Bridging pharmacodynamic biomarkers to clinical outcomes in pediatric inflammatory diseases

摘要： 每日给予高剂量糖皮质激素是治疗许多糖尿病的标准护理。 小儿炎症性疾病，包括杜氏肌营养不良症（DMD）和炎性 肠道疾病（IBD）。这些强效药物在儿童中的副作用可能很严重， 生长发育迟缓、骨骼脆弱、情绪变化和睡眠障碍等。是 糖皮质激素很少被批准和标记用于儿科疾病， 尽管有这些严重的副作用糖皮质激素首次被批准用于 20世纪50年代在成人疾病中使用，但在发现和开发下一个 具有显著改善的副作用特征的药物的产生令人惊讶地缓慢。这 这归因于糖皮质激素作用机制的复杂性（关于 安全性和有效性），许多儿科疾病使用生物制剂的增长，以及缺乏 由于传统的药物的普遍使用和低成本， 糖皮质激素然而，特别是在儿童中，生活质量的下降和 由糖皮质激素副作用引起的临床护理“成本”是巨大的，但一直很差， 研究了该U 54 RPDP应用程序来自一个具有儿科专业知识的成熟小组 药理学（包括临床儿科药理学新资助的NICHD T32），儿科 药物开发和儿童慢性炎性疾病。在本应用程序中，我们重点关注 儿科炎症性疾病，使用两种疾病范例，DMD和IBD，因为这些可能证明， 是糖皮质激素治疗慢性儿科疾病的伟大代表。的研究小组 儿童国家卫生系统（CNHS）与一家创新的风险慈善机构合作， ReveraGen BioPharma公司，将药效学生物标志物与临床结果联系起来， 儿科人群。在IBD和DMD纵向研究的初步数据中，我们 描述了经验证的药效学生物标志物组的多个安全性方面， 以及抗炎功效。这些药效学安全性和有效性生物标志物正在 用于评估有前途的下一代抗炎类固醇（VBP 15/vamorolone）。的 本申请中提出的项目的目标是将药效学生物标志物与 糖皮质激素（泼尼松）和 VBP15。这将为瓦莫罗龙和其他抗炎药物的临床试验奠定基础， 儿科炎症性疾病，其中获得的数据有望使更多的急性和 使用充分表征的药效学在儿科患者中客观读出药物作用 生物标志物作为结果测量。

Abstract: Daily administration of high dose glucocorticoids is standard of care for the treatment of many pediatric inflammatory diseases, including Duchenne Muscular Dystrophy (DMD) and Inflammatory Bowel Disease (IBD). The side effect profiles of these potent drugs in children can be severe, with stunting of growth, bone fragility, mood changes, and sleep disturbances among many others. It is rare for glucocorticoids to be approved and labeled for pediatric disorders where they are routinely being prescribed, despite these serious side effect profiles. Glucocorticoids were first approved for use in adult disorders in the 1950s, yet progress on discovery and development of the next generation drugs with significantly improved side effect profiles has been surprisingly slow. This has been attributed to the complexity of mechanisms of actions of glucocorticoids (both with regards to safety and efficacy), the growth in use of biologics for many pediatric diseases, and the lack of interest from the pharmaceutical industry given the pervasive use and low cost of traditional glucocorticoids. However, particularly in children, the decrease in quality of life and the increase in clinical care ‘costs’ caused by side effects of glucocorticoids are substantial, but have been poorly studied. This U54 RPDP application is from an established group with expertise in pediatric pharmacology (inclusive of a newly funded NICHD T32 in clinical pediatric pharmacology), pediatric drug development, and chronic inflammatory diseases in children. In this application, we focus on pediatric inflammatory disorders, using two disease exemplars, DMD and IBD, as these may prove to be great representatives of chronic pediatric diseases treated with glucocorticoids. The team at the Children’s National Health System (CNHS) has partnered with an innovative venture philanthropy company, ReveraGen BioPharma, to bridge pharmacodynamic biomarkers to clinical outcomes in the pediatric population. In preliminary data presented in longitudinal studies of both IBD and DMD, we describe validated panels of pharmacodynamic biomarkers for both multiple aspects of safety, as well as anti-inflammatory efficacy. These pharmacodynamic safety and efficacy biomarkers are being used to evaluate a promising next generation anti-inflammatory steroid (VBP15/vamorolone). The goals of the proposed projects in this application are to bridge pharmacodynamic biomarkers to clinical outcomes for specific safety and efficacy aspects of both glucocorticoids (prednisone) and VBP15. This will set the stage for clinical trials of vamolorone and other anti-inflammatory drugs in pediatric inflammatory diseases, where the data obtained is expected to enable more acute and objective readouts of drug action in pediatric patients using well-characterized pharmacodynamic biomarkers as outcome measures.