New Phase 2 SYNAPSE-CMT Study to Test Effects of NMD670 in Charcot-Marie-Tooth Disease Type 1 and 2

Yessar Hussain, MD

Dosing has begun for a new phase 2 trial, dubbed SYNAPSE-CMT (NCT06482437) that will assess the therapeutic potential of NMD670 (NMD Pharma), an investigational small molecule inhibitor of the skeletal muscle specific chloride ion channel 1 (CIC-1), in patients with Charcot-Marie-Tooth (CMT) disease. The first patient dosing came after the FDA recently cleared the company’s investigational new drug application for the trial.¹

The new study, a randomized, double-blind, placebo-controlled trial, tests the efficacy, safety, and tolerability of the agent in 80 adults with any genetically confirmed CMT1 or CMT2 subtype. Over a 21-day treatment period, participants will be tested on changes in 6-minute walk test (6MWT), time to complete the 10-meter walk/run test (10MW/R), and time to complete timed-up-and-go test (TUG). To be included, patients must be between 18-70 years old and have body mass index between 18 and 35 kg/m2, inclusive, at screening.

"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,” Yessar Hussain, MD, a neuromuscular specialist at Austin Neuromuscular Medicine, said in a statement.¹ "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."

SYNAPSE-CMT tests the efficacy and safety of a twice daily oral dose of NMD670 in patients with CMT. The study, which spans across several sites in both the US and Europe, also includes several secondary outcomes, including change in 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. Investigators will also pay attention to several safety outcomes, such as incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, clinically significant abnormalities, and significant ECG abnormalities, among others.

NMD Pharma previously completed an observational study, dubbed ESTABLISH, that highlighted neuromuscular junction (NMJ) transmission deficits as an unappreciated disease characteristic in CMT. The study compared electrophysiological assessments and clinical testing between 21 patients with CMT types 1 and 2 and 10 healthy age=matched individuals.²

In the study, the level of NMJ transmission deficit in patients with CMT was associated with disease severity assessed through a range of clinical measurements of muscle strength and motor function. The study also provided important information on tolerability and reliability of clinical and electrophysiological outcomes which will aid the selection of relevant outcomes in future clinical trials.

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"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," Thomas Holm Pedersen, chief executive officer at NMD Pharma, said in a statement.¹

He added, "Our focus is to develop treatments that address the symptoms of CMT across multiple subtypes and provide needed muscle strength, power and endurance that can help patients gain and maintain ability to independently perform daily activities. I look forward to keeping patient communities updated on our progress."

SYNAPSE-CMT is the third initiated trial for NMD670, following a previously initiated phase 2 study (NCT05794139) in adults with spinal muscular atrophy (SMA) type 3 and a phase 2b study of patients with generalized myasthenia gravis (gMG). Earlier this year, at the 2024 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, investigators presented the outline of SYNAPSE-SMA, a proof-of-concept, double-blind, placebo-controlled, 2-way crossover study to test the effects of NMD670 vs placebo in ambulatory adults with SMA.³

Similar to SYNAPSE-CMT, SYNAPSE-SMA will use change in 6MWT as the primary outcome, with secondary end points that include safety and tolerability, muscle strength, motor function, fatigue, and neuromuscular transmission. In the link below, Jorge Quiroz, MD, MBA, chief medical officer at NMD Pharma, discussed the mechanism of action behind NMD670 and what it could provide for patients with SMA. He spoke on the differences of this therapy compared with previously approved products, and whether there is potential to produce synergistic effects.

REFERENCES
1. NMD Pharma Initiates Phase 2 Study of NMD670 in Patients with Charcot-Marie-Tooth Disease Type 1 and 2. News release. November 18, 2024. Accessed November 18, 2024. https://www.globenewswire.com/news-release/2024/11/18/2982429/0/en/NMD-Pharma-Initiates-Phase-2-Study-of-NMD670-in-Patients-with-Charcot-Marie-Tooth-Disease-Type-1-and-2.html
2. NMD Pharma Reports Results from the ESTABLISH Study – an International Observational Study of Neuromuscular Function in Charcot-Marie-Tooth Type 1 and 2. News release. June 20, 2023. Accessed November 18, 2024. https://www.nmdpharma.com/news/cmt-establish2
3. Kiyasova V Gronnebaek TT, Cornwall C, et al. Design and status update on the SYNAPSE-SMA phase 2 trial of NMD670 in ambulatory adults with spinal muscular atrophy type 3. Presented at: MDA Clinical and Scientific Conference; March 3-6, 2024; Orlando, FL. POSTER S114