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 杜氏肌营养不良症 (DMD) 是由 X 连锁 DMD 基因突变引起的，大多数 由于高突变率，突变现在作为从头事件发生。 DMD基因也是其中之一 人类基因组中最大的，有 79 个外显子，覆盖 Xp21 的 2.3Mb。运营商筛查存在问题，原因是 突变率高、基因量大，DMD发病率较过去没有明显下降 十年来，活产雄性的数量仍保持在约 1/5,000。该疾病是进行性的，伴随骨骼肌的发作 病理学（炎症、变性/再生）从出生时就存在，但近端的临床症状 肌肉无力通常要到学龄早期（约 4 至 6 岁）才会被发现。 DMD 男孩通常会失败 除非通气，否则在第二个十年内无法行走，并在第三个十年内死于呼吸或心力衰竭。 DMD 的临床试验在过去十年中急剧扩大，已有 5 种药物获得批准。 然而，其中 4 个批准是基于骨骼肌肌营养不良蛋白表达的加速批准。 肌肉作为主要结果（替代生物标志物）和临床疗效尚未得到证实。 事实上，外显子跳跃药物的批准在 FDA 和临床研究中一直存在很大争议 社区。唯一获得临床结果批准的药物是地夫可特，其批准基于学术研究 几十年前就进行了试验，这一批准也引起了争议。因此，目前还没有批准的药物 当代试验中的临床结果，以及许多最近的临床试验使用临床结果 措施未能根据运动结果显示出有效性。 DMD 临床试验的一个挑战是 疾病的进展性质，适当的运动结果随着患者年龄的变化而变化，以及 缺乏能够监测药物对肌肉炎症或纤维化的作用和/或随后预测的血液生物标志物 运动结果的变化。在此 DMD 临床试验准备申请中，我们提出了两项​​研究 炎症的血清生物标志物 MDC 和 CD23，我们之前已证明它们对 皮质类固醇抗炎治疗 4 种疾病状态（小儿 DMD、小儿炎症性肠病） 病、青少年皮肌炎和成人血管炎）。这些生物标志物也被证明是剂量- 在治疗 DMD 的两周内对瓦莫龙（一种正在开发的新型解离类固醇药物）有反应 治疗，并协助最近完成的验证性关键试验 (VBP15-004) 的剂量选择 121 DMD 男孩。拟议的目标是确定与毒品相关的 MDC 和/或 3 个月治疗时的 CD23 预计 6 个月和 12 个月时运动结果的临床改善 治疗。双盲 VBP15-004 试验将 DMD 男孩随机分为 4 个组（安慰剂、伐莫龙 2.0 mg/kg/天，瓦莫龙 6.0 mg/kg/天，泼尼松 0.75 mg/kg/天），并包括安慰剂和安慰剂的交叉 在研究中点将泼尼松改为瓦莫龙。 VBP15-004 展示了 2.0 和 6.0 的功效 mg/kg/天伐莫龙组与安慰剂组（满足主要结果和 4 个连续的次要结果）并显示 与泼尼松相比，安全性更高（不会阻碍生长，骨生物标志物不会发生有害变化）。这 预期结果是 MDC 和/或 CD23 预测以后的运动结果，然后可以进行常规整合 纳入 DMD 临床试验设计以监测全身和/或肌肉炎症状态。