Wolff Andreas W, Leha Andreas, Koch Jan C, Demleitner Antonia F, Neuwirth Christoph, Friede Tim, Weber Markus, Lingor Paul
Clinical Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany.
medRxiv. 2025 Sep 4:2025.09.02.25334770. doi: 10.1101/2025.09.02.25334770.
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.
肌萎缩侧索硬化症（ALS）是一种进行性神经退行性疾病，其特征是肌肉无力在身体各部位扩散。ROCK-ALS试验是一项多中心、随机、双盲、安慰剂对照的2期研究，评估Rho激酶抑制剂法舒地尔作为利鲁唑附加药物在ALS患者中的安全性、耐受性和疗效。一个关键的探索性目标是使用运动单位数量指数（MUNIX）评估法舒地尔对肌肉无力扩散的影响，MUNIX是一种评估下运动神经元完整性的定量电生理生物标志物。在基线、第26天、第90天和第180天对10块肌肉（身体两侧各5块）进行MUNIX评估。评估基线血清生物标志物神经丝轻链（NfL）和胶质纤维酸性蛋白（GFAP）与基线临床指标（ALSFRS-R、慢肺活量和MUNIX总分）之间的相关性，以及它们的每月变化率，以探索潜在的预后关系。对于疾病扩散分析，根据MUNIX相对于对侧值或先前测量值的下降情况，将肌肉分类为新受影响的肌肉，使用的阈值为≥10%、≥20%或≥30%。意向性治疗人群包括118名参与者，78名在基线时有完整的MUNIX数据集，67名至少有一次随访。基线MUNIX总分与随后的ALSFRS-R下降相关，提示其具有预后价值。此外，在第90天，与安慰剂相比，法舒地尔在不同阈值下以剂量依赖的方式显著减少了新受影响肌肉的数量。这些发现支持MUNIX作为监测疾病扩散的敏感生物标志物，并表明法舒地尔可能减缓ALS中下运动神经元受累的进展。
