Dissociation of efficacy from side effects of anti-inflammatory therapies in Duchenne muscular dystrophy

摘要： 每日给予高剂量的糖皮质激素是治疗许多糖尿病的标准护理。 儿科炎性疾病，包括杜氏肌营养不良症（DMD）。副作用简介 严重的，生长发育迟缓，骨质脆弱，情绪变化和睡眠障碍，导致 儿童生活质量下降，临床护理费用增加。初步数据显示， 在DMD患者的纵向研究中，我们描述了经验证的药效学生物标志物组， 安全性的多个方面，以及糖皮质激素的抗炎功效。我们集团，在 与Reveragen biopharma合作，还鉴定了一种解离的糖皮质激素（VBP 15）， 强大的抗炎和膜稳定活性，是非常有效的改善 包括肌营养不良蛋白缺陷型mdx小鼠在内的多种炎性疾病模型中的疾病表型。 在88名成年志愿者中进行的VBP 15的1期临床试验显示，高达30倍泼尼松剂量的安全性 (20 mg/kg/天），肾上腺抑制、胰岛素抵抗和免疫抑制相对丧失。 该项目的总体目标是将安全性和有效性生物标志物与临床结局联系起来， 特定的药效学生物标志物可用于促进临床研究的设计和实施， 在1-4岁的年轻DMD患者中进行的临床试验，其临床结果尚不明确。实现 为此，我们提出了四个具体目标1）。桥接新的推定安全性和有效性药效学 使用现有的CINRG DNHS自然史数据和来自 GC治疗（治疗前和治疗后）DMD患者; 2）定义GC与 在成人志愿者和DMD患者中使用单次给药PK/PD时间序列的VBP 15，3）验证和 鉴定GC和VBP 15治疗的安全性和有效性生物标志物，以及4）建立2b期 1-4岁DMD儿童的临床试验方案，包括已确定的和新的安全性， 有效性生物标志物与年龄较大儿童的临床结果相关联。这将为临床试验奠定基础 VBP 15和其他抗炎药物，其中获得的数据预计将使更多的急性 和客观的读数的药物作用在儿科患者使用良好的特点和非侵入性 药效学生物标志物作为结果指标。

Abstract: Daily administration of high doses of glucocorticoids is standard of care for the treatment of many pediatric inflammatory diseases, including Duchenne muscular dystrophy (DMD). The side effect profiles of are severe, with stunting of growth, bone fragility, mood changes, and sleep disturbances, leading to a decrease in quality of life of children, and an increase in the costs of clinical care. In preliminary data from longitudinal studies of DMD patients, we describe validated panels of pharmacodynamic biomarkers for multiple aspects of safety, as well as anti-inflammatory efficacy of glucocorticoids. Our group, in collaboration with Reveragen biopharma, has also identified a dissociated glucocorticoid (VBP15) with powerful anti-inflammatory and membrane stabilizing activity that is highly effective in ameliorating disease phenotype in multiple inflammatory disease models including the dystrophin deficient mdx mouse. Phase 1 clinical trials of VBP15 in 88 adult volunteers have shown safety up to a 30-fold prednisone dose (20 mg/kg/day), with a relative loss of adrenal suppression, insulin resistance, and immune suppression. The overarching goal of this project is to bridge safety and efficacy biomarkers to clinical outcomes so that specific pharmacodynamic biomarkers can be used to facilitate the design and conduct of clinical trials in younger DMD patients, 1-4 years old, where clinical outcomes are poorly established. To achieve this goal we propose four specific aims 1). Bridge the novel putative safety and efficacy pharmacodynamic markers to clinical outcomes using the existing CINRG DNHS natural history data, and sample set from GC treated (pre and post) DMD patients; 2) define the differences in acute pharmacodynamics of GC vs. VBP15 using single dose PK/PD time series in both adult volunteers and DMD patients, 3) validate and qualify safety and efficacy biomarkers identified for GC and VBP15 treatment and 4) establish a Phase 2b clinical trial protocol for 1-4 yr old DMD children, with inclusion of both established and novel safety and efficacy biomarkers bridged to clinical outcomes in older children. This will set the stage for clinical trials of VBP15 and other anti-inflammatory drugs, where the data obtained is expected to enable more acute and objective readouts of drug action in pediatric patients using well-characterized and noninvasive pharmacodynamic biomarkers as outcome measures.