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

Joshua J Todd; Tokunbor A Lawal; Irene C Chrismer; Angela Kokkinis; Christopher Grunseich; Minal S Jain; Melissa R Waite; Victoria Biancavilla; Shavonne Pocock; Kia Brooks; Christopher J Mendoza; Gina Norato; Ken Cheung; Willa Riekhof; Pooja Varma; Claudia Colina-Prisco; Magalie Emile-Backer; Katherine G Meilleur; Andrew R Marks; Yael Webb; Eugene E Marcantonio; A Reghan Foley; Carsten G Bönnemann; Payam Mohassel

doi:10.1016/j.eclinm.2024.102433

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

EClinicalMedicine. 2024 Jan 25:68:102433. doi: 10.1016/j.eclinm.2024.102433. eCollection 2024 Feb.

Authors

Joshua J Todd^{1

2

3}, Tokunbor A Lawal², Irene C Chrismer², Angela Kokkinis⁴, Christopher Grunseich⁴, Minal S Jain⁵, Melissa R Waite⁵, Victoria Biancavilla⁵, Shavonne Pocock², Kia Brooks^{1

3}, Christopher J Mendoza¹, Gina Norato³, Ken Cheung⁶, Willa Riekhof², Pooja Varma², Claudia Colina-Prisco⁷, Magalie Emile-Backer², Katherine G Meilleur², Andrew R Marks⁸, Yael Webb⁹, Eugene E Marcantonio⁹, A Reghan Foley¹, Carsten G Bönnemann¹, Payam Mohassel¹

Affiliations

¹ Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA.
² National Institute of Nursing Research, National Institutes of Health, Bethesda, MD 20814, USA.
³ Clinical Trials Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
⁴ Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA.
⁵ Mark O. Hatfield Clinical Research Center, Rehabilitation Medicine Department, National Institutes of Health, Bethesda, MD 20814, USA.
⁶ Mailman School of Public Health, Columbia University, NY 10032, USA.
⁷ Section of Sensory Science and Metabolism, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20814, USA.
⁸ Department of Physiology and Cellular Biophysics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
⁹ ARMGO Pharma, Inc, Ardsley, NY 10591, USA.

Abstract

Background: RYR1-related myopathies (RYR1-RM) are caused by pathogenic variants in the RYR1 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 RYR1-RM pathogenesis. Loss of RyR1-calstabin1 association, SR calcium leak, and increased RyR1 open probability were observed in 17 RYR1-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 RYR1-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 dose-dependent 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 RYR1-RM affected individuals. Most participants who received 200 mg/day S48168 (ARM210) reported decreased fatigue, a key symptom of RYR1-RM. These results set the foundation for a randomized, double-blind, placebo-controlled proof of concept trial to determine efficacy of S48168 (ARM210) in RYR1-RM.

Funding: NINDS and NINR Intramural Research Programs, NIH Clinical Center Bench to Bedside Award (2017-551673), ARMGO Pharma Inc., and its development partner Les Laboratoires Servier.

Keywords: Central core disease; Congenital myopathies.

Associated data

ClinicalTrials.gov/NCT04141670

Grants and funding

K22 NS104135/NS/NINDS NIH HHS/United States