Establishing a biomarker framework for feasibility studies of vamorolone in vasculitis

Project Summary Abstract Antineutrophil cytoplasmic antibodyANCAassociated vasculitisAAVis a group of rare organ and lifethreatening multisystem diseases involving inflammation and destruction of small blood arteriesAAV appears mediated by neutrophilsbut the mechanisms underlying the neutrophil infiltration and activation are poorly understoodThe disease is treated with glucocorticoids and other anti inflammatory and immunosuppressive medicationsIn most cases of new or relapsing AAVinduction of remission in AAV is accomplished by several months of high dose daily oral glucocorticoids combined with either cyclophosphamide or rituximabfollowed by a maintenance phase of treatment with often chronicdailylow dose glucocorticoids along with another immunosuppressive agentDue to the intensity and duration of the treatment with glucocorticoids and high relapse ratethe overall burden to patients in terms of drug toxicity and permanent damage is substantialVamorolone 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 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 sera samples from patients with AAV that will lead to an IND and proofof concept trial of vamorolone for the treatment of AAVThe proposed research integratesand creates synergismbetween two NIH funded centersthe NIAMS supported Vasculitis Clinical Research ConsortiumVCRCand the NICHD Research Program on Developmental Pharmacologyin partnership with the NINDSfunded vamorolone orphan drug development program of ReveraGen BiopharmaWe propose to build on our recently reported glucocorticoid responsive pharmacodynamic biomarkers in both DMD and pediatric inflammatory bowel diseaseIBDthat are in current use in the Phasetrials in DMDIn this proposal we plan to use samples from our VCRC Biorepository to carry out ia validation study of these existing DMD IBD biomarkersand iideep biomarker discovery of AAV specific markers of response to glucocorticoidsThese cross disease and vasculitis specific biomarkers will then be translated to a targeted paneltargeted mass spectrometryimmunoassaysMSDLumineximmunoblotsThe deliverable of Aimwill be a set of robustvalidated pharmacodynamic biomarkers for glucocorticoid response and toxicitysome markers will be common to AAVDMDand IBDand some specific to AAVWe propose in Aimto design a smallshorttermdose rangingPhase IIa proof of concept clinical trial using these biomarkers as the primary endpointand subsequently submit an IND to the FDA for this trialBoth the NIAMS RFA and thest Century Cures Act encourages innovative approaches to expediting drug efficacy and safety studiesincluding the use of fit forpurpose biomarkersespecially for expansion of labelingour research plan speaks directly to these goals Project Narrative Antineutrophil cytoplasmic antibodyANCAassociated vasculitisAAVis a group of rare organ and lifethreatening multisystem diseases treated in most cases with several months of high dose daily oral glucocorticoids combined with another immunosuppressive agentfollowed by months years of low dose daily glucocorticoidswith the substantial toxicity and permanent damage associated with glucocorticoidsVamorolone is a first in class dissociative steroidal drug that has orphan designation with both FDA and EMA and ihas been granted Fast Track designation by FDA for first in patient studies in Duchenne muscular dystrophyDMDand iishows complete loss of most or all side effects associated with glucocorticoids in both pre clinicalmurineand human studiesHerewe propose research on banked sera samples from patients with AAV to develop biomarkers of glucocorticoid toxicity and response that will lead to an IND and proof ofconcept trial of vamorolone for the treatment of AAV