Rycal S48168 (ARM210) for RYR1-related myopathies: a phase one, open-label, dose-escalation trialResearch in context
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-co...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-02-01
|
| Series: | EClinicalMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589537024000129 |
| _version_ | 1797342212421320704 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Joshua J. Todd |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T10:30:01Z |
| format | Article |
| id | doaj.art-eaee208d483c458182ce30c47fd601c7 |
| institution | Directory Open Access Journal |
| issn | 2589-5370 |
| language | English |
| last_indexed | 2024-03-08T10:30:01Z |
| publishDate | 2024-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EClinicalMedicine |
| spelling | doaj.art-eaee208d483c458182ce30c47fd601c72024-01-27T06:55:53ZengElsevierEClinicalMedicine2589-53702024-02-0168102433Rycal S48168 (ARM210) for RYR1-related myopathies: a phase one, open-label, dose-escalation trialResearch in contextJoshua J. Todd0Tokunbor A. Lawal1Irene C. Chrismer2Angela Kokkinis3Christopher Grunseich4Minal S. Jain5Melissa R. Waite6Victoria Biancavilla7Shavonne Pocock8Kia Brooks9Christopher J. Mendoza10Gina Norato11Ken Cheung12Willa Riekhof13Pooja Varma14Claudia Colina-Prisco15Magalie Emile-Backer16Katherine G. Meilleur17Andrew R. Marks18Yael Webb19Eugene E. Marcantonio20A. Reghan Foley21Carsten G. Bönnemann22Payam Mohassel23Neuromuscular 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, USANational Institute of Nursing Research, National Institutes of Health, Bethesda, MD 20814, USANational Institute of Nursing Research, National Institutes of Health, Bethesda, MD 20814, USANeurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USANeurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USAMark O. Hatfield Clinical Research Center, Rehabilitation Medicine Department, National Institutes of Health, Bethesda, MD 20814, USAMark O. Hatfield Clinical Research Center, Rehabilitation Medicine Department, National Institutes of Health, Bethesda, MD 20814, USAMark O. Hatfield Clinical Research Center, Rehabilitation Medicine Department, National Institutes of Health, Bethesda, MD 20814, USANational Institute of Nursing Research, National Institutes of Health, Bethesda, MD 20814, USANeuromuscular 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, USANeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USAClinical Trials Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USAMailman School of Public Health, Columbia University, NY 10032, USANational Institute of Nursing Research, National Institutes of Health, Bethesda, MD 20814, USANational Institute of Nursing Research, National Institutes of Health, Bethesda, MD 20814, USASection of Sensory Science and Metabolism, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20814, USANational Institute of Nursing Research, National Institutes of Health, Bethesda, MD 20814, USANational Institute of Nursing Research, National Institutes of Health, Bethesda, MD 20814, USADepartment of Physiology and Cellular Biophysics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USAARMGO Pharma, Inc, Ardsley, NY 10591, USAARMGO Pharma, Inc, Ardsley, NY 10591, USANeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USANeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USANeuromuscular 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.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.http://www.sciencedirect.com/science/article/pii/S2589537024000129Central core diseaseCongenital myopathies |
| spellingShingle | 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 Rycal S48168 (ARM210) for RYR1-related myopathies: a phase one, open-label, dose-escalation trialResearch in context EClinicalMedicine Central core disease Congenital myopathies |
| title | Rycal S48168 (ARM210) for RYR1-related myopathies: a phase one, open-label, dose-escalation trialResearch in context |
| title_full | Rycal S48168 (ARM210) for RYR1-related myopathies: a phase one, open-label, dose-escalation trialResearch in context |
| title_fullStr | Rycal S48168 (ARM210) for RYR1-related myopathies: a phase one, open-label, dose-escalation trialResearch in context |
| title_full_unstemmed | Rycal S48168 (ARM210) for RYR1-related myopathies: a phase one, open-label, dose-escalation trialResearch in context |
| title_short | Rycal S48168 (ARM210) for RYR1-related myopathies: a phase one, open-label, dose-escalation trialResearch in context |
| title_sort | rycal s48168 arm210 for ryr1 related myopathies a phase one open label dose escalation trialresearch in context |
| topic | Central core disease Congenital myopathies |
| url | http://www.sciencedirect.com/science/article/pii/S2589537024000129 |
| work_keys_str_mv | AT joshuajtodd rycals48168arm210forryr1relatedmyopathiesaphaseoneopenlabeldoseescalationtrialresearchincontext AT tokunboralawal rycals48168arm210forryr1relatedmyopathiesaphaseoneopenlabeldoseescalationtrialresearchincontext AT irenecchrismer rycals48168arm210forryr1relatedmyopathiesaphaseoneopenlabeldoseescalationtrialresearchincontext AT angelakokkinis rycals48168arm210forryr1relatedmyopathiesaphaseoneopenlabeldoseescalationtrialresearchincontext AT christophergrunseich rycals48168arm210forryr1relatedmyopathiesaphaseoneopenlabeldoseescalationtrialresearchincontext AT minalsjain rycals48168arm210forryr1relatedmyopathiesaphaseoneopenlabeldoseescalationtrialresearchincontext AT melissarwaite rycals48168arm210forryr1relatedmyopathiesaphaseoneopenlabeldoseescalationtrialresearchincontext AT victoriabiancavilla rycals48168arm210forryr1relatedmyopathiesaphaseoneopenlabeldoseescalationtrialresearchincontext AT shavonnepocock rycals48168arm210forryr1relatedmyopathiesaphaseoneopenlabeldoseescalationtrialresearchincontext AT kiabrooks rycals48168arm210forryr1relatedmyopathiesaphaseoneopenlabeldoseescalationtrialresearchincontext AT christopherjmendoza rycals48168arm210forryr1relatedmyopathiesaphaseoneopenlabeldoseescalationtrialresearchincontext AT ginanorato rycals48168arm210forryr1relatedmyopathiesaphaseoneopenlabeldoseescalationtrialresearchincontext AT kencheung rycals48168arm210forryr1relatedmyopathiesaphaseoneopenlabeldoseescalationtrialresearchincontext AT willariekhof rycals48168arm210forryr1relatedmyopathiesaphaseoneopenlabeldoseescalationtrialresearchincontext AT poojavarma rycals48168arm210forryr1relatedmyopathiesaphaseoneopenlabeldoseescalationtrialresearchincontext AT claudiacolinaprisco rycals48168arm210forryr1relatedmyopathiesaphaseoneopenlabeldoseescalationtrialresearchincontext AT magalieemilebacker rycals48168arm210forryr1relatedmyopathiesaphaseoneopenlabeldoseescalationtrialresearchincontext AT katherinegmeilleur rycals48168arm210forryr1relatedmyopathiesaphaseoneopenlabeldoseescalationtrialresearchincontext AT andrewrmarks rycals48168arm210forryr1relatedmyopathiesaphaseoneopenlabeldoseescalationtrialresearchincontext AT yaelwebb rycals48168arm210forryr1relatedmyopathiesaphaseoneopenlabeldoseescalationtrialresearchincontext AT eugeneemarcantonio rycals48168arm210forryr1relatedmyopathiesaphaseoneopenlabeldoseescalationtrialresearchincontext AT areghanfoley rycals48168arm210forryr1relatedmyopathiesaphaseoneopenlabeldoseescalationtrialresearchincontext AT carstengbonnemann rycals48168arm210forryr1relatedmyopathiesaphaseoneopenlabeldoseescalationtrialresearchincontext AT payammohassel rycals48168arm210forryr1relatedmyopathiesaphaseoneopenlabeldoseescalationtrialresearchincontext |