Safety, Pharmacokinetics, and Pharmacodynamics of a First-in-Class ClC-1 Inhibitor to Enhance Muscle Excitability: Phase I Randomized Controlled Trial.

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, randomized, double-blind, placebo-controlled study, which evaluated the safety, pharmacokinetics, and pharmacodynamics of single and multiple doses of NMD670 in healthy male and female subjects. Single-ascending doses (50-1,600 mg) were administered in a (partial) cross-over design; multiple-ascending doses (200-600 mg q.d.; 400 mg b.i.d.) were administered in a parallel design. Differences in pharmacokinetics between males/females and fed/fasted states were evaluated. Pharmacodynamic effects were evaluated using muscle velocity recovery cycles (MVRC) and analyzed using mixed-effects modeling. NMD670 was generally safe and well-tolerated in healthy subjects, with the only dose-related adverse event being myotonia occurring at the highest dose levels tested (single dose of 1,200, and 1,600 mg). Moreover, NMD670 significantly increased the following MVRC parameters after a single dose of 1,200 mg compared with 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 at well-tolerated dose levels in healthy subjects; firstly, because myotonia was an expected exaggerated on-target pharmacological effect, and 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.