Objective: Evaluate the efficacy and safety of ATH434 treatment in individuals with MSA

Background: Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder without approved therapy. ATH434 is an orally administered, moderate affinity iron chaperone which inhibits α‑synuclein aggregation and reduces oxidative injury by redistributing excess labile iron in the CNS.

Method: In this randomized, double-blind, placebo-controlled, 3-arm Phase 2 trial, patients received 12 months treatment (1:1:1) with oral ATH434 (50 or 75 mg bid) or placebo. Participants had clinically probable or clinically established MSA, motor symptoms ≤4 years and elevated plasma neurofilament light chain (NfL). The modified Unified MSA Rating Scale, Part I (UMSARS I) and the 75th percentile of iron content in the substantia nigra (SN) were the key secondary and primary endpoints, respectively. The change from baseline to Week 52 in UMSARS I was analyzed using an ANCOVA model and the corresponding change in iron content was analyzed using an MMRM model.

Results: The mean (SD) baseline values for 77 enrolled patients were: age 62.8 (6.5) years, motor symptom duration 2.5 (0.9) years, modified UMSARS I score 15.5 (4.5), plasma NfL 33.1 (10.1) pg/mL, and were similar across groups; higher rates of striatonigral degeneration on MRI and severe orthostatic hypotension were observed in the 75 mg group compared to the 50 mg group. In the full analysis set (n=71), the LS mean difference in UMSARS I score from Baseline to week 52 for the 50 and 75 mg groups vs placebo was ‑3.8 (p=0.02) and ‑2.4 (p=0.16) points, respectively, representing disease slowing of 48% and 30%, respectively. Reduced iron concentration was observed in the SN, putamen, and globus pallidus (GP) at 50 mg and in the GP at 75 mg. ATH434 was well-tolerated with similar adverse event rates in the 50 and 75 mg treatment groups and placebo. No serious AEs were assessed as related to ATH434 treatment.

Conclusion: Treatment with ATH434 50 mg and 75 mg bid for one year led to robust efficacy on the modified UMSARS I activities of daily living scale with a favorable safety profile.  ATH434 demonstrated target engagement by stabilizing or reducing iron content in MSA affected areas. ATH434 is a potential disease modifying treatment based on its ability to redistribute excess labile iron, reduce α‑synuclein aggregation and reduce oxidative injury.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/ath434-slowed-disease-progression-in-a-phase-2-study-in-multiple-system-atrophy/