Rycal S48168 (ARM210) for RYR1-related myopathies: a phase one, open-label, dose-escalation trial

Background RYRT-related myopathies (RYRT-RM) are caused by pathogenic variants in the RYRT gene which encodes the type 1 ryanodine receptor (RyR1). RyR1 is the sarcoplasmic reticulum (SR) calcium release channel that mediates excitation-contraction coupling in skeletal muscle. RyR1 sub-conductance, SR calcium leak, reduced RyR1 expression, and oxidative stress often contribute to RYRT-RM pathogenesis. Loss of RyR1-calstabin1 association, SR calcium leak, and increased RyR1 open probability were observed in 17 RYRT-RM patient skeletal muscle biopsies and improved following ex vivo treatment with Rycal compounds. Thus, we initiated a first-in-patient trial of Rycal S48168 (ARM210) in ambulatory adults with genetically confirmed RYRT-RM. Methods Participants received 120 mg (n = 3) or 200 mg (n = 4) S48168 (ARM210) daily for 29 days. The primary endpoint was safety and tolerability. Exploratory endpoints included S48168 (ARM210) pharmacokinetics (PK), target engagement, motor function measure (MFM)-32, hand grip and pinch strength, timed functional tests, PROMIS fatigue scale, semi-quantitative physical exam strength measurements, and oxidative stress biomarkers. The trial was registered with clinicaltrials.gov (NCT04141670) and was conducted at the National Institutes of Health Clinical Center between October 28, 2019 and December 12, 2021. Findings S48168 (ARM210) was well-tolerated, did not cause any serious adverse events, and exhibited a dosedependent PK profile. Three of four participants who received the 200 mg/day dose reported improvements in PROMIS-fatigue at 28 days post-dosing, and also demonstrated improved proximal muscle strength on physical examination. Interpretation S48168 (ARM210) demonstrated favorable safety, tolerability, and PK, in RYRT-RM affected individuals. Most participants who received 200 mg/day S48168 (ARM210) reported decreased fatigue, a key symptom of RYRT-RM. These results set the foundation for a randomized, double -blind, placebo-controlled proof of concept trial to determine efficacy of S48168 (ARM210) in RYRT-RM. Funding NINDS and NINR Intramural Research Programs, NIH Clinical Center Bench to Bedside Award (2017551673), ARMGO Pharma Inc., and its development partner Les Laboratoires Servier. Copyright (c) 2024 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).