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 approved disease modifying treatments. ATH434 is a moderate affinity iron chaperone which inhibits α-synuclein aggregation and reduces oxidative injury by redistributing excess labile iron.

In this randomized, double-blind, placebo-controlled, 3-arm study, patients received oral ATH434 (75 or 50 mg bid) or placebo for 12 months. Participants had parkinsonism, autonomic impairment, ataxia and/or pyramidal signs, less than 4 years of motor symptoms and elevated plasma neurofilament light chain (NfL). The primary endpoint was change in iron content in SN. Motor and functional performance were assessed with the NNIPPS Parkinson Plus Syndromes Scale (PPS) and Unified MSA Rating Scale-Part I (UMSARS-I), respectively. NfL was measured with an ultrasensitive Simoa assay. Iron content and volume of subcortical structures were measured with 3T MRI and compared to age-matched controls.

Of 77 patients enrolled, 58.4% were male, mean(SD) age was 63(6.4) years, motor symptom duration was 2.5(0.8) years, UMSARS-I scores were 18.6(5.0), PPS motor scores were 52.9(17.8), and NfL was 31.4(11.4) pg/mL. Increased iron content was observed in the SN (95%), PT (77%), GP (69%), and DN (51%). Subcortical volume was decreased in PT (62%), brainstem (53%), GP (40%) and cerebellum (31%).

Early MSA patients have elevated plasma NfL and increased iron in multiple brain regions, most commonly in the SN. Reduced subcortical volume was most frequent in the PT. ATH434 is a potential disease modifying treatment based on its ability to redistribute excess labile iron and reduce α-synuclein aggregation in the CNS. Efficacy, biomarker and safety data will be available in Q12025 and will be presented.