Bridging pharmacodynamic biomarkers to clinical outcomes in pediatric inflammatory diseases

摘要： 每天服用大剂量糖皮质激素是治疗许多 儿童炎症性疾病，包括杜氏肌营养不良症(DMD)和炎症性疾病 肠病(IBD)。这些强效药物在儿童中的副作用可能很严重， 发育迟缓、骨骼脆弱、情绪变化和睡眠障碍等。它是 糖皮质激素很少被批准并贴上标签用于儿科疾病，而这些疾病通常是 尽管有这些严重的副作用，但仍在处方中。糖皮质激素首次被批准用于 在20世纪50年代用于成人障碍，但在下一代的发现和发展方面取得了进展 副作用显著改善的新一代药物的开发速度令人惊讶地缓慢。这有 归因于糖皮质激素作用机制的复杂性(与 安全性和有效性)，许多儿科疾病使用生物制品的增长，以及缺乏 由于传统药物的广泛使用和低成本，制药业对其感兴趣 糖皮质激素。然而，特别是在儿童中，生活质量的下降和儿童生活质量的增加 糖皮质激素副作用造成的临床护理“成本”很高，但一直很低 学习。此U54 RPDP应用程序来自具有儿科专业知识的成熟团队 药理学(包括一项新资助的NICHD T32临床儿科药理学)，儿科 药物开发和儿童慢性炎症性疾病。在本应用程序中，我们重点介绍 儿科炎症性疾病，使用两种疾病样本，DMD和IBD，这些可能被证明 成为糖皮质激素治疗的慢性儿科疾病的伟大代表。这支队伍在 儿童国家健康系统(CNHS)与一家创新的慈善机构合作 ReveraGen BioPharma公司将药效生物标记物与临床结果联系起来 儿科人口。在对IBD和DMD的纵向研究中提供的初步数据中，我们 描述经过验证的药效学生物标记物小组，用于安全性的多个方面，如 以及抗炎功效。这些药效学的安全性和有效性生物标记物正在 用于评估一种有前景的新一代抗炎类固醇(VBP15/艾美龙)。这个 本申请中提出的项目的目标是将药效学生物标志物连接到 糖皮质激素(泼尼松)和联合用药在特定安全性和有效性方面的临床结果 VBP15。这将为阿莫洛酮和其他抗炎药的临床试验奠定基础。 儿科炎症性疾病，在那里获得的数据预计将使更急性和 用特征明确的药效学方法对儿科患者药物作用的客观读数 生物标记物作为结果衡量标准。

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.