P.08 Phase 1 open-label trial of Rycal S48168 (ARM210) for RYR1-related myopathies

Abstract

Pathogenic variants in the <i>RYR1</i> gene, encoding the skeletal muscle ryanodine receptor (RyR1), are the most common cause of non-dystrophic neuromuscular disorders. Pathogenic <i>RYR1</i> variants exhibit downstream consequences, including aberrant sarcoplasmic reticulum (SR) Ca²⁺ leak, hypersensitivity to RyR1 agonists, diminished SR Ca²⁺ release, and/or decreased RyR1 protein expression. Decreased RyR1-calstabin1 association, due to <i>RYR1</i> variants and/or post-translational modifications of the RyR1 channel, exacerbates SR Ca²⁺ leak with detrimental downstream effects on muscle function. Rycal compounds have been shown to restore RyR1-calstabin1 association, stabilize the <i>RyR1</i> closed state, and mitigate aberrant Ca²⁺ leak in <i>RYR1</i>-related myopathy (<i>RYR1</i>-RM) muscle biopsies. We conducted a phase 1 trial of S48168 (ARM210), a Rycal compound, in ambulatory adults with <i>RYR1</i>-RM (NCT04141670). The primary endpoint was safety and tolerability over a one-month dosing period. Pharmacokinetic (PK) studies, muscle biopsies, motor/muscle function tests, and a patient-reported fatigue questionnaire were also included. Seven eligible individuals were enrolled and received either the low dose (120 mg, n=3) or high dose (200 mg, n=4) of S48168 (ARM210) daily. Three treatment emergent adverse effects grade 2 or above were reported, all unrelated to S48168 (ARM210) and there were no serious adverse events. S48168 (ARM210) showed a dose-dependent PK profile and C_max remained within pre-defined safety margins. At one month, self-reported fatigue scores decreased and shoulder abduction strength trended higher in the high dose group, while handgrip strength increased in both dose groups, though these exploratory comparisons were descriptive. Other preliminary efficacy results were mixed. Given the favorable safety profile and efficacy trends, further clinical development of S48168 (ARM210) is warranted for <i>RYR1</i>-RM.