α-syn SAA (+) 91% 92% 96% OH symptom assessment 13.5 (9.8) 13.8 (13.2) 15.0 (12.2) Clinical phenotype: MSA-P (%) 59.1% 60.0% 70.8% Severe orthostatic hypotension2 4.5% 4.0% 29.2% 20 Baseline characteristics ATH434-201 Groups balanced at baseline except for severe orthostatic hypotension (OH) OH is a predictor of rapid disease progression Clinical Analysis Population 1Payan et al. PlosOne 2011 | 2Decrease in Systolic BP ≥ 30 mmHg 14 16 18 20 22 24 26 * P =0.037 for 50 mg 0 13 26 39 52 Week ATH434-201 worsening Modified UMSARS I Change ATH434 − Change Placebo Change Placebo Relative Treatment Effect: 21 Clinically Significant Efficacy on 11-Item UMSARS I ATH434 50 mg N=25 Placebo N=22 ATH434 75 mg N=24 Difference v. placebo LS mean (SE) Relative treatment effect -3.7 (1.7) 46% -2.7 (1.8) 34% Change from Baseline to Week 52 Both doses exceeded the MCID Minimal clinically important difference (MCID) on UMSARS I1 = -1.5 Clinical Analysis Population, incl CSF NfL as covariate 1Krismer. Mov Disord, Vol. 31, No. 10, 2016 ç Improvement -6 -5 -4 -3 -2 -1 0 1 bowel urinary OH falling walking hygiene dressing cutting food handwriting swallowing speech mod. total 50 mg BID Difference vs placebo UMSARS Part I item -6 -5 -4 -3 -2 -1 0 1 bowel urinary OH falling walking hygiene dressing cutting food handwriting swallowing speech mod. total 75 mg BID Difference vs placebo UMSARS Part I item ç Improvement Consistent efficacy across multiple domains on 11-item UMSARS 22 LS mean (SE) ATH434 treatment demonstrates a similar pattern of efficacy in both dose groups vs. placebo at 52 weeks Clinical Analysis Population, incl. CSF NfL as covariate Achieved Efficacy on Clinical Global Impression of Severity 23 CGI-S • 7-point scale • higher score indicates a worse outcome Assesses total picture over prior 28 days • illness severity, impact of illness on function, level of distress and any other aspects of impairment ATH434-201 0.0 0.5 1.0 1.5 Change in CGIS (Week 52-Baseline) * p=0.006 Worsening ATH434 50 mg ATH434 75 mg Placebo LS mean (SE) Clinician Reported Outcome Clinical Analysis Population, incl. CSF NfL as covariate Achieved Efficacy on Swallowing Disturbance Questionnaire 24 ATH434-201 0 5 10 Change in SDQ (Week 52-Baseline) * p=0.003 Worsening Placebo ATH434 50 mg ATH434 75 mg LS Mean (SE) Validated Scale for Detecting Dysphagia 15-item questionnaire that assesses swallowing impairment (choking, coughing when drinking liquids, etc.) Patient Reported Outcome Clinical Analysis Population, incl. CSF NfL as covariate Improvement on Orthostatic Hypotension Symptom Assessment (OHSA) 25 Assesses symptoms of low blood pressure when going from sitting to standing (e.g., dizziness / feeling faint / lightheadedness) 10 5 -5 0 Change In OHSA (week S2‒ BL) worsening LS Mean (SE) ATH434 50 mg ATH434 75 mg Placebo ATH434-201 Patient Reported Outcome Clinical Analysis Population, incl. CSF NfL as covariate | Kaufmann, et al. Clin Auton Res 2012.. -40 -30 -20 -10 0 Change in minutes/day Worsening p=0.1049 p=0.1506 !"# !$# # %C'()*+,(+-.'(/,-,0(12'3 !"#$%&'&( -80 -60 -40 -20 0 Change in minutes/day Worsening ATH434 preserved walking in outpatient setting 26 ATH434-201 Step count Total time walking Sit-to-stand transitions Pendant Wearable movement sensor ATH434-201 50 mg ATH434-201 75 mg Placebo Walking periods -3000 -2000 -1000 0 Change in Steps/day * P=0.0436 P=0.1071 Worsening Change from baseline to Week 52 Clinical Analysis Population, incl. CSF NfL as covariate 27 1 - Reporting one or more event 2 - None related to Study Drug Placebo ATH434-201 ATH434-201 twice daily 50 mg 75 mg Any Adverse Event (AE) 24 (92.3%) 21 (84.0%) 25 (96.2%) N=25 N=26 N=26 ATH434-201 N (%) of subjects 1 • Similar rates of AEs in ATH434 and placebo participants • No severe or