Clinical Trial Readiness for Monitoring Muscle Inflammation in Duchenne Muscular Dystrophy

监测杜氏肌营养不良症肌肉炎症的临床试验准备

• 批准号: 10725465
• 负责人: ERIC P. HOFFMAN
• 金额: $ 23.74万
• 依托单位: STATE UNIVERSITY OF NY,BINGHAMTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10725465
• 关键词: Acceleration; Acute; Address; Adrenal Cortex Hormones; Adult; Age; Anti-Inflammatory Agents; Biochemical; Biological Markers; Birth; Blood; CCL22 gene; Childhood; Chronic; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Code; Communities; Data; Development; Disease; Disease Progression; Dose; Double-Blind Method; Double-blind trial; Drug Approval; Drug Exposure; Drug Monitoring; Drug usage; Duchenne muscular dystrophy; Dystrophin; Event; Exons; Fibrosis; Gene therapy trial; Genes; Growth; Heart; Heart failure; Human Genome; Incidence; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Investigational Therapies; Juvenile Dermatomyositis; Link; Membrane; Modeling; Molecular; Monitor; Motor; Muscle; Muscle Weakness; Mutation; Myopathy; Natural regeneration; Nature; Neuromuscular Diseases; Outcome; Outcome Study; Participant; Pathology; Patient observation; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phase; Placebos; Prednisone; Process; Production; Program Development; Proteins; Proteomics; Randomized; Rare Diseases; Regulatory Pathway; Replacement Therapy; Research; Respiratory Failure; Risk; Safety; Sampling; School-Age Population; Serum; Serum Proteins; Skeletal Muscle; Surrogate Markers; Symptoms; Testing; Therapeutic; Tissues; Vasculitis; arm; bone; boys; carrier testing; clinical application; clinical care; clinical efficacy; clinical outcome measures; clinical predictors; clinical trial readiness; deflazacort; disability; drug development; efficacy outcomes; exon skipping; improved; macrophage-derived chemokine; male; multiplex assay; novel; open label; pharmacodynamic biomarker; pharmacokinetics and pharmacodynamics; phase III trial; predict clinical outcome; predictive marker; primary outcome; randomized trial; response; secondary outcome; treatment arm; ventilation; week trial

Abstract Duchenne muscular dystrophy (DMD) is caused by mutations of the X-linked DMD gene, with the majority of mutations now occurring as de novo events due to the high mutation rate. The DMD gene is also one of the largest in the human genome, with 79 exons covering 2.3Mb of Xp21. Carrier screening is problematic due to high mutation rate and large gene size, and the incidence of DMD has not declined significantly over the last decade, remaining at about 1/5,000 live born males. The disease is progressive, with onset of skeletal muscle pathology (inflammation, degeneration/regeneration) present from birth, but clinical symptoms of proximal muscle weakness typically not recognized until early school age (~4 to 6 years). DMD boys typically lose ambulation in the second decade and succumb to respiratory or cardiac failure in 3rd decade unless ventilated. Clinical trials in DMD have expanded dramatically over the last decade, and 5 drugs have been approved. However, 4 of these approvals were based on accelerated approval with dystrophin expression in skeletal muscle as the primary outcome (surrogate biomarker) and clinical efficacy has not yet been demonstrated. Indeed, the approvals of exon skipping drugs have been highly controversial within FDA and clinical research community. The only drug approved on clinical outcomes is deflazacort, with approval based on an academic trial done decades earlier, and this approval was also controversial. Thus, there are no drugs approved based on clinical outcomes in contemporary trials, with many more recent clinical trials using clinical outcomes measures failing to show efficacy based on motor outcomes. A challenge with DMD clinical trials is the progressive nature of the disease with appropriate motor outcomes changing as function of patient age, and the lack of blood biomarkers able to monitor drug effect on muscle inflammation or fibrosis, and/or predict later changes in motor outcomes. In this application for clinical trial readiness in DMD, we propose the study of two serum biomarkers of inflammation, MDC and CD23, that we have previously shown to be responsive to corticosteroid anti-inflammatory treatment in 4 disease states (pediatric DMD, pediatric inflammatory bowel disease, juvenile dermatomyositis, and adult vasculitis). These biomarkers were also shown to be dose- responsive to vamorolone, a novel dissociative steroidal drug under development in DMD, within 2-weeks of treatment, and aided in dose-selection for the recently completed confirmatory, pivotal trial (VBP15-004) in 121 DMD boys. The proposed aims are to determine the extent to which drug-related reductions in MDC and/or CD23 at 3 months treatment anticipate clinical improvement of motor outcomes at 6 months and 12 months treatment. The double-blind VBP15-004 trial randomized DMD boys into 4 arms (placebo, vamorolone 2.0 mg/kg/day, vamorolone 6.0 mg/kg/day, prednisone 0.75 mg/kg/day), and included a cross-over of placebo and prednisone to vamorolone at study midpoint. The VBP15-004 demonstrated efficacy of both 2.0 and 6.0 mg/kg/day vamorolone groups vs. placebo (met primary and 4 sequential secondary outcomes) and showed improved safety vs. prednisone (no stunting of growth, no deleterious changes in bone biomarkers). The anticipated result is that MDC and/or CD23 predict later motor outcomes and can then be routinely integrated into DMD clinical trial designs to monitor systemic and/or muscle inflammatory state.

