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

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

EClinicalMedicine (Feb 2024)

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

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

Affiliations

Joshua J. Todd: Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA; National Institute of Nursing Research, National Institutes of Health, Bethesda, MD 20814, USA; Clinical Trials Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA
Tokunbor A. Lawal: National Institute of Nursing Research, National Institutes of Health, Bethesda, MD 20814, USA
Irene C. Chrismer: National Institute of Nursing Research, National Institutes of Health, Bethesda, MD 20814, USA
Angela Kokkinis: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA
Christopher Grunseich: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA
Minal S. Jain: Mark O. Hatfield Clinical Research Center, Rehabilitation Medicine Department, National Institutes of Health, Bethesda, MD 20814, USA
Melissa R. Waite: Mark O. Hatfield Clinical Research Center, Rehabilitation Medicine Department, National Institutes of Health, Bethesda, MD 20814, USA
Victoria Biancavilla: Mark O. Hatfield Clinical Research Center, Rehabilitation Medicine Department, National Institutes of Health, Bethesda, MD 20814, USA
Shavonne Pocock: National Institute of Nursing Research, National Institutes of Health, Bethesda, MD 20814, USA
Kia Brooks: Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA; Clinical Trials Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA
Christopher J. Mendoza: Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA
Gina Norato: Clinical Trials Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA
Ken Cheung: Mailman School of Public Health, Columbia University, NY 10032, USA
Willa Riekhof: National Institute of Nursing Research, National Institutes of Health, Bethesda, MD 20814, USA
Pooja Varma: National Institute of Nursing Research, National Institutes of Health, Bethesda, MD 20814, USA
Claudia Colina-Prisco: Section of Sensory Science and Metabolism, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20814, USA
Magalie Emile-Backer: National Institute of Nursing Research, National Institutes of Health, Bethesda, MD 20814, USA
Katherine G. Meilleur: National Institute of Nursing Research, National Institutes of Health, Bethesda, MD 20814, USA
Andrew R. Marks: Department of Physiology and Cellular Biophysics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
Yael Webb: ARMGO Pharma, Inc, Ardsley, NY 10591, USA
Eugene E. Marcantonio: ARMGO Pharma, Inc, Ardsley, NY 10591, USA
A. Reghan Foley: Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA
Carsten G. Bönnemann: Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA
Payam Mohassel: Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA; Corresponding author. National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA.

Journal volume & issue: Vol. 68
p. 102433

Abstract

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Summary: 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.

Published in EClinicalMedicine

ISSN: 2589-5370 (Online)
Publisher: Elsevier
Country of publisher: United Kingdom
LCC subjects: Medicine: Medicine (General)
Website: https://www.thelancet.com/journals/eclinm/home

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