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  3. The ClC-1 chloride channel inhibitor NMD670 improves skeletal muscle function in rat models and patients with myasthenia gravis

The ClC-1 chloride channel inhibitor NMD670 improves skeletal muscle function in rat models and patients with myasthenia gravis

  • Sci Transl Med. 2024 Mar 20;16(739):eadk9109. doi: 10.1126/scitranslmed.adk9109.
Martin Skov 1,  Titia Q Ruijs 2 3,  Thomas S Grønnebæk 1,  Marianne Skals 1,  Anders Riisager 1,  Jeppe Blichfeldt Winther 1,  Kamilla Løhde Tordrup Dybdahl 1,  Anders Findsen 1,  Jeanette J Morgen 1,  Nete Huus 1,  Martin Broch-Lips 1,  Ole B Nielsen 1 4,  Catherine M K E de Cuba 2 3,  Jules A A C Heuberger 2,  Marieke L de Kam 2,  Martijn Tannemaat 3,  Jan J G M Verschuuren 3,  Lars J S Knutsen 1,  Nicholas M Kelly 1,  Klaus G Jensen 1,  William D Arnold 5,  Arthur H Burghes 6 7,  Claus Olesen 1 4,  Jane Bold 1,  Thomas K Petersen 1,  Jorge A Quiroz 1,  John Hutchison 1,  Eva R Chin 1,  Geert J Groeneveld 2 3,  Thomas H Pedersen 1 4
Affiliations

Affiliations

  • 1 NMD Pharma A/S, Palle Juul-Jensens Boulevard 82, 8200 Aarhus N, Denmark.
  • 2 Centre for Human Drug Research, 2333 CL Leiden, Netherlands.
  • 3 Leiden University Medical Centre, 2333 ZA Leiden, Netherlands.
  • 4 Department of Biomedicine, Aarhus University, Ole Worms Alle 4, 8000 Aarhus C, Denmark.
  • 5 NextGen Precision Health, University of Missouri, 1030 Hitt St, Columbia, MO 65212, USA.
  • 6 Department of Biological Chemistry and Pharmacology, Ohio State University Wexner Medical Center, 1060 Carmack Road, Columbus, OH 43210, USA.
  • 7 Department of Neurology, Neuromuscular Division, Ohio State University Wexner Medical Center, 395 W. 12(th) Ave, Columbus, OH 43210, USA.
PMID: 38507469 DOI: 10.1126/scitranslmed.adk9109
Abstract

Myasthenia gravis (MG) is a neuromuscular disease that results in compromised transmission of electrical signals at the neuromuscular junction (NMJ) from motor neurons to skeletal muscle fibers. As a result, patients with MG have reduced skeletal muscle function and present with symptoms of severe muscle weakness and fatigue. ClC-1 is a skeletal muscle specific chloride (Cl-) ion channel that plays important roles in regulating neuromuscular transmission and muscle fiber excitability during intense exercise. Here, we show that partial inhibition of ClC-1 with an orally bioavailable small molecule (NMD670) can restore muscle function in rat models of MG and in patients with MG. In severely affected MG rats, ClC-1 inhibition enhanced neuromuscular transmission, restored muscle function, and improved mobility after both single and prolonged administrations of NMD670. On this basis, NMD670 was progressed through nonclinical safety pharmacology and toxicology studies, leading to approval for testing in clinical studies. After successfully completing phase 1 single ascending dose in healthy volunteers, NMD670 was tested in patients with MG in a randomized, placebo-controlled, single-dose, three-way crossover clinical trial. The clinical trial evaluated safety, pharmacokinetics, and pharmacodynamics of NMD670 in 12 patients with mild MG. NMD670 had a favorable safety profile and led to clinically relevant improvements in the quantitative myasthenia gravis (QMG) total score. This translational study spanning from single muscle fiber recordings to patients provides proof of mechanism for ClC-1 inhibition as a potential therapeutic approach in MG and supports further development of NMD670.

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