Trials in pediatric Inflammatory Bowel Disease (IBD) (Crohn?s disease [CD] and ulcerative colitis [UC]) are challenging because of the lack of validated patient-reported outcome measures and non-invasive biomarkers of disease response, as well as poor correlation between symptoms and objective measures of inflammation. Vamorolone is a novel dissociative glucocorticoid which offers significant safety benefits for children with IBD, particularly the lack of steroid-associated effects on growth and bone mineral density, side effects of which children with IBD are particularly vulnerable. Within the context of planning a short-term phase 2 trial design of vamorolone in the treatment of pediatric ulcerative colitis (UC) (Aim 4), we are exploring the use of non-invasive pharmacodynamic (PD) biomarkers that may be bridged to both safety and efficacy outcomes. The short-term treatment course and relatively quick symptom response to steroids experienced by patients with IBD allows for correlation of symptom response with changes in serum proteins. In addition, the objective endpoint of endoscopic assessment of inflammation (visually and histologically), expected not with GCs but with anti-TNF therapy, is a critical outcome to be bridged to changes in efficacy PD biomarkers, which may be seen acutely (predictive) or after a longer treatment course (reflective of a target endpoint). To generate a cohort of candidate serum efficacy biomarkers that may be correlated with symptom-based and objective clinical outcomes related to reduction of inflammation, we used a SomaScan? aptamer-based proteomic discovery platform to identify proteins that are elevated at baseline, and decrease across both GC and anti-TNF treatment groups. In Project 2, we aim to collect serum and mucosal biopsies samples to correlate novel candidate efficacy PD biomarkers with clear symptom-based and objective measures of disease activity in UC and CD. As supportive data for Project 2, we also demonstrated an increase in serum proteins among IBD patients treated with GCs that mirror those safety biomarkers increased by longer-term GC treatment of children with another inflammatory disease, Duchenne muscular dystrophy (DMD). If GC-specific safety biomarkers are to be used in clinical trials of vamorolone in pediatric UC, their increased acute expression must be correlated with physical findings reflecting side effects associated with GC, as has been accomplished in studies of DMD (Project 1). The development of outcome- bridged efficacy PD biomarkers would improve clinical patient care for children with UC and Crohn?s disease (CD) by providing early evidence of physiologic response, alleviating the need to blindly wait-and-see if the patient will respond before altering therapy. PD safety and efficacy biomarkers would also support clinical trials of vamorolone, and other novel anti-inflammatory therapies. PD markers and patient-reported outcome measures may prove ideal co-endpoints for IBD trials, reducing costs and complications associated with endoscopy, and supporting extrapolation of data between patient cohorts.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZHD1-DSR-Z (50))
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Children's Research Institute
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Ziesenitz, Victoria C; Vaughns, Janelle D; Koch, Gilbert et al. (2018) Pharmacokinetics of Fentanyl and Its Derivatives in Children: A Comprehensive Review. Clin Pharmacokinet 57:125-149
Fiorillo, Alyson A; Tully, Christopher B; Damsker, Jesse M et al. (2018) Muscle miRNAome shows suppression of chronic inflammatory miRNAs with both prednisone and vamorolone. Physiol Genomics 50:735-745
Conklin, Laurie S; Damsker, Jesse M; Hoffman, Eric P et al. (2018) Phase IIa trial in Duchenne muscular dystrophy shows vamorolone is a first-in-class dissociative steroidal anti-inflammatory drug. Pharmacol Res 136:140-150