O39 Defining serum CCL22 and trefoil factor 3 (TFF3) as pharmacodynamic biomarkers for use in a proof-of-concept clinical trial of vamorolone in paediatric ulcerative colitis
Authors: Conklin LS , Panigrahi A , Gordish-Dressman H , Hoffman EP , Hathout Y , van den Anker JN , Diaz-Calderon L 
Published: May 2019

BackgroundPaediatric ulcerative colitis (UC) patients would be well-served by a non-steroidal drug to control mucosal inflammation, without long-term and costly commitment to biologics. Vamorolone is a first-in-class alternative to glucocorticoids (GCs), under development for children with Duchenne muscular dystrophy (DMD); preliminary findings demonstrate improved safety compared with GCs1,2. We sought to define NFkB-regulated, GC-responsive serum biomarkers for use in a proof-of-concept pilot trial of vamorolone in UC, focusing on TFF3 (produced by intestinal epithelia, GC-responsive in UC), and CCL22 (produced by macrophages, GC-responsive in UC and other inflammatory diseases)3,4.MethodsSera from 10 children with IBD (7 UC, 3 CD) were tested pre and post prednisone/prednisolone (1 mg/kg/day, max 40 mg, 1–4 weeks); 210 proteins responsive to GCs in UC 3 were analyzed using SOMAscan. Proteins that showed significant change over time were correlated with change in Paediatric Ulcerative Colitis Activity Index (PUCAI) (p < 0.05 significance). Percent change in circulating CCL22 was compared with percent change in DMD patients treated with vamorolone (2 and 6 mg/kg/day, 2 weeks)2. Immunoassays were utilized to validate SOMAscan data.ResultsCCL22 and TFF3 validated as decreased by GCs in IBD (p=0.005, p < 0.001). Decrease in TFF3 correlated with decrease in PUCAI (r=0.741, p=0.022); decrease in CCL22 did not correlate with change in PUCAI. Magnitude of CCL22 decrease in GC-treated UC patients was comparable to that seen in DMD patients treated with 6 mg/kg of vamorolone (47% vs. 33%). SOMAscan findings in UC validated by immunoassays.ConclusionDecreases in serum CCL22 likely reflect effect on innate immune response, while decreases in serum TFF3 may reflect intestinal-specific effects of GCs in UC. CCL22 and TFF3, measured by immunoassays, may be useful as objective secondary outcomes reflective of NFkB inhibition and anti-inflammatory activity in a proof-of-concept trial of vamorolone in paediatric UC.ReferencesHoffman EP, et al. Phase 1 trial of vamorolone, a first-in-class steroid, shows improvements in side effects via biomarkers bridged to clinical outcomes. Steroids. 2018 Jun;134:43–52.Conklin LS, et al. Phase IIa trial in Duchenne muscular dystrophy shows vamorolone is a first-in-class dissociative steroidal anti-inflammatory drug. Pharmacol Res. 2018 Oct;136:140–150.Heier CM, et al. Identification of pathway-specific serum biomarkers of response to glucocorticoid and infliximab treatment in children with inflammatory bowel disease. Clin Transl Gastroenterol. 2016 Sep 15;7(9): e192.Conklin LS, et al. Serum biomarkers of glucocorticoid response and safety in anti-neutrophil cytoplasmic antibody-associated vasculitis and juvenile dermatomyositis. Steroids. 2018 Dec; 140:159–166.Disclosure(s)LSC, JNvdA, and EPH are employees of ReveraGen BioPharma. LSC and JNvdA own stock options of ReveraGen. EPH is a co-founder of ReveraGen and owns founder shares.