Background

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.

Methods

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.

Results

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.

Conclusion

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.

中文翻译：

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AMO-02 (Tideglusib) 在先天性和儿童期发病的 1 型肌强直性营养不良 (DM1) 中的第 2 阶段研究。

背景

GSK3β 是一种细胞内调节激酶，在 1 型肌强直性营养不良的多个组织中失调，这是一种罕见的神经肌肉疾病，可出现在任何年龄。AMO-02 (tideglusib) 在 1 型肌强直性营养不良的临床前模型中抑制 GSK3β 活性，促进细胞成熟并使异常分子和行为表型正常化。这项 2 期研究评估了 AMO-02 在患有先天性和儿童期发病的 1 型肌强直性营养不良的青少年和成人中的药代动力学、安全性和耐受性以及初步疗效。

方法

16 名患有先天性和儿童期发病的 1 型肌强直性营养不良的受试者（13 至 34 岁）接受了 12 周的单盲固定剂量口服治疗，包括 400 毫克（n = 8）或 1000 毫克（n = 8）AMO- 02 (NCT02858908)。获得血样用于药代动力学评估。获得了安全性评估，例如实验室测试和心电图，以及对综合征、认知和肌肉功能的有效性评估。

结果

AMO-02 血浆浓度符合具有一级吸收和消除的二室模型，并且观察到暴露量（曲线下面积）的剂量依赖性增加。AMO-02 通常安全且耐受性良好。没有发生因不良事件或 AMO-02 剂量调整而提前停药的情况。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/天的剂量水平上注意到更大的反应。AMO-02 暴露（曲线下的累积面积 ）与几个关键功效评估的基线变化显着相关（P < 0.01）。

结论

AMO-02 具有良好的药代动力学和临床风险/获益特征，值得进一步研究作为先天性和儿童期发病的 1 型肌强直性营养不良的潜在治疗方法。