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Abstract：
GSK3β is an intracellular regulatory kinase that is dysregulated in multiple tissues in type 1 myotonic dystrophy, a rare neuromuscular disorder that manifests at any age. AMO-02 (tideglusib) inhibits GSK3β activity in preclinical models of type 1 myotonic dystrophy and promotes cellular maturation as well as normalizes aberrant molecular and behavioral phenotypes. This phase 2 study assessed the pharmacokinetics, safety and tolerability, and preliminary efficacy of AMO-02 in adolescents and adults with congenital and childhood-onset type 1 myotonic dystrophy.
Sixteen subjects (aged 13 to 34 years) with congenital and childhood-onset type 1 myotonic dystrophy received 12 weeks of single-blind fixed-dose oral treatment with either 400 mg (n = 8) or 1000 mg (n = 8) AMO-02 (NCT02858908). Blood samples were obtained for pharmacokinetic assessment. Safety assessments, such as laboratory tests and electrocardiograms, as well as efficacy assessments of syndromal, cognitive, and muscular functioning, were obtained.
AMO-02 plasma concentrations conformed to a two-compartment model with first-order absorption and elimination, and dose-dependent increases in exposure (area under the curve) were observed. AMO-02 was generally safe and well-tolerated. No early discontinuations due to adverse events or dose adjustments of AMO-02 occurred. The majority of subjects manifested clinical improvement in their central nervous system and neuromuscular symptoms after 12 weeks of treatment compared with the placebo baseline, with a larger response noted at the 1000 mg/day dose level. AMO-02 exposure (cumulative area under the curve) was significantly correlated (P < 0.01) with change from baseline on several key efficacy assessments.
AMO-02 has favorable pharmacokinetic and clinical risk/benefit profiles meriting further study as a potential treatment for congenital and childhood-onset type 1 myotonic dystrophy.
Sixteen subjects (aged 13 to 34 years) with congenital and childhood-onset type 1 myotonic dystrophy received 12 weeks of single-blind fixed-dose oral treatment with either 400 mg (n = 8) or 1000 mg (n = 8) AMO-02 (NCT02858908). Blood samples were obtained for pharmacokinetic assessment. Safety assessments, such as laboratory tests and electrocardiograms, as well as efficacy assessments of syndromal, cognitive, and muscular functioning, were obtained.
AMO-02 plasma concentrations conformed to a two-compartment model with first-order absorption and elimination, and dose-dependent increases in exposure (area under the curve) were observed. AMO-02 was generally safe and well-tolerated. No early discontinuations due to adverse events or dose adjustments of AMO-02 occurred. The majority of subjects manifested clinical improvement in their central nervous system and neuromuscular symptoms after 12 weeks of treatment compared with the placebo baseline, with a larger response noted at the 1000 mg/day dose level. AMO-02 exposure (cumulative area under the curve) was significantly correlated (P < 0.01) with change from baseline on several key efficacy assessments.
AMO-02 has favorable pharmacokinetic and clinical risk/benefit profiles meriting further study as a potential treatment for congenital and childhood-onset type 1 myotonic dystrophy.
摘要：
GSK3β是一种细胞内调节激酶，在1型强直性肌营养不良的多个组织中失调，一种罕见的神经肌肉疾病，表现在任何年龄。在1型强直性肌营养不良的临床前模型中,AMO-02(tideglusib)抑制GSK3β活性并促进细胞成熟以及使异常分子和行为表型正常化。这项2期研究评估了药代动力学，安全性和耐受性，AMO-02在患有先天性和儿童期发作的1型强直性肌营养不良的青少年和成人中的初步疗效。
16名患有先天性和儿童期发作的1型肌强直性营养不良的受试者（年龄在13至34岁之间）接受了12周的单盲固定剂量口服治疗，其中400mg（n=8）或1000mg（n=8）AMO-02（NCT02858908）。获得血液样品用于药代动力学评估。安全评估,如实验室检查和心电图，以及综合征的疗效评估，认知，和肌肉功能，已获得。
AMO-02血浆浓度符合具有一阶吸收和消除的两室模型，并观察到暴露量（曲线下面积）的剂量依赖性增加。AMO-02通常是安全且耐受性良好的。没有发生由于AMO-02的不良事件或剂量调整而导致的早期停药。与安慰剂基线相比，大多数受试者在治疗12周后表现出中枢神经系统和神经肌肉症状的临床改善。在1000毫克/天的剂量水平下观察到更大的反应。在几个关键功效评估中,AMO-02暴露(曲线下累积面积)与从基线的变化显著相关(P<0.01)。
AMO-02具有良好的药代动力学和临床风险/益处特征，值得进一步研究作为先天性和儿童期发作的1型强直性肌营养不良的潜在治疗方法。
16名患有先天性和儿童期发作的1型肌强直性营养不良的受试者（年龄在13至34岁之间）接受了12周的单盲固定剂量口服治疗，其中400mg（n=8）或1000mg（n=8）AMO-02（NCT02858908）。获得血液样品用于药代动力学评估。安全评估,如实验室检查和心电图，以及综合征的疗效评估，认知，和肌肉功能，已获得。
AMO-02血浆浓度符合具有一阶吸收和消除的两室模型，并观察到暴露量（曲线下面积）的剂量依赖性增加。AMO-02通常是安全且耐受性良好的。没有发生由于AMO-02的不良事件或剂量调整而导致的早期停药。与安慰剂基线相比，大多数受试者在治疗12周后表现出中枢神经系统和神经肌肉症状的临床改善。在1000毫克/天的剂量水平下观察到更大的反应。在几个关键功效评估中,AMO-02暴露(曲线下累积面积)与从基线的变化显著相关(P<0.01)。
AMO-02具有良好的药代动力学和临床风险/益处特征，值得进一步研究作为先天性和儿童期发作的1型强直性肌营养不良的潜在治疗方法。
