RYR-1 Myopathy Clinical Trial
Official title:
Safety and Tolerability of S 48168 (ARM 210) for the Treatment of RYR1-related Myopathies (RYR1-RM)
This study proposes to test S 48168 (ARM210) in a Phase 1 trial in RYR1-RM patients, specifically. The objectives of this study are to explore the safety and tolerability, pharmacokinetics (PK), pharmacodynamics (PD)/target engagement (TE) of S 48168 (ARM210), as well as effects on muscle/motor function, and fatigue in RYR1-RM patients. The study population will include adult patients (≥18 years of age) who have demonstrated leaky RyR1 channels that are responsive to S48168 (ARM210) ex vivo.
RYR1- related myopathy comprises a group of rare neuromuscular diseases. Affected individuals generally present with delayed motor milestones, muscle weakness, impaired ambulation, and, in severe cases, scoliosis, ophthalmoplegia, and respiratory distress all due to skeletal muscle weakness. Causative variants in RYR1, which encodes the major calcium (Ca2+) release channel in skeletal muscle, RyR1, exert different effects on the RyR1 channel. They generally disrupt the normal Ca2+ flow between the sarcoplasmic reticulum (SR) and muscle cell cytosol and commonly result in excessive Ca2+ leak into the cytosol. Persistent Ca2+ leaks reduce its availability in the SR that is necessary for excitation-contraction coupling leading to the muscle weakness characteristic of this disease. This open-label study consists of ten participants, randomized to two dose groups. All participants will have a diagnosis of RYR1-RM. In addition they have a prior muscle biopsy demonstrating a leaky RYR1 channel which responds to S48168 (ARM210) ex vivo. The first group of three participants will receive a low dose of S 48168 (ARM210) daily for 28 days. The second group of seven participants will receive a higher dose for 28 days. The decision to escalate to the higher dose will be made by an independent Data and Safety Monitoring Board (DSMB) after review of safety, tolerability and PK of the low daily dose. Safety and tolerability will be the primary objective in this study. In addition, exploratory objectives will include PK, PD/TE as well as measures of muscle/motor function and fatigue. ;