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.

摘要 Duchenne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，突变现在作为新生事件发生。DMD基因也是 在人类基因组中最大的，有79个外显子覆盖2.3Mb的Xp 21。携带者筛查存在问题， 高突变率和大基因大小，DMD的发病率在过去没有明显下降 十年，仍保持在约1/5，000活产男性。这种疾病是进行性的，以骨骼肌的发病为特征。 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（~4至6岁）才被发现。DMD男孩通常 在第二个十年中出现呼吸衰竭，在第三个十年中死于呼吸衰竭或心力衰竭，除非进行通气。 在过去的十年中，DMD的临床试验急剧扩大，已经批准了5种药物。 然而，其中4项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 社区唯一一种根据临床结果批准的药物是deflazacort，其批准是基于一项学术研究。 几十年前进行的试验，这次批准也是有争议的。因此，没有任何药物批准基于 在当代试验中的临床结果，与许多最近的临床试验使用临床结果 未能显示基于运动结果的有效性的措施。DMD临床试验的挑战是 疾病的进行性，适当的运动结果随患者年龄而变化，以及 缺乏能够监测药物对肌肉炎症或纤维化的影响和/或预测以后的血液生物标志物 运动结果的变化。在DMD临床试验准备的申请中，我们提出了两项研究， 炎症的血清生物标志物，MDC和CD 23，我们以前已经证明是响应于 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 疾病、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2周内对vamorolone反应，vamorolone是一种正在开发的新型游离甾体药物，用于DMD， 治疗，并协助剂量选择最近完成的确证性，关键试验（VBP 15 -004）在121 DMD男孩。拟议的目标是确定与药物有关的MDC和/或 治疗3个月时的CD 23预期6个月和12个月时运动结局的临床改善 治疗VBP 15 -004双盲试验将DMD男孩随机分为4组（安慰剂、vamorolone 2.0 0 mg/kg/天，伐莫龙6.0mg/kg/天，泼尼松0.75mg/kg/天），并包括安慰剂和泼尼松的交叉。 在研究中点将泼尼松改为瓦莫龙。VBP 15 -004证明了2.0和6.0的有效性 mg/kg/天伐莫龙组与安慰剂组（满足主要和4个连续次要结局），并显示 与泼尼松相比，安全性提高（无生长迟缓，骨生物标志物无有害变化）。的 预期的结果是MDC和/或CD 23预测以后的运动结果，然后可以常规整合 用于DMD临床试验设计，以监测全身和/或肌肉炎症状态。