Abstract Details

Title A Phase 2 Study of ATH434, a Novel Inhibitor of a-synuclein Aggregation, for the Treatment of Multiple System Atrophy (MSA)

Topic Movement Disorders

Presentation(s) P2 - Poster Session 2 (11:45 AM-12:45 PM)

Poster/Presentation
Number 3-004

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.

Authors/Disclosures
David A. Stamler, MD (Alterity Therapeutics) PRESENTER	Dr. Stamler has received personal compensation for serving as an employee of Alterity Therapeutics. Dr. Stamler has stock in Alterity Therapeutics.
Cynthia Wong	Cynthia Wong has received personal compensation for serving as an employee of Alterity Therapeutics. An immediate family member of Cynthia Wong has received personal compensation for serving as an employee of RefleXion Medical. Cynthia Wong has stock in Teva. An immediate family member of Cynthia Wong has stock in 10x Genomics.
Paula Trujillo Diaz	Paula Trujillo Diaz has nothing to disclose.
Margaret Bradbury (Alterity Therpeutics)	Margaret Bradbury has received personal compensation for serving as an employee of Alterity Therapeutics. The institution of Margaret Bradbury has received research support from Alterity Therapeutics.
Christine Lucas (Alterity Therapeutics Ltd)	Christine Lucas has received personal compensation for serving as an employee of Alterity Therapeutics, Inc.
Daniel O. Claassen, MD, FAAN (Vanderbilt University Medical Center)	Dr. Claassen has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Alterity. Dr. Claassen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lundbeck. Dr. Claassen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Teva. Dr. Claassen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for AskBio. Dr. Claassen has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for University of Michigan. Dr. Claassen has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Cognition Therapeutics . Dr. Claassen has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Amylyx. The institution of Dr. Claassen has received research support from NIH. The institution of Dr. Claassen has received research support from CHDI. The institution of Dr. Claassen has received research support from HDSA. The institution of Dr. Claassen has received research support from Department of Defense. The institution of Dr. Claassen has received research support from CHDI.

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