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

Abstract

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.

Figure 1

Schematic overview of the study design. The single‐ascending dose study followed a partial cross‐over design, the multiple‐ascending dose study followed a parallel design. Dose levels highlighted in gray indicate a different set‐up, namely: (i) subjects who received 800 mg NMD670 in fasted state, received NMD670 800 mg in fed state in the same randomization; (ii) subjects in Cohort 3 all received 1,200 mg and placebo in a full (as opposed to partial) cross‐over randomization; (iii) female subjects received only a single dose. Abbreviations: b.i.d., bis in diem/twice a day; q.d., quaque die/once a day.

Figure 2

Mean of NMD670 concentrations in plasma (ng/mL) for all single‐ascending dose levels, presented on a semi‐log scale. Sample size: n = 6 for 50, 100, 200, 400, 800 (fasted), 800 mg (fed), and 800 mg NMD670 (female); n = 15 for 1,200 mg NMD670; n = 1 for 1,600 mg NMD670.

Figure 3

Mean of NMD670 concentrations in plasma (ng/mL) for all multiple‐ascending dose levels, presented on a semi‐log scale on Day 1 (first day of dosing) and Day 10 (last day of dosing). Sample size: n = 6 for all dose levels, except for 200 mg NMD670 q.d. (Day 10) where n = 5.

Figure 4

Mean recordings of recovery cycles, as measured post‐dose for NMD670 1,200 mg (green) and placebo (gray). (a) Percentual latency change after one conditioning stimulus at different interstimulus intervals. (b) Upper graph: the percentual latency change after five conditioning stimuli at different interstimulus intervals; Lower graph: the difference in latency change, between five and one conditioning stimuli. The standard error is visualized in error bars. Parameters with statistically significant findings of NMD670 vs. placebo are visualized with dotted lines: 5ESN, early supernormality after 5 conditioning stimuli; ESN, early supernormality; SN20, supernormality at interstimulus interval 20 ms. This graph does not reflect the statistical analysis, because the statistical model includes baseline as a covariate.