Category: MSA, PSP, CBS: Clinical Trials
Objective: Evaluate efficacy and biomarker response of ATH434 in MSA, including CSF neurofilament light chain (NfL), a prespecified but previously unreported analysis using this disease-severity covariate
Background: MSA is an aggressive neurodegenerative disorder characterized by aggregated α-synuclein and excess iron. ATH434 is a moderate-affinity iron chaperone that inhibits α-synuclein aggregation and reduces oxidative injury by redistributing excess labile iron. CSF NfL is an established prognostic biomarker of clinical decline in MSA.
Method: 77 participants received ATH434 75 mg BID, 50 mg BID, or placebo (1:1:1) for 12 months and 61 had post-baseline MRI and UMSARS. Iron content was quantified by Quantitative Susceptibility Mapping (QSM) MRI in substantia nigra, basal ganglia, and cerebellum. Clinical severity was assessed using the modified UMSARS-I. Analysis included baseline CSF NfL as a covariate.
Results: Mean(SD) age was 63(6.4) years; motor symptom duration 2.5(0.8) years; baseline UMSARS-I 15.2(4.6); plasma NfL 31.4(11.4) pg/mL, and CSF NfL 3,822(1,869) pg/mL. Higher baseline CSF NfL predicted greater functional decline at Week 52, with each 1,000 pg/mL increase associated with approximately 0.9 additional points of worsening on UMSARS-I (β = 0.90, p = 0.033). ATH434 slowed functional decline at Week 52 at 50 mg (−4.64, p=0.032; ~52% slowing) and 75 mg (-2.87, p=0.179); combined active arms (−3.75, p=0.047). QSM showed reduced iron accumulation in putamen and globus pallidus with ATH434 vs. placebo; dentate nucleus iron signal increased in ATH434 arms vs. placebo at Week 52.
Conclusion: These data further support that ATH434 50 and 75 mg BID slow functional decline in MSA, with a significant effect at 50 mg and a consistent trend at 75 mg. QSM findings are consistent with the iron-chaperone mechanism of ATH434. Increased dentate iron is hypothesized to reflect glymphatic redistribution. ATH434 is a promising disease-modifying therapy for MSA.
To cite this abstract in AMA style:
D. Claassen, C. Wong, P. Trujillo, M. Bradbury, C. Lucas, D. Stamler. Results from a Randomized, Double-Blind, Placebo-Controlled Study of ATH434 in MSA using CSF NfL as a Covariate [abstract]. Mov Disord. 2026; 41 (suppl 1). https://www.mdsabstracts.org/abstract/results-from-a-randomized-double-blind-placebo-controlled-study-of-ath434-in-msa-using-csf-nfl-as-a-covariate/. Accessed October 1, 2026.« Back to 2026 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/results-from-a-randomized-double-blind-placebo-controlled-study-of-ath434-in-msa-using-csf-nfl-as-a-covariate/