ATH434 reduced disease progression on the modified UMSARS Part I at 52 weeks with a 48% relative treatment effect at 50 mg (p=0.02, uncorrected) and 30% at 75 mg versus placebo in a randomized Phase 2 trial of MSA (clinical analysis population n=71). After adjusting for a baseline imbalance in severe orthostatic hypotension, the 75 mg arm’s effect strengthened to a 35% relative treatment effect (-2.8 points). Orthostatic Hypotension Symptom Assessment scores worsened by about six points on placebo but remained stable on both ATH434 doses over one year. Safety was comparable to placebo with no severe adverse events attributed to the drug. Imaging showed reduced iron accumulation in disease-relevant regions, and wearable sensors captured increases in real-world mobility.
Alterity Therapeutics presented these data and new analyses from its double-blind Phase 2 study at the International Congress of Parkinson’s Disease and Movement Disorders. The three-arm study randomized 77 participants to 50 mg BID, 75 mg BID, or placebo for 12 months. Beyond the UMSARS signal and OH stabilization, the 50 mg dose reached significance on the Clinical Global Impression of Severity (p=0.009). MRI-based quantitative susceptibility mapping indicated target engagement, with reductions in iron in the globus pallidus at both doses and in the putamen and substantia nigra at 50 mg. Separate presentations from the program highlighted diagnostic performance of multimodal measures: imaging supported an MSA phenotype in 96% of enrolled subjects versus 79% for CSF α‑synuclein aggregation alone, with quantitative MRI showing 90% concordance with clinical subtyping and capturing discordant biology in 10%.
Strategically, the company is using this mid-stage dataset to set the contours of a registrational plan in a rare, high-unmet-need indication with no approved disease-modifying therapies. Two choices will define the Phase 3 posture: dose selection after an apparent efficacy-safety balance favors 50 mg on unadjusted analyses, and an endpoint strategy that leans into functional ADL change on UMSARS I while elevating OH symptom stabilization and digital mobility readouts as supportive evidence of clinical benefit. The covariate-adjusted analysis addresses an enrollment imbalance but also underscores the need for tighter baseline control of autonomic dysfunction in the next study. The imaging package and CSF α‑syn readouts point to an enrichment approach aimed at reducing diagnostic heterogeneity and misclassification that can dilute the signal in MSA.
For sites, the operational footprint is nontrivial: serial MRI with susceptibility mapping, potential CSF sampling, and deployment of wearables demand standardized workflows, imaging core coordination, and patient adherence support. CROs and vendors in imaging, central reads, and digital endpoints stand to be integral to execution, while regulators will scrutinize the modified UMSARS construct, multiplicity across analyses, and the clinical meaning of OH stabilization alongside functional measures. Sponsors watching MSA as an entry point into synucleinopathies will note the feasibility of integrating multimodal diagnostics to tighten cohorts, a tactic that could reduce sample-size needs but may constrain enrollment velocity and geographic reach.
Next, the field will look for a Phase 3 protocol that clarifies primary endpoint hierarchy, co-primary or key secondary roles for OH PROs, durability expectations beyond 52 weeks, and whether imaging biomarkers will be prospectively positioned for enrichment or as supportive pharmacodynamic evidence. Dose selection will be a litmus test of confidence in covariate-adjusted findings versus the cleaner 50 mg signal. With Fast Track and Orphan status in hand, a Breakthrough Therapy pathway could be in play if confirmatory data hold, but small-sample, uncorrected p-values and reliance on modified scales raise replication risk. Watch for site mix with advanced imaging capabilities, tighter baseline autonomic criteria, and pre-specified digital measures that translate into decision-relevant outcomes.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
