■RYR1相关的肌病(RYR1-RM)是由编码1型ryanodine受体(RyR1)的RYR1基因的致病变体引起的。RyR1是肌浆网(SR)钙释放通道,其介导骨骼肌中的兴奋-收缩耦合。RyR1亚电导,SR钙渗漏,降低RyR1表达,氧化应激通常有助于RYR1-RM的发病机制。RyR1-calstabin1协会的损失,SR钙渗漏,在17例RYR1-RM患者骨骼肌活检中观察到RyR1开放概率增加,并且在用Rycal化合物离体治疗后得到改善。因此,我们在基因证实为RYR1-RM的非卧床成人中启动了RycalS48168(ARM210)的首次住院试验.
■参与者每天接受120mg(n=3)或200mg(n=4)S48168(ARM210),共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),目标交战,运动功能测量(MFM)-32,握力和捏力,定时功能测试,PROMIS疲劳量表,半定量体检力量测量,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。
■S48168(ARM210)耐受性良好,没有引起任何严重的不良事件,并表现出剂量依赖性PK曲线。接受200mg/天剂量的四名参与者中有三名报告在给药后28天时PROMIS疲劳有所改善。并且在体格检查中还显示出改善的近端肌肉力量。
■S48168(ARM210)证明了良好的安全性,耐受性,PK,在RYR1-RM受影响的个体中。大多数接受200毫克/天S48168(ARM210)的参与者报告疲劳减少,RYR1-RM的主要症状。这些结果为随机化奠定了基础,双盲,安慰剂对照概念验证试验,以确定S48168(ARM210)在RYR1-RM中的疗效。
■NINDS和NINR校内研究计划,美国国立卫生研究院临床中心工作台到床边奖(2017-551673),ARMGO制药公司,及其开发合作伙伴LesLaboratoiresServier。
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.