Definition of pharmacodynamic biomarkers for juvenile dermatomyositis for clinical trials

Definition of pharmacodynamic biomarkers for juvenile dermatomyositis for clinical trials Juvenile dermatomyositisJDMis a rare disease with an incidence rate in the United States ofchildren per million per yearMendez et aland is the most commonmember of the group of inflammatory juvenile myopathiesJMChildren with JDM display a classic heliotrope rashGottronandapos s papulessymmetrical proximal muscle weaknessand elevated muscle derived enzymes in bloodMuscle biopsy shows perifascicular muscle fiber atrophy and an associated progressive capillary occlusion and an inflammatory infiltrateChronic treatment with glucocorticoids leads to significant side effects that detract from patient quality of lifeincluding osteopenia with risk for bone fracture and cataractsVamorolone is a first in class dissociative steroidal drug that has orphan designation with both FDA and EMAand has been granted Fast Track designation by FDA for first in patient studies in Duchenne muscular dystrophyDMDVamorolone shows complete loss of most or all side effects associated with glucocorticoids in both pre clinicalmurinestudiesand human Phasetrials to dosestimes typical glucocorticoid dosesHerewe propose research on banked JDM patient samples that will lead to an IND and proof of concept trial of vamorolone in JDMThe proposed SBIR research integrates and creates synergism between a NIH funded centersNICHD Research Program on Developmental Pharmacologywith the vamorolone orphan drug development program of ReveraGen BiopharmaWe propose to build on our recently reported glucocorticoid responsive pharmacodynamic biomarkers in both Duchenne muscular dystrophyDMDand pediatric inflammatory bowel diseaseIBDThese biomarkers are in current utilization in the ongoing DMD Phasetrials sponsored by ReveraGenIn this current SBIRwe plan to carry out a validation of these existing DMD IBD pharmacodynamic biomarkers in JDM patient samplesas well as carry out deep biomarker discovery in banked blood samples from our JDM BiorepositoryThe mean age of disease onset in JDM isyearsThese cross diseaseand JDM specific biomarkers will be translated to a targeted panelMSDimmunoblotsor targeted mass specThe deliverable of Aimwill be a robustvalidated pharmacodynamic biomarker panel for glucocorticoid responsesome markers are anticipated to be shared with DMD and IBDand some specific to JDMWe then propose to design a Phase II proof of concept clinical trial using these biomarkers in the context of use of a feasibility studyand submit a FDA IND for this trialThe trial is envisioned as a smallshort term dose ranging pilot trialwith pharmacodynamic efficacy biomarkers as the primary endpointsAimThis proposal is for design of the trial onlyfuture PhaseSBIR funding will be sought to submit the FDA INDorphan drug designationand to carry out the trial The goal of this project is to define pharmacodynamic biomarkers of steroid response in juvenile dermatomyositisthen utilize these as endpoints in design of a short term trial of vamorolone