serious AEs related to study drug • No hematologic side effects Severe AEs 2 8 (30.8%) 3 (12.0%) 6 (23.1%) Serious AEs 2 10 (38.5%) 5 (20.0%) 7 (26.9%) 1 (3.8%) 3 (12.0%) 2 (7.7%) 2 (7.7%) 1 (4.0%) 5 (19.2%) 1 (3.8%) 6 (24.0%) 4 (15.4%) 8 (30.8%) 7 (28.0%) 8 (30.8%) 14 (53.8%) 10 (40.0%) 7 (26.9%) Back pain Fatigue Covid-19 Fall UTI Favorable safety profile for ATH434 Neuroimaging Substantia Nigra Midbrain axial view Putamen / Globus Pallidus Basal ganglia axial view QSM: Quantitative Susceptibility Mapping І QSM overlay: warm colors = higher magnetic susceptibility (iron content) Measuring Iron Content with MRI (QSM) 29 Regional increases in iron in MSA Patient 30 Iron Deposition on MRI in Placebo: Change Baseline → Week 52 Mean ± 95% CI ATH434-201 Iron Deposition on MRI: ATH434 vs. Placebo ATH434-201 31 MMRM with sex, age, baseline CSF NfL, and baseline iron as covariates 32 ATH434 decouples iron accumulation from clinical worsening Correlation Between Change in Iron and Change in UMSARS I Score at Week 52 Controlling for Sex, Age, Baseline CSF NfL, Baseline QSM Summary: ATH434 Interrupts the Pathologic Process in MSA 33 In ATH434-treated patients, change in iron weakly correlates with change in disease severity. ATH434 leads to a decoupling of iron accumulation and clinical worsening as assessed by UMSARS I Iron builds up in the basal ganglia of MSA patients, most prominently in the globus pallidus and putamen. QSM allows quantitation of total brain iron but does not distinguish between reactive (toxic in excess) and stable forms of iron. In placebo-treated patients, change in iron strongly correlates with change in disease severity. ATH434 showed trends in preserving brain volume in MSA Regions of Interest Subject 1 Change in Brain Volume* 0.0000 -0.1000 -0.2000 -0.3000 -0.4000 -0.5000 -0.6000 worsening Z-score ATH434-201 50 mg BID ATH434-201 75 mg BID Placebo 26 weeks 52 weeks Subject 2 34 * MSA Atrophy Index: composite z-score of putamen, GP, cerebellum and brainstem vs. healthy age-matched population Carefully designed Phase 2 program demonstrates potential for ATH434 in MSA 35 ATH434 demonstrated clinically significant efficacy in slowing disease progression in MSA Both dose levels efficacious on 11-Item UMSARS and important secondary endpoints Demonstrated target engagement with reduced iron accumulation in MSA affected brain regions Stabilized orthostatic hypotension, one of the most challenging MSA symptoms to manage Preserved walking in outpatient setting as measured with objective digital biomarker Open-label trial showed comparable safety and efficacy in advanced MSA No safety signals and well-tolerated No serious AEs related to study drug Successful End-of-Phase 2 meeting with FDA alignment on on key elements of the Phase 3 design 36 Primary endpoint: Selection and scoring of the 11-Item UMSARS Part I Population: ~200 patients with clinical and biomarker evidence of MSA Dosing regimen: 50 mg dose administered twice-daily for 12 months Key secondary endpoints: Swallowing Disturbance Questionnaire (SDQ), Orthostatic Hypotension Symptom Assessment (OHSA), and the Clinical Global Impression of Severity (CGIS) Statistics: Methods for analyzing primary and secondary efficacy endpoints acceptable Safety database: Anticipated safety database at the conclusion of Phase 3 reasonable FDA alignment on Phase 3 trial design 37 N = ~200 Study design: Efficacy Endpoints: Patient criteria: • Clinical diagnosis of MSA • Ambulatory without assistance • No severe impairment • Brain atrophy in MSA affected regions on MRI • Elevated plasma NfL 1 : 1 * Primary endpoint Selection and scoring of the 11-Item UMSARS Part I 50 mg twice daily ATH434 11-item UMSARS Part I (previously described as modified UMSARS I): Unified Multiple System