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.
