NMD670 is an inhibitor of skeletal muscle-specific chloride channel protein 1 (ClC-1) that enhances neuromuscular transmission and is being developed for the treatment of neuromuscular diseases, including myasthenia gravis (MG), in which neuromuscular junction (NMJ) transmission is impaired. Despite available treatments, MG patients continue to experience muscle weakness and fatigue.
In a recent proof-of-mechanism study in 12 MG patients with mild symptoms (baseline QMG of 9 +/- 3.6), two single doses of NMD670 (400mg and 1200mg) and a single dose of placebo was administered in a three-way cross over fashion. Recently published data showed significant improvements in the QMG total score with NMD670 versus placebo. A post-hoc responder analysis was subsequently made to better characterize the responders and understand the clinically meaningfulness of the data.
The post hoc responder analysis revealed that 42-50% achieved clinically meaningful improvement of 2 points or more with NMD670 versus placebo regardless of dose. A similar trend was observed for the QMG item of grip strength where responder rates between 25-67% were noted dependent on dose and post-dose timepoint. A sensitivity responder analysis revealed that 9 out of 12 patients achieved at least one point improvement with NMD670 versus placebo.
The baseline QMG total score predicted the change from baseline in the QMG total score with NMD670 versus placebo (r= -0.47, p=0.02). When only including patients with baseline QMG scores of 6 or more, average improvements of -3.5 and -1.7 points for 400mg and 1200mg doses were observed. Similar trends were noted between baseline QMG total score and the change from baseline versus placebo on such items as hand grip strength and leg outstretch.
In conclusion, high responder rates were noted with NMD670 despite a relatively mild phenotype of patients enrolled. Worse disease severity was associated with a larger response, indicating that more pronounced treatment benefits with NMD670 may be expected in a more severe population.