Atrophy Rating Scale, 11-Items include: Orthostatic symptoms, Swallowing, Speech, Handwriting, Cutting food, Dressing, Hygiene, Walking, Falling, Urinary and Bowel function. | SDQ - Swallowing Disturbance questionnaire | OHSA - Orthostatic Hypotension Symptom Assessment | CGIS – Clinical Global Impression of Severity Key Secondary endpoints SDQ, OHSA, CGIS Placebo 12 months treatment twice daily * Randomization stratified by screening plasma NfL Efficacy Analysis Includes baseline CSF NfL as covariate Expect to initiate trial activities by YE 2026 Commercial assessment & corporate overview Independent commercial assessment in MSA 39 USD $2.4 Billion Potential worldwide annual peak sales for ATH434 in MSA Severely debilitating illness with no approved treatment ripe for new entrants Critical need for a tolerable, disease modifying therapy Importance of inhibiting α‐synuclein aggregation to address the underlying pathology of disease Slowing disease progression is key driver of physician interest Stabilizing orthostatic hypotension^, one of the most challenging symptoms in MSA, strongly positions ATH434 Over 70% of neurologists were “extremely likely” or “very likely’ to prescribe ATH434 based on its profile Target product profile based on positive Phase 2 data ^Orthostatic hypotension is the drop in blood pressure on standing; Global peak sales number in U.S. Dollars; Independent market research survey conducted in 2025. Peak sales estimate based on U.S. prevalence of ~19,000 40 Positioned for Success ✓ REGULATORY MILESTONES • FDA alignment on Phase 3 study design • Type C alignment on clinical pharmacology and non-clinical elements • Type C alignment on Chemistry, Manufacturing & Controls (CMC) • Clinical site identification and qualification • Manufacture and packaging of clinical drug supply • Initiate trial start-up activities expected by year-end 2026 • New U.S. composition of matter patent granted for ATH434 with protection out to 2045 • Evaluate additional high-value indications • Strengthen the team to enhance organizational capabilities PHASE 3 READINESS ACTIVITIES BUILDING VALUE ASX: ATH NASDAQ: ATHE APPENDIX 42 43 Inadequately chaperoned cellular iron drives MSA pathology Promotes α-synuclein cross linking1 Directly increases α‐synuclein translation2 ODG toxicity due to limited endogenous glutathione3 Free radicals promote α‐synuclein aggregation4 Impaired lysosomal autophagy5 1Duce JA, et al. Mol Neurodegener. 2017;12(1):45. 2Febbraro F, et al. NeuroReport. 2012;23(9):576-580. 3Thorburne SK, Juurlink BH. Neurochem. 1996;67(3):1014-1022. 4Souza JM, J Biol Chem. 2000;275(24):18344-18349. 5Tanji, K, et al. Neurobiol Dis. 2013;49:190-198. doi 10.3233/JAD-170601 (2018); doi.org/10.3390/ijms25084269 (2024) Christine Kaindlstorfer, Kurt A Jellinger, Sabine Eschlbök, Nadia Stefanova, Günter Weiss, Gregor K Wenning Seojin Lee, Ivan Martinez-Valbuena , Anthony E. Lang, Gabor G. Kovacs Iron converts native α-SYN into a β-sheet conformation and promotes its aggregation either directly or via increasing levels of oxidative stress. The disturbance of iron homeostasis leads to abnormal iron deposition in the brain and causes neurotoxicity via generation of free radicals and oxidative stress. Importantly, extensive evidence suggests a molecular relationship between iron accumulation and α-syn pathology. Cellular iron deposition patterns predict clinical subtypes of multiple system atrophy Neurobiology of Disease. 2024. https://doi.org/10.1016/j.nbd.2024.106535 Journal of Alzheimer’s Disease (2018) DOI 10.3233/JAD-170601 Veh 3 10 30 WT 2000 3000 4000 5000 6000 Total SNpc neurons *** *** *** ATH434 (mg/kg) 44 Animal data supporting Phase 2 dose selection PLP-α-syn MSA Mouse model 0 1 3 10 30 80 C 0 3000 6000 Total SNpc neurons ATH434 (mg/kg) *** *** ** * MPTP Mouse model Exposure at 3 mg/kg ~ to 50 mg BID in man ATH434 affinity for Fe2+ and Fe3+ relative to endogenous iron binding proteins 45 Fe2+ Fe3+ µM constant µM constant ATH434 4.6a 10-5.33 0. 