Rycal S48168 (ARM210) for RYR1-related myopathies: a phase one, open-label, dose-escalation trial.
Rycal S48168 (ARM210) for RYR1-related myopathies: a phase one, open-label, dose-escalation trial.
复制标题
Rycal S48168 (ARM210) 用于治疗 RYR1 相关肌病：一期、开放标签、剂量递增试验。
DOI：
10.1016/j.eclinm.2024.102433
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发表时间：
2024
影响因子：
15.1
通讯作者：
Varma
中科院分区：
文献类型：
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作者：
Todd,JoshuaJ;Lawal,TokunborA;Chrismer,IreneC;Kokkinis,Angela;Grunseich,Christopher;Jain,MinalS;Waite,MelissaR;Biancavilla,Victoria;Pocock,Shavonne;Brooks,Kia;Mendoza,ChristopherJ;Norato,Gina;Cheung,Ken;Riekhof,Willa;Varma
背景RYR1相关肌病（RYR1-RM）是由编码1型兰尼碱受体（RyR1）的RYR1基因的致病性变异引起的。 RyR1 是肌浆网 (SR) 钙释放通道，介导骨骼肌中的兴奋-收缩耦合。 RyR1 亚电导、SR 钙渗漏、RyR1 表达减少和氧化应激常常导致 RYR1-RM 发病机制。在 17RYR1-RM 患者骨骼肌活检中观察到 RyR1-calstabin1 关联丧失、SR 钙渗漏和 RyR1 开放概率增加，并在使用 Rycal 化合物进行体外治疗后得到改善。因此，我们在基因证实的 RYR1-RM 的门诊成人中启动了 Rycal S48168 (ARM210) 的首例患者试验。方法参与者每天接受 120 mg (n = 3) 或 200 mg (n = 4) S48168 (ARM210)，持续 29 天。主要终点是安全性和耐受性。探索性终点包括 S48168 (ARM210) 药代动力学 (PK)、目标参与度、运动功能测量 (MFM)-32、握力和捏力、定时功能测试、PROMIS 疲劳量表、半定量体检强度测量和氧化应激生物标志物。该试验已在 ClinicalTrials.gov (NCT04141670) 注册，并于 2019 年 10 月 28 日至 2021 年 12 月 12 日在美国国立卫生研究院临床中心进行。 结果S48168 (ARM210) 耐受性良好，未引起任何严重不良事件，并表现出剂量依赖性 PK 特征。接受 200 毫克/天剂量的四名参与者中的三名报告称，在给药后 28 天，PROMIS 疲劳有所改善，并且在体检时也表现出近端肌肉力量的改善。InterpretationS48168 (ARM210) 在 RYR1-RM 受影响的个体中表现出良好的安全性、耐受性和 PK。大多数每天接受 200 毫克 S48168 (ARM210) 治疗的参与者报告疲劳减轻，这是 RYR1-RM 的一个关键症状。这些结果为随机、双盲、安慰剂对照的概念验证试验奠定了基础，以确定 S48168 (ARM210) 在 RYR1-RM 中的疗效。资助 NINDS 和 NINR 校内研究项目、NIH 临床中心床边奖 (2017-551673)、ARMGO Pharma Inc. 及其开发合作伙伴 Les Laboratoires Servier。
BackgroundRYR1-related myopathies (RYR1-RM) are caused by pathogenic variants in theRYR1gene 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 toRYR1-RM pathogenesis. Loss of RyR1-calstabin1 association, SR calcium leak, and increased RyR1 open probability were observed in 17RYR1-RM patient skeletal muscle biopsies and improved followingex vivotreatment with Rycal compounds. Thus, we initiated a first-in-patient trial of Rycal S48168 (ARM210) in ambulatory adults with genetically confirmedRYR1-RM.MethodsParticipants 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.FindingsS48168 (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.InterpretationS48168 (ARM210) demonstrated favorable safety, tolerability, and PK, inRYR1-RM affected individuals. Most participants who received 200 mg/day S48168 (ARM210) reported decreased fatigue, a key symptom ofRYR1-RM. These results set the foundation for a randomized, double-blind, placebo-controlled proof of concept trial to determine efficacy of S48168 (ARM210) inRYR1-RM.FundingNINDS and NINR Intramural Research Programs, NIH Clinical Center Bench to Bedside Award (2017-551673), ARMGO Pharma Inc., and its development partner Les Laboratoires Servier.