A Phase 2 Study of ATH434, a Novel Inhibitor of α-synuclein Aggregation, for the Treatment of Multiple System Atrophy (MSA)
David Stamler1, Cynthia Wong1, Paula Trujillo Diaz2, Margaret Bradbury1, Christine Lucas1, Daniel Claassen2
1Alterity Therapeutics, 2Vanderbilt University Medical Center
Objective:
Describe baseline biomarker, disease-related and demographic data of ATH434-201 study population.
Background:
MSA is a rapidly progressive neurodegenerative disorder characterized by aggregated α‑synuclein and excess labile iron in the putamen, globus pallidus (GP), substantia nigra (SN) and dentate nucleus of the cerebellum (DN). There are no disease modifying treatments available. ATH434 inhibits α‑synuclein aggregation and reduces oxidative stress by redistributing excess iron across membranes in the CNS.
Design/Methods:
In this randomized, double-blind, placebo-controlled, 3-arm study, patients with clinically probable MSA receive ATH434 (2 dose levels) or placebo for 12 months. Inclusion criteria required clinical evidence of parkinsonism, autonomic impairment, and ataxia and/or pyramidal dysfunction, with less than 4 years of motor symptoms. Severe gait and swallowing impairments were exclusionary. The primary endpoint is change in brain iron content in affected areas of basal ganglia. Motor severity and function were assessed with the Parkinson Plus Scale (PPS) and Unified MSA Rating Scale-Part I (UMSARS, items 1-10), respectively. Plasma neurofilament light chain (NfL) was quantified for comparison to reported healthy control values. 3T MRI was employed and iron content was measured using quantitative susceptibility mapping (QSM) methods.
Results:
Sixty-five patients were enrolled. Baseline demographic and biomarker descriptors [Mean(SD)] include 63(6.4) years of age, 2.7(0.8) years of motor symptoms, and 61.5% male. UMSARS part 1 score was 14.2(4.5) and PPS motor score was 53.1(17.8). Plasma NfL levels were 30.3(10.4) pg/mL. Increased iron content, based on comparison to age-matched control data, was determined on a patient-specific level, with elevations noted in the putamen (69% of patients), GP (82%), SN (95%) and DN (55%).
Conclusions:
Clinically probable MSA patients have elevated plasma NfL and significantly increased iron in multiple brain regions, with predominant accumulation in the SN and GP. ATH434 will be evaluated as a disease modifying treatment based on its ability to redistribute excess iron in the CNS.