Project Summary/Abstract
Antineutrophil cytoplasmic antibody (ANCA) – associated vasculitis (AAV) is a group of rare organ-and life-
threatening multisystem diseases involving inflammation and destruction of small blood arteries. AAV appears
mediated by neutrophils, but the mechanisms underlying the neutrophil infiltration and activation are poorly
understood. The disease is treated with glucocorticoids and other anti-inflammatory and immunosuppressive
medications. In most cases of new or relapsing AAV, induction of remission in AAV is accomplished by
several months of high-dose daily oral glucocorticoids combined with either cyclophosphamide or rituximab,
followed by a maintenance phase of treatment with often chronic, daily, low-dose glucocorticoids along with
another immunosuppressive agent. Due to the intensity and duration of the treatment with glucocorticoids and
high relapse rate, the overall burden to patients in terms of drug toxicity and permanent damage is substantial.
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 sera samples from patients with AAV that will lead to an IND and proof-
of-concept trial of vamorolone for the treatment of AAV. The proposed research integrates, and creates
synergism, between two NIH-funded centers: the NIAMS-supported Vasculitis Clinical Research Consortium
(VCRC), and the NICHD Research Program on Developmental Pharmacology, in partnership with the NINDS-
funded vamorolone orphan drug development program of ReveraGen Biopharma. We propose to build on our
recently-reported glucocorticoid-responsive pharmacodynamic biomarkers in both DMD and pediatric
inflammatory bowel disease (IBD) that are in current use in the Phase 2 trials in DMD. In this proposal we plan
to use samples from our VCRC Biorepository to carry out i) a validation study of these existing DMD/IBD
biomarkers; and ii) deep biomarker discovery of AAV-specific markers of response to glucocorticoids. These
cross-disease and vasculitis-specific biomarkers will then be translated to a targeted panel (targeted mass
spectrometry, immunoassays [MSD, Luminex, immunoblots]). The deliverable of Aim 1 will be a set of robust,
validated pharmacodynamic biomarkers for glucocorticoid response and toxicity; some markers will be
common to AAV, DMD, and IBD, and some specific to AAV. We propose in Aim 2 to design a small, short-
term, dose-ranging, Phase IIa proof-of-concept clinical trial using these biomarkers as the primary endpoint,
and subsequently submit an IND to the FDA for this trial. Both the NIAMS RFA and the 21st Century Cures Act
encourages innovative approaches to expediting drug efficacy and safety studies, including the use of fit-for-
purpose biomarkers, especially for expansion of labeling; our research plan speaks directly to these goals.
