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.
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