Vamorolone trial in Becker muscular dystrophy

摘要 贝克营养不良是由肌肉组织中肌营养不良蛋白的部分功能丧失和一些肌营养不良蛋白的功能丧失引起的。 非肌细胞，骨骼肌和心肌进行性功能障碍。DMD基因突变 导致贝克尔肌营养不良和杜氏肌营养不良（DMD）; DMD是肌营养不良蛋白的完全丧失， 而Becker营养不良患者在肌肉中保留了部分功能性肌营养不良蛋白， 进行性疾病DMD的治疗努力在过去十年中取得了显著进展， FDA批准的治疗DMD的药物贝克营养不良的临床研究相对于 DMD，没有药物被批准，也没有药物开发工作。这种治疗努力的不一致性是 可能部分是由于在美国贝克尔营养不良相对于DMD的患病率较低（贝克尔营养不良 0.36/10，000; DMD 1.02/10，000），以及贝克营养不良的非常可变的临床表型（并发 临床试验结果的解释）。皮质类固醇（泼尼松和Emflaza）被认为是标准药物 护理DMD，但不是贝克营养不良，因为患者和他们的医生普遍认为， 长期使用皮质类固醇在力量和活动性方面的作用大于益处。在这里，我们寻求启动临床 伐莫龙（一种糖皮质激素受体的部分解离激动剂和糖皮质激素受体的拮抗剂）的开发 盐皮质激素受体）治疗贝克尔营养不良。Vamorolone显示出独特的结构/活性关系 与皮质类固醇类相比，并显示DMD的初步数据表明， 有效性，但失去了皮质类固醇类药物的安全性问题。Vamorolone可能会改善 与DMD相比，在Becker营养不良中的功效，因为已显示vamorolone抑制肌营养不良蛋白mRNA- 靶向微小RNA，并因此预期增加贝克尔营养不良患者肌肉中的肌营养不良蛋白水平。 因此，瓦莫龙在贝克营养不良中可能具有多种功效作用机制：1.抑制亲- 炎症性NF-κB通路; 2.通过肌营养不良蛋白靶向microRNA增加肌肉的肌营养不良蛋白含量 抑制; 3.盐皮质激素拮抗作用对心脏有益。本研究的目的1是评估 6 mg/kg/天伐莫龙治疗Becker患者24周的安全性、耐受性和疗效 营养不良目的2是评价24周内血清生物标志物的治疗反应性 贝克营养不良患者的治疗。目的3是使用开放标签功能结局数据（NSAA， TTRW），进行样本量计算，以充分把握度和设计一个在美国的维莫龙注册试验。 贝克营养不良。

Abstract Becker dystrophy is caused by partial loss of function of the dystrophin protein in muscle tissues and some non-muscle cells, with progressive dysfunction of skeletal and cardiac muscle. Mutations of the DMD gene cause both Becker dystrophy and Duchenne muscular dystrophy (DMD); DMD is complete loss of dystrophin, whereas Becker dystrophy patients retain partly functional dystrophin in muscle that reduces the severity of the progressive disease. Therapeutic efforts for DMD have significantly advanced over the last decade, with 4 drugs now approved by FDA for DMD. Clinical research in Becker dystrophy is under-represented relative to DMD, with no drugs approved, and few drug development efforts. This discordance in therapeutic efforts is likely partly due to somewhat lower prevalence of Becker dystrophy vs. DMD in the USA (Becker dystrophy 0.36/10,000; DMD 1.02/10,000), and the very variable clinical phenotype of Becker dystrophy (complicating interpretation of outcomes in clinical trials). Corticosteroids (prednisone and Emflaza) are considered standard of care for DMD, but not Becker dystrophy, as patients and their physicians generally feel that the poor safety profile of chronic corticosteroid use outweighs benefits in strength and mobility. Here, we seek to initiate clinical development of vamorolone (a partial dissociative agonist of the glucocorticoid receptor, and antagonist of the mineralocorticoid receptor) for Becker dystrophy. Vamorolone shows unique structure/activity relationships compared to the corticosteroid class and has shown preliminary data in DMD suggestive of retention of efficacy but loss of safety concerns of the corticosteroid class of drugs. Vamorolone may show improved efficacy in Becker dystrophy compared to DMD, as vamorolone has been shown to inhibit dystrophin mRNA- targeting microRNAs, and thus is anticipated to increase dystrophin levels in Becker dystrophy patient muscle. Thus, vamorolone may have multiple mechanisms of action of efficacy in Becker dystrophy: 1. Inhibition of pro- inflammatory NF-κB pathways; 2. Increase in dystrophin content of muscle via dystrophin-targeting microRNA inhibition; 3. Cardiac benefit via mineralocorticoid antagonism. Aim 1 of the proposed research is to evaluate safety, tolerability, and efficacy of 6mg/kg/day vamorolone for 24 weeks treatment of patients with Becker dystrophy. Aim 2 is to evaluate treatment responsiveness of serum biomarkers over 24 weeks vamorolone treatment of patients with Becker dystrophy. Aim 3 is to use open-label functional outcome data (NSAA, TTRW), carry out sample size calculations to adequately power and design a registration trial of vamorolone in Becker dystrophy.