Definition of pharmacodynamic biomarkers for juvenile dermatomyositis for clinical trials Juvenile dermatomyositis (JDM) is a rare disease with an incidence rate in the United States of 3.2 children per million per year (Mendez et al 2003), and is the most common (85%) member of the group of inflammatory juvenile myopathies (JM). Children with JDM display a classic heliotrope rash, Gottron's papules, symmetrical proximal muscle weakness, and elevated muscle-derived enzymes in blood. Muscle biopsy shows perifascicular muscle fiber atrophy and an associated progressive capillary occlusion and an inflammatory infiltrate. Chronic treatment with glucocorticoids leads to significant side effects that detract from patient quality of life, including osteopenia with risk for bone fracture and cataracts. Vamorolone is a first-in-class dissociative steroidal drug that has orphan designation with both FDA and EMA, and has been granted Fast-Track designation by FDA for first-in-patient studies in Duchenne muscular dystrophy (DMD). Vamorolone shows complete loss of most or all side effects associated with glucocorticoids in both pre-clinical (murine) studies, and human Phase 1 trials to doses 30-times typical glucocorticoid doses. Here, we propose research on banked JDM patient samples that will lead to an IND and proof-of-concept trial of vamorolone in JDM. The proposed SBIR research integrates and creates synergism between a NIH-funded centers ? NICHD Research Program on Developmental Pharmacology ? with the vamorolone orphan drug development program of ReveraGen Biopharma. We propose to build on our recently reported glucocorticoid-responsive pharmacodynamic biomarkers in both Duchenne muscular dystrophy (DMD) and pediatric inflammatory bowel disease (IBD). These biomarkers are in current utilization in the ongoing DMD Phase 2 trials sponsored by ReveraGen. In this current SBIR, we plan to carry out a validation of these existing DMD/IBD pharmacodynamic biomarkers in JDM patient samples, as well as carry out deep biomarker discovery in banked blood samples from our JDM Biorepository. The mean age of disease onset in JDM is 6.7 years. These cross-disease, and JDM-specific biomarkers will be translated to a targeted panel (MSD, immunoblots, or targeted mass spec). The deliverable of Aim 1 will be a robust, validated pharmacodynamic biomarker panel for glucocorticoid response; some markers are anticipated to be shared with DMD and IBD, and some specific to JDM. We then propose to design a Phase II proof of concept clinical trial using these biomarkers in the context of use of a feasibility study, and submit a FDA IND for this trial. The trial is envisioned as a small, short-term dose-ranging pilot trial, with pharmacodynamic efficacy biomarkers as the primary endpoints (Aim 2). This proposal is for design of the trial only ? future Phase 2 SBIR funding will be sought to submit the FDA IND, orphan drug designation, and to carry out the trial.
