Alterity Therapeutics Ltd. · ASX:ATH
Alterity Therapeutics — MSA Trust Symposium 2025
20 slides from Alterity Therapeutics's conference presentation, Apr 28, 2025
Slide 1: Phase 2 Study of ATH434 in Multiple System Atrophy
A Randomized, Double Blind, Placebo Controlled Phase 2 Study of ATH434 in Multiple System Atrophy David Stamler 1 , Cynthia Wong 1 , Paula Trujillo 2 , Margaret Bradbury 1 , Christine Lucas 1 and Daniel Claassen 2 1 Alterity Therapeutics, Newark, CA, USA 2 Department of Neurology, Vanderbilt Univers
Slide 2: Disclosures
Disclosures 2 The authors are either employees of Alterity Therapeutics or received research support for their participation in the study.
Slide 3: Study Rationale
Study Rationale • Labile iron essential for key cellular functions • Iron accumulation occurs in MSA affected brain areas (putamen, pallidum, s. nigra) • Indicative of impaired iron trafficking • Excess labile iron promotes • Alpha - synuclein aggregation • Oxidative injury • ATH434: Iron chaperone
Slide 4: Iron accumulation in MSA histopathology and MRI data
4 • Histopathology data • MRI data The close association of iron accumulation with distinct α - synuclein - pathology - related anatomical regions of the two disease subtypes supports the critical involvement of pathological iron in disease progression… doi 10.3233/JAD - 170601 (2018) doi.org/10.339
Slide 5: Excess Labile Iron and Misfolding α-Synuclein are Important Drivers of MSA Pathology
Excess Labile Iron and Misfolding α - Synuclein are Important Drivers of MSA Pathology Neuroinflammation Iron Imbalance Stored iron Labile iron • Needed for cellular functions Oxidative Injury Vicious cycle of cellular injury Effect Pathology Driver Alpha - synuclein aggregation Excess labile iron F
Slide 6: Development Approach: Address Underlying Pathology
Development Approach: Address Underlying Pathology Redistribute excess labile iron in the CNS Reduce α - synuclein aggregation and o xidative injury Preserve neurons and ODGs Stabilize or Improve Function 6
Slide 7: Study Objectives
Study Objectives 7 • Evaluate the efficacy, biomarker response, and safety of ATH434 treatment in MSA patients
Slide 8: ATH434 Study Design
ATH434 - 201 Study Design • Clinical diagnosis of MSA • Elevated plasma NfL • MRI evidence of Iron • Motor symptoms ≤4 years • No severe impairment MSA* (N=60) 75 mg bid 50 mg bid Placebo 12 mo treatment 12 mo treatment 12 mo treatment Quantitative MRI MSA patient Confidential 8 * Claassen et al.
Slide 9: Populations and Key Endpoints
Populations and Key Endpoints 9 Criteria^ Population Change BL to Week 52 Protocol Endpoint ≥ 1 post - baseline MRI (26 weeks) (+) aggregating α - synuclein SAA Imaging Iron content in s. nigra by MRI Primary (Biomarker) ≥ 1 post - baseline UMSARS I (13 weeks) Clinical Modified UMSARS Part I Key Sec
Slide 10: Baseline Characteristics (mITT)
Baseline Characteristics (mITT) 10 Mean (SD) 75mg BID (n = 21) 50mg BID (n = 21) Placebo (n = 19) Parameter 64.0 (6.3) 62.9 (6.3) 61.5 (7.0) Age (yr) 57.1% 57.1% 63.2% Gender (% male) 14.4 (4.7) 15.4 (4.6) 16.8 (4.2) Modified UMSARS I 1 49.1 (17.7) 48.6 (16.0) 57.9 (15.2) Motor score of NNIPPS 2 32.
