P272 NMD670, a novel first-in-class muscle ClC-1 inhibitor, improves symptoms of myasthenia gravis: a randomized, single-dose, double-blind, placebo-controlled study

NMD670 is a novel first-in-class neuromuscular transmission enhancer working through selective inhibition of the skeletal muscle ClC-1 chloride ion channel, which is being developed for the treatment of patients with myasthenia gravis (MG) and other neuromuscular disorders. The objective of the study was to investigate safety and tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of NMD670 in patients with MG. This was a randomized, double-blind, placebo-controlled, three-way crossover study of two dose levels of NMD670 (400mg and 1200mg) and placebo. Pharmacodynamic outcomes were assessed pre- and post-dose (3-5h) on each of the three treatment days and included Quantitative Myasthenia Gravis (QMG) score and electrophysiological assessments. A total of 12 patients were enrolled and completed the study; mean age of 58yr (range: 36-78), 7 female patients, and a mean baseline QMG score of 9 points (SD: 3.6). NMD670 was safe and well tolerated. No serious or severe TEAEs were reported and the incidence of TEAEs was similar across treatment arms. Plasma concentrations increased with increasing dose. Time to maximal concentration was ∼2h and terminal half-life was ∼5h for both doses. Improvements in QMG total score and individual items were observed with NMD670 vs. placebo. The change from baseline vs. placebo for QMG total score [95%CI] was -1.5 points [-2.8;-0.1], p=0.03, for the overall NMD670 400mg treatment arm and -1.0 point [2.3,0.3], p=0.14, for the overall NMD670 1200mg treatment arm. The largest treatment effect observed 5h post-dose was of -1.7 points [-3.3;-0.2], p=0.02 for NMD670 400mg vs. placebo. Importantly, clinically relevant improvements on QMG of 2 points or more vs. placebo was achieved for 42-50% of patients dependent on dose level and timepoint. The QMG item of right-hand grip strength was improved overall by 1.4kg [ 0.8;3.6], p=0.19, for NMD670 400mg and 2.8kg [0.7;5.0], p=0.01, for NMD670 1200mg vs. placebo. Similar directional changes were observed in left hand grip strength, ability to keep leg outstretched, ptosis, double vision, and dysarthria. Changes in electrophysiological parameters further confirmed pharmacological target engagement. In conclusion, NMD670 was safe and well tolerated and showed statistically significant and clinically relevant improvements in QMG in patients with MG, despite mild baseline severity. These results represent the first proof-of-mechanism for ClC-1 inhibition in MG which warrants further investigation of NMD670 in MG patients with increased severity and in other neuromuscular diseases. NMD670 is a novel first-in-class neuromuscular transmission enhancer working through selective inhibition of the skeletal muscle ClC-1 chloride ion channel, which is being developed for the treatment of patients with myasthenia gravis (MG) and other neuromuscular disorders. The objective of the study was to investigate safety and tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of NMD670 in patients with MG. This was a randomized, double-blind, placebo-controlled, three-way crossover study of two dose levels of NMD670 (400mg and 1200mg) and placebo. Pharmacodynamic outcomes were assessed pre- and post-dose (3-5h) on each of the three treatment days and included Quantitative Myasthenia Gravis (QMG) score and electrophysiological assessments. A total of 12 patients were enrolled and completed the study; mean age of 58yr (range: 36-78), 7 female patients, and a mean baseline QMG score of 9 points (SD: 3.6). NMD670 was safe and well tolerated. No serious or severe TEAEs were reported and the incidence of TEAEs was similar across treatment arms. Plasma concentrations increased with increasing dose. Time to maximal concentration was ∼2h and terminal half-life was ∼5h for both doses. Improvements in QMG total score and individual items were observed with NMD670 vs. placebo. The change from baseline vs. placebo for QMG total score [95%CI] was -1.5 points [-2.8;-0.1], p=0.03, for the overall NMD670 400mg treatment arm and -1.0 point [2.3,0.3], p=0.14, for the overall NMD670 1200mg treatment arm. The largest treatment effect observed 5h post-dose was of -1.7 points [-3.3;-0.2], p=0.02 for NMD670 400mg vs. placebo. Importantly, clinically relevant improvements on QMG of 2 points or more vs. placebo was achieved for 42-50% of patients dependent on dose level and timepoint. The QMG item of right-hand grip strength was improved overall by 1.4kg [ 0.8;3.6], p=0.19, for NMD670 400mg and 2.8kg [0.7;5.0], p=0.01, for NMD670 1200mg vs. placebo. Similar directional changes were observed in left hand grip strength, ability to keep leg outstretched, ptosis, double vision, and dysarthria. Changes in electrophysiological parameters further confirmed pharmacological target engagement. In conclusion, NMD670 was safe and well tolerated and showed statistically significant and clinically relevant improvements in QMG in patients with MG, despite mild baseline severity. These results represent the first proof-of-mechanism for ClC-1 inhibition in MG which warrants further investigation of NMD670 in MG patients with increased severity and in other neuromuscular diseases.