Alterity Therapeutics presents data from ATH434 Phase 2 trial

Alterity Therapeutics (ATHE) announced that data from the ATH434-201 randomized, double-blind Phase 2 clinical trial in Multiple System Atrophy was featured at the 2025 International Congress of Parkinson’s Disease and Movement Disorders that took place in Honolulu, HI, USA. ATH434 Slowed Disease Progression in a Phase 2 Study in Multiple System Atrophy: Dr. Stamler’s oral platform presentation provided results from the ATH434-201 trial with new analyses related to orthostatic hypotension, one of the most debilitating MSA symptoms. Clinical endpoints were analyzed in the clinical analysis population that included patients randomized to treatment who had at least one post-baseline assessment of the key clinical endpoint, the UMSARS I. There were three arms in the trial comparing two dose levels of ATH434 50 mg and 75 mg to placebo, all of which were administered twice daily. Treatment with ATH434 resulted in a clinically significant reduction in disease severity relative to placebo on the modified UMSARS I activities of daily living scale at both dose levels, with a 48% relative treatment effect at the 50 mg dose and a 30% relative treatment effect at the 75 mg dose at 52 weeks. UMSARS I is the key outcome measure of interest to regulatory authorities such as the FDA. The presentation described additional analysis regarding OH, which is a form of low blood pressure that occurs when a person stands up from a sitting or lying position, resulting in symptoms like dizziness, lightheadedness, or fainting. It is defined as a sustained decrease in systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of at least 10 mm Hg within three minutes of standing. Because baseline data revealed that severe OH was substantially higher in the 75 mg group at enrollment, a new analysis of the USMARS I was conducted that included the baseline OH systolic blood pressure change as a covariate. When this variable was included in the analysis of the UMSARS I at 52 weeks, the efficacy signal in 75 mg dose group strengthened to -2.8 points for a relative treatment effect of 35%. This baseline difference in severe OH largely explains the different responses in 50 mg and 75 mg treatment groups. Notably, ATH434 demonstrated a beneficial effect on OH symptoms as assessed with the OH Symptom Assessment, a patient reported outcome. On this scale, placebo patients worsened on average by approximately 6 points over 52 weeks whereas the 50 mg and 75 mg groups were stable over the same period of time. Additional efficacy assessments showed improvement consistent with the UMSARS I findings. The Clinical Global Impression of Severity Scale3 demonstrated improvement compared to placebo at both dose levels, with difference at 50 mg achieving statistical significance. Increased activity in the outpatient setting, as measured by wearable movement sensors, was observed at both dose levels as compared to placebo, with clinically meaningful improvements in step count, total walking time, bouts of walking, and total standing time. Regarding neuroimaging data in 61 participants, ATH434 demonstrated target engagement by reducing iron accumulation at both dose levels compared to placebo in the globus pallidus, and in the putamen and substantia nigra at the 50 mg dose level. In addition, ATH434 demonstrated trends in reducing brain atrophy at both dose levels compared to placebo. ATH434 was well tolerated with similar adverse event rates compared to placebo and no serious or severe adverse events attributed to ATH434. Relationship Between Alpha-Synuclein Aggregation Profiles, Imaging Biomarkers, and Disease Severity in a Phase 2 Study of ATH434 in MSA: As a Parkinsonian disorder, MSA shares several symptoms with Parkinson’s disease that can hamper accurate diagnoses and differentiation between the two diseases. Alterity’s ATH434-201 trial provides an opportunity to compare alpha-synuclein aggregation profiles, imaging biomarkers, and disease severity at baseline to inform future patient selection. In Dr. Bradbury’s presentation the imaging biomarkers utilized in the ATH434-201 trial presented supportive features of MSA in 96.1% of the 77 enrolled subjects as compared to 78.9% for alpha-synuclein aggregation profiles in cerebrospinal fluid alone. Of the 11 participants with an alpha-synuclein aggregation profile consistent with Parkinson’s disease and/or dementia with Lewy bodies, 80% demonstrated supportive imaging features of MSA. Two of the 5 participants without evidence of alpha-synuclein aggregation had imaging consistent with MSA. Therefore, the presentation concludes that a multimodal approach combining alpha-synuclein aggregation profiles with clinical and imaging data may enhance diagnostic accuracy in MSA. Differences Between Clinical and Imaging Phenotypes in Phase 2 Study of ATH434 in Multiple System Atrophy: Dr. Trujillo’s presentation assessed the two main clinical phenotypes of MSA in Alterity’s ATH434-201 trial: the parkinsonian and cerebellar. The clinical subtypes were assigned by the site investigators and were compared with multiple neuroimaging assessments including MRI, quantitative susceptibility mapping to measure brain iron, and automated segmentation to measure brain atrophy. The results show that quantitative MRI largely complements clinical classification, reinforcing its role as an objective biomarker. The observed discordance suggests MRI may capture underlying pathology not evident clinically, highlighting its value in refining diagnosis and tracking disease evolution.