Safety, Pharmacokinetics, And Pharmacodynamics Of A Clc-1 Inhibitor - A First-In-Class Compound That Enhances Muscle Excitability: A Phase I, Single- And Multiple-Ascending Dose Study

NMD670 is a first-in-class inhibitor of skeletal muscle-specific chloride channel ClC-1, developed to improve muscle weakness and fatigue in neuromuscular diseases. Preclinical studies show that ClC-1 inhibition enhances muscle excitability, improving muscle contractility and strength. We describe the first-in-human administration of ClC-1 inhibitor NMD670. In this randomized, double-blind, placebo-controlled study we evaluated safety, pharmacokinetics, and pharmacodynamics of single and multiple doses of NMD670 in healthy male and female subjects. Single-ascending doses were administered in a (partial) cross-over design; multiple-ascending doses were administered in a parallel design. Differences in pharmacokinetics between males/females and fed/fasted state were evaluated. Pharmacodynamic effects were evaluated using muscle velocity recovery cycles (MVRC), and analyzed using mixed effects modelling, with baseline as covariate. NMD670 was considered safe and well-tolerated. Symptoms of myotonia were observed at the highest dose levels. Moreover, NMD670 significantly increased the following MVRC parameters after a single dose of 1200mg compared to placebo: early supernormality (estimated difference (ED) 2.04; 95% confidence interval (CI) (0.379, 3.70); p=0.0242); early supernormality after 5 conditioning stimuli (ED 2.51; 95%CI (0.599, 4.41); p=0.0177; supernormality at 20 ms (ED 2.78; 95%CI (1.377, 4.181); p=0.0021. Importantly, the results of this study indicate pharmacological target engagement of NMD670 as ClC-1 inhibitor, at dose levels that were considered safe in healthy subjects. Firstly, because myotonia was an expected exaggerated on-target pharmacological effect. Secondly, because the effects on MVRC indicate increased muscle cell excitability. This study in healthy subjects indicates proof-of-mechanism and provides a solid base for translation to patients with neuromuscular diseases.