0003b 10-9.6 PCBPs 0.9c 5.8c 10-6.04 10-5.24 Glutathione ~8d 10-5.10 Transferrin 10-23 e a: Pall et al 2024 | b: Finkelstein et al 2017, consistent with data from (a) collected at pH 5.5 when adjusted for neutral pH. Traditional chelators have constants of ~ 10-30 (Crisponi 2015, Hilder 2014) |c: Shi 2008; binds irons with 2 constants | d: Hider 2011 | e: Aisen 1978 46 Reactive iron Generates free radicals Promotes α-synuclein aggregation α-synuclein aggregation Neuronal toxicity Impaired myelin production Oxidative stress Disrupts multiple cellular functions Promotes α-synuclein aggregation Iron is a key driver of the MSA Pathology ATH434 chaperones excess iron to reduce neuronal injury Overwhelms natural iron buffering systems, leading to iron accumulation in MSA brain regions MSA Pathology Cycle Disrupted Control of CNS Iron 46 Key disease drivers 47 Correlation Between Change in Iron and Change in UMSARS I Score at Week 52 ATH434 decouples iron accumulation from clinical worsening Controlling for Sex, Age, Baseline CSF NfL, Baseline QSM ATH434-201: Populations and key endpoints 48 Imaging analysis population Clinical analysis population 71 61 6 no post baseline UMSARS I 5 neg. CSF α-syn SAA 10 d/c before week 26 1 completed week 26 w/o MRI Endpoint Change from BL to week 52 Population Biomarker (Primary) Imaging Clinical (Key secondary) Clinical Iron content in s. nigra by MRI Change in Modified UMSARS Part I Randomized 77 ATH434-201 All patients in Imaging and Clinical analysis populations were randomized and treated ATH434-202: Open label study in advanced MSA 49 1 MSA affected areas by MSA-atrophy index. Trujillo, P. et al Annals of Clin and Trans Neuro, 2025 *ATH434-201 listed for comparative purposes, data are not from a head-to-head study Design Single arm, open-label Objective Assess safety and efficacy in advanced MSA Population Advanced MSA (n=10) Treatment ATH434 75 mg BID x 12 months Brain MRI Biomarkers Volume, Iron Key Clinical Measure UMSARS I ATH434-202 The study indicates the potential of ATH434 to slow disease progression in advanced MSA No serious Adverse Events (AEs) related to study drug AEs consistent with underlying disease Comparable efficacy observed at same dose in double blind study Outcomes: ATH434-202: Open label study in advanced MSA 50 Key objective was to assess efficacy and safety of ATH434 75 mg dose for comparison to 75 mg dose in 201 double-blind study Parameter ATH434-202 75 mg BID N=10 ATH434-201 75mg BID N=24 Age (yr) 64.5 (7.5) 63.9 (6.7) Duration of motor symptoms (yr) 3.9 (1.8) 2.3 (0.9) Modified UMSARS I1 19.2 (5.3) 14.4 (4.4) Motor score of Parkinson Plus Scale2 57.5 (20.4) 48.9 (16.8) Plasma NfL (pg/mL) 42.1 (14.1) 32.3 (9.0) OH Symptom Assessment 16.7 (14.8) 15.0 (12.2) Severe Orthostatic Hypotension 40.0% 29.2% Mean (SD) 1 MSA affected areas by MSA-atrophy index. Trujillo, P. et al Annals of Clin and Trans Neuro, 2025 ATH434-202 Change over 12 Months ATH434-202 75 mg BID N=10 ATH434-201 75mg BID N=24 Modified UMSARS I 3.5 (4.7) 5.6 (5.6) Clinical global impression of change (% stable) 30% 21% Patient global impression of change (% stable) 30% 26.4% Brain volume1 -0.44 (0.14) -0.42 (0.29) Mean (SD) ATH434-202: Key data at 75 mg dose Comparison to double blind study at 12 mo 51 • No serious AEs related to study drug • AEs consistent with underlying disease ATH434-202 The 75 mg dose demonstrated comparable efficacy to that observed in the double-blind study 1 In MSA affected areas by MSA-atrophy index. Trujillo, P. et al. Annals of Clin and Trans Neuro, 2025