Objective: To investigate the relationships between α-synuclein aggregation profiles, imaging biomarkers, and UMSARS I scores in the ATH434-201 Phase 2 study.

Background: Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder without approved therapy. Patient selection in clinical trials is hampered by significant overlap in symptoms between MSA and PD. Imaging and fluid biomarkers may increase diagnostic accuracy. Categorizing subjects by α‑synuclein (α-syn) aggregation profiles with a seed amplification assay (SAA) is a promising approach. While SAAs report >90% accuracy in PD based on multiple studies, data in MSA are comparatively sparse¹. In the ATH434-201 phase 2 study, 12 months treatment with ATH434 slowed disease progression by 29-48% on the Unified MSA Rating Scale Part I (UMSARS I). ATH434‑201 provides an opportunity to compare SAA profiles, imaging biomarkers, and disease severity.

Method: 77 patients with clinically probable or clinically established MSA² and motor symptoms ≤ 4 years were enrolled. 3T MRI was used to assess volume and iron content (by QSM) in MSA-affected subcortical regions. SAA aggregation profiles in 76 subjects that provided baseline CSF samples were classified as MSA, PD/DLB, or not detected (ND) using the Amprion SAAmplify™-ɑSYN assay, supplemented with a research use only SAA assay. Baseline (n=76) and end-treatment (n=71) UMSARS I scores were analyzed by SAA category.

Results: In this MSA population, 96% had radiographic evidence of MSA; 78.9% had MSA-SAA profiles, 14.5% had PD/DLB profiles, and 6.6% were ND. Of PD/DLB-SAA subjects, 81.8% (9/11) had radiographic evidence of MSA, either olivopontocerebellar atrophy (marked brainstem and cerebellar atrophy with dentate nucleus and SN iron deposition) or striatonigral degeneration (atrophy and iron deposition in SN, putamen, and globus pallidus). UMSARS I scores in PD/DLB-SAA subjects were similar to those of MSA-SAA subjects at Baseline (PD/DLB:16-23; MSA:10-24) and Week 52 (PD/DLB: 24-36; MSA: 16-37).

Conclusion: In a clinically defined Phase 2 MSA population, approximately 80% of patients had concordant SAA data. Over 80% of MSA patients with a PD/DLB SAA profile had radiographic evidence of MSA. These findings confirm the need to combine α-syn SAA results in a multimodal approach including clinical and neuroimaging data to improve the diagnostic accuracy of MSA.

References: 1. Ma, Y et al. Lancet Neurology, 23:1225-37 (2024).
2. Wenning, G et al. Mov. Disord. 37, No. 6, 1131-1148 (2022).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/relationship-between-alpha-synuclein-aggregation-profiles-imaging-biomarkers-and-disease-severity-in-a-phase-2-study-of-ath434-in-msa/