Background Paediatric 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. Methods Sera 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 Results CCL22 and TFF3 validated as decreased by GCs in IBD (p=0.005, p Conclusion Decreases 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. References Hoffman 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.

https://adc.bmj.com/content/archdischild/104/6/e17.1.full.pdf

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

Background Physiologic changes associated with pregnancy may have a large impact on drug disposition. The goal of this study was to build PBPK maternal-fetal models to predict the fetal exposure to antiviral drugs including emtricitabine and acyclovir. Methods PBPK models were built in the Open Systems Pharmacology Software Suite version 7.3 (www.open-systems-pharmacology.org). The maternal-fetal PBPK model structure was developed in MoBi and exported to PK-Sim for population simulations. Placental transfer was parameterized based on data from ex vivo cotyledon perfusion experiments. The predictive performance of the PBPK models was evaluated via comparison with in vivo data. The pregnancy data for those drugs were from in vivo maternal and fetal blood samples taken at delivery. Results In the acyclovir ex vivo experimental data simulation, the fitted was 0.056 L/h (95% confidence interval: 0.043 - 0.069 L/h) and the fitted was 0.49 (95% confidence interval