Fasudil attenuates disease spreading in ALS - a post-hoc analysis of the ROCK-ALS trial.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the spread of muscle weakness across body regions. The ROCK-ALS trial was a multicenter, randomized, double-blind, placebo-controlled phase 2 study assessing the safety, tolerability, and efficacy of the Rho kinase inhibitor fasudil as an add-on to riluzole in ALS patients. A key exploratory objective was to evaluate fasudil's effect on the spread of muscle weakness using the Motor Unit Number Index (MUNIX), a quantitative electrophysiological biomarker of lower motor neuron integrity. MUNIX was assessed in 10 muscles (5 on each body side) at baseline, day 26, day 90, and day 180. Correlations were assessed between baseline serum biomarkers-neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP)-and baseline clinical measures (ALSFRS-R, slow vital capacity, and MUNIX sum scores) as well as their monthly rates of change, to explore potential prognostic relationships. For the analysis of disease spreading, muscles were classified as newly affected based on MUNIX decline relative to contralateral values or prior measurements, using thresholds of ≥10%, ≥20%, or ≥30%. 118 participants were included in the intention-to-treat population, 78 had full MUNIX datasets at baseline and 67 had at least one follow-up. Baseline MUNIX sum scores correlated with subsequent ALSFRS-R decline, suggesting prognostic value. Additionally, at day 90, fasudil significantly reduced the number of newly affected muscles compared to placebo in a dose dependent manner over different thresholds. These findings support MUNIX as a sensitive biomarker for monitoring disease spreading and demonstrate that fasudil may attenuate the progression of lower motor neuron involvement in ALS.