Objective: Describe baseline fluid and neuroimaging biomarker data of an early MSA study population

Background: MSA is a rapidly progressive neurodegenerative disorder characterized by aggregated α‑synuclein and excess iron in the putamen (PT), globus pallidus (GP), substantia nigra (SN) and dentate nucleus of the cerebellum (DN). There are no disease modifying treatments approved. ATH434 is a moderate affinity iron chaperone which inhibits α‑synuclein aggregation and reduces oxidative stress by redistributing excess labile iron for cellular export or sequestration.

Method: In this randomized, double-blind, placebo-controlled, 3-arm study, patients with clinically probable MSA received ATH434 (2 dose levels) or placebo for 12 months. Inclusion criteria required clinical evidence of parkinsonism, autonomic impairment, and ataxia and/or pyramidal signs, less than 4 years of motor symptoms and elevated plasma neurofilament light chain (NfL). Severe gait or swallowing impairment was exclusionary. The primary endpoint is change in brain iron content in affected areas of basal ganglia. Motor impairment and functional performance were assessed with the Natural History and Neuroprotection in Parkinson Plus Syndromes Scale (NNIPPS) and Unified MSA Rating Scale-Part I (UMSARS-I), respectively. Alpha-synuclein aggregation was assessed with a seed amplification assay on CSF and 3T MRI was used to measure iron content and volume of subcortical structures.

Results: Of 77 patients enrolled, 58.4% were male, with a mean (SD) age of 63 (6.4) years, motor symptom duration of 2.5 (0.8) years, UMSARS-I scores of 18.6 (5.0) and NNIPPS motor scores of 52.9 (17.8). Plasma NfL levels were 31.4 (11.4) pg/mL. Increased iron content, based on comparison to age-matched controls, was determined on a patient-specific basis, with elevations noted in the SN (95% of patients), PT (77%), GP (69%), and DN (51%). Subcortical volume data and α-synuclein aggregation-defined diagnostic determinations will be presented.

Conclusion: Clinically probable MSA patients have elevated plasma NfL and significantly increased iron in multiple brain regions, with predominant accumulation in the SN, PT and GP. ATH434 is being evaluated as a disease modifying treatment based on its ability to redistribute excess iron and reduce α-synuclein aggregation in the CNS.

These data were presented at the AAN Annual Meeting on 4/14/24

« Back to 2024 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/a-phase-2-study-of-ath434-a-novel-inhibitor-of-%ce%b1-synuclein-aggregation-for-the-treatment-of-multiple-system-atrophy/