抽象的 Duchenne肌肉营养不良（DMD）是由X连锁DMD基因的突变引起的，大部分 由于高突变率，现在作为从头事件发生的突变。 DMD基因也是 人类基因组中最大，有79个外显子覆盖2.3MB的XP21。由于运营商筛查是有问题的 高突变率和较大的基因大小，而DMD的发生率尚未显着下降 十年，剩下约1/5,000名现实男性。疾病是进行性的，骨骼肌发作 病理学（炎症，变性/再生）出生，但近端的临床症状 肌肉无力通常要等到早年（〜4至6岁）才被识别。 DMD男孩通常会输 在第二个十年中的行动，除非通风，否则在第三个十年内屈服于呼吸道或心脏衰竭。 在过去的十年中，DMD的临床试验急剧扩展，并批准了5种药物。 但是，其中4个批准是基于骨骼中肌营养不良蛋白表达的加速批准 肌肉是主要结果（替代生物标志物）和临床功效。 实际上，在FDA和临床研究中，外显子跳过药物的批准一直存在争议 社区。根据学术 几十年前进行的试验，此批准也引起了争议。因此，没有批准的药物 关于当代试验的临床结果，使用临床结果进行了许多最近的临床试验 无法根据运动结果显示功效的措施。 DMD临床试验的挑战是 疾病的渐进性，适当的运动结果随着患者年龄的功能而变化，并且 缺乏能够监测药物对肌肉炎症或纤维化的影响的血液生物标志物和/或稍后预测 运动结果的变化。在此DMD中的临床试验准备申请中，我们提出了两个 炎症，MDC和CD23的血清生物标志物，我们以前已证明对 4种疾病状态的皮质类固醇抗炎治疗（小儿DMD，小儿炎症肠 疾病，青少年皮肌炎和成年血管炎）。这些生物标志物也被证明是剂量 对DMD中开发的一种新型解离类固醇药物的Vamorolone敏感，在2周内 治疗，并有助于剂量选择，以进行最近完成的确认性，关键试验（VBP15-004）121 DMD男孩。拟议的目的是确定MDC和/或中与药物相关的减少的程度 在3个月治疗时CD23预测6个月零12个月的运动结果的临床改善 治疗。双盲VBP15-004试验随机DMD男孩进入4臂（安慰剂，vamorolone 2.0 mg/kg/day，vamorolone 6.0 mg/kg/day，泼尼松0.75 mg/kg/day），包括安慰剂的交叉 研究中点泼尼松。 VBP15-004表现出2.0和6.0的功效 mg/kg/day vamorolone群体与安慰剂（Met otirth和4个顺序次要结果），并显示 改善的安全性与泼尼松（没有生长的阻碍，没有有害的骨骼生物标志物变化）。这 预期的结果是MDC和/或CD23预测以后的电动机结果，然后可以定期整合 进入DMD临床试验设计，以监测系统性和/或肌肉炎症状态。