Slide 11: Modified UMSARS Part I
0 13 39 52 26 Week 12 14 16 20 18 22 24 26 Modified UMSARS I Placebo (n=22) ATH434 50 mg BID (n=25) ATH434 75 mg BID (n=24) P =0.07 for 75 mg P =0.02 for 50 mg Worsening Modified UMSARS Part I Relative treatment effect* Mean difference vs. placebo Dose 48% - 3.8 50 mg 30% - 2.4 75 mg * Change ATH434
Slide 12: Clinical Global Impression of Severity
Clinical Global Impression of Severity Change from Baseline to Week 52 0.0 0.5 1.0 1.5 Change in CGIS (W52 - BL) Placebo ATH434 50 mg BID ATH434 75 mg BID P =0.009 Mean (SE) * Worsening 7 - point Likert scale Clinical Analysis Population 12 • Higher score = worse outcome • Total picture of patient o
Slide 13: Orthostatic Hypotension Symptom Assessment
- 5 0 5 10 Change in OHSA (W52 - BL) Placebo ATH434 50 mg BID ATH434 75 mg BID P =0.08 P =0.14 Orthostatic Hypotension Symptom Assessment Change from Baseline to Week 52 13 Mean (SE) Patient reported outcome Assesses severity of 6 items • Dizziness/lightheadedness/feeling faint/like blacking out • P
Slide 14: Wearable Sensors: Activity in Outpatient Setting
Wearable Sensors: Activity in Outpatient Setting Change from Baseline to Week 52 Step Count Total Time Walking - 3000 - 2000 - 1000 0 Change in steps/day P =0.0437 P =0.1041 * - 40 - 30 - 20 - 10 0 Change in Minutes/day Placebo ATH434 50 mg BID ATH434 75 mg BID P =0.1267 P =0.1535 - 100 - 50 0 Bouts
Slide 15: Summary of Adverse Events
75mg BID (n=26) 50mg BID (n=25) Placebo BID (n=26) Number (%) of Subjects 25 (96.2%) 21 (84.0%) 24 (92.3%) Any Adverse Event (AE) 1 7 (26.9%) 10 (40.0%) 14 (53.8%) UTI 8 (30.8%) 7 (28.0%) 8 (30.8%) Fall 4 (15.4%) 6 (24.0%) 1 (3.8%) Covid - 19 5 (19.2%) 1 (4.0%) 2 (7.7%) Fatigue 2 (7.7%) 3 (12.0%) 1
Slide 16: Change in Iron Content by MRI (QSM)
75 mg BID 50 mg BID Region Week 52 Week 26 Week 52 Week 26 S. nigra ^ Putamen * Pallidum Compared to placebo: Iron content, No observable difference, ^ P = 0.025, * P = 0.08 Group - wise analysis • Iron increases in key regions over time in placebo > ATH434 • Evidence for iron accu
Slide 17: ATH434 Demonstrated Trends in Reduced Brain Atrophy
ATH434 Demonstrated Trends in Reduced Brain Atrophy Change from Baseline in Brain Volume – MSA Atrophy Index^ 26 weeks 52 weeks 17 - 0.6000 - 0.5000 - 0.4000 - 0.3000 - 0.2000 - 0.1000 0.0000 Placebo ATH434 50 mg BID ATH434 75 mg BID ^ Composite z - score of the putamen, globus pallidus, cerebellum
Slide 18: Summary and Conclusions
Summary and Conclusions 18 • ATH434 showed clinically significant efficacy in modifying disease progression • UMSARS I plus important secondary clinical outcomes • Baseline differences in disease severity and pathology likely explain different response in 50 mg and 75 mg treatment groups • ATH434 de
Slide 19: Acknowledgements
Acknowledgements 19 Institution Study Coordinator Investigator Country Groupe Hospitalier Pellegrin, Bordeaux Sandrine Villars Wassilios Meissner France Hôpital Universitaire Pitié Salpêtrière, Paris Carine Lefort Jean - Christophe Corvol Hôpital Pierre - Paul Riquet, Toulouse Nadera Ainaoui Olivier
Slide 20: Thank You
Thank You 20