To evaluate efficacy of ATH434, a novel iron chaperone that reduces α-synuclein aggregation by redistributing excess brain iron using the Multiple System Atrophy Combined Outcome Assessment (MuSyCA) 

The Unified MSA Rating Scale (UMSARS) has shown limited sensitivity for detecting treatment effects, particularly in early-stage MSA trials. MuSyCA is a novel composite endpoint (range 0-44) combining the most clinically relevant and responsive items from UMSARS Parts I and II.

This randomized, double-blind, placebo-controlled trial enrolled adults aged 30-75 years with clinically probable MSA, motor symptoms ≤4 years, elevated brain iron on MRI, and plasma neurofilament light ≥16.5 pg/mL. Participants were randomized 1:1:1 to ATH434 50mg or 75mg twice daily, or placebo for 52 weeks. Change in MuSyCA score from baseline to weeks 26 and 52.

71 participants were analyzed (placebo n=22, 50mg n=25, 75mg n=24; mean age 62.6 years, 58% male). At Week 26, placebo participants progressed by 6.1 (1.2) points whereas ATH434 50mg and 75mg demonstrated treatment effects of -2.2 (1.6) points (p=0.166) and -2.7 (1.6) points (p=0.099), respectively. At Week 52, placebo increased 10.0 (1.9) points from baseline. ATH434 50mg slowed progression to 5.7 (1.7) points with treatment effect of -4.0 (1.9) points (p=0.0335), representing 41% reduction in functional decline. The 75mg dose showed treatment effect of -1.9 (1.9) points (p=0.322).

MuSyCA, a novel composite scale, demonstrated superior sensitivity to disease progression compared to traditional measures, with robust detection of functional decline over 52 weeks. These results establish MuSyCA as an improved outcome measure with enhanced ability to track disease progression in MSA trials.

Reference: Kaufmann H, Palma JA, Millar Vernetti P, et al for the MuSyCA Working Group. Multiple System Atrophy Combined Outcome Assessment (MuSyCA): Process, format, and validation plan (Clinical Autonomic Research, in Press)