Bridging pharmacodynamic biomarkers to clinical outcomes in pediatric inflammatory diseases

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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.