Dosing has commenced in the Phase 2 SYNAPSE-CMT trial (NCT06482437) to investigate the therapeutic potential of NMD670 in patients with Charcot-Marie-Tooth (CMT) disease. NMD670, developed by NMD Pharma, is an investigational small molecule inhibitor targeting the skeletal muscle-specific chloride ion channel 1 (ClC-1). The FDA recently cleared the company’s investigational new drug application, paving the way for this trial.
The SYNAPSE-CMT study is a randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy, safety, and tolerability of NMD670 in 80 adults with genetically confirmed CMT1 or CMT2 subtypes. Participants will receive twice daily oral doses of NMD670 or placebo over a 21-day treatment period. The primary outcome measures include changes in the 6-minute walk test (6MWT), time to complete the 10-meter walk/run test (10MW/R), and time to complete the timed-up-and-go test (TUG).
"Patients with CMT are very excited about entering into this study. This is the only clinical study with a clinically feasible treatment to address the muscle weakness and fatigue with a pharmaceutical therapy at the moment," said Yessar Hussain, MD, a neuromuscular specialist at Austin Neuromuscular Medicine. "The fact that this study enrolls patients with all types of CMT 1 and 2 is also encouraging and motivating to the community. I am happy to be involved in this exciting clinical study."
Secondary outcomes of the trial include changes in the CMT Functional Outcome Measure total score, Overall Neuropathy Limitation Scale total score, CMT Health Index total score and individual domains, and SF-36 total score. Safety outcomes being monitored include the incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, clinically significant abnormalities, and significant ECG abnormalities.
NMD Pharma's prior observational study, ESTABLISH, indicated that neuromuscular junction (NMJ) transmission deficits are an underappreciated characteristic of CMT. This study compared electrophysiological assessments and clinical testing between 21 CMT patients (types 1 and 2) and 10 healthy, age-matched individuals. The level of NMJ transmission deficit correlated with disease severity, as assessed by clinical measurements of muscle strength and motor function. The ESTABLISH study also provided data on the tolerability and reliability of clinical and electrophysiological outcomes, aiding in the selection of relevant outcomes for future clinical trials.
According to Thomas Holm Pedersen, chief executive officer at NMD Pharma, "As a highly debilitating disease with no currently approved medicines or a cure, there is an urgent need for new therapeutic approaches to help improve the quality of life of patients with CMT and their families. NMD670 has demonstrated promising clinical results in a proof-of-mechanism study in patients with NMJ dysfunction in the rare neuromuscular disease myasthenia gravis, and we are confident that our novel therapeutic approach has the potential to also provide benefit to those affected by CMT."
Prior Phase 1 trials evaluating NMD670 in healthy volunteers demonstrated that the drug was generally safe and well-tolerated. Myotonia was observed at the highest dose levels but resolved spontaneously within hours and was not considered a safety hazard. These Phase 1 results, published in Clinical Pharmacology & Therapeutics, support the ongoing Phase 2 trials.
SYNAPSE-CMT is the third ongoing trial for NMD670, following a Phase 2 study in adults with spinal muscular atrophy (SMA) type 3 and a Phase 2b study in patients with generalized myasthenia gravis (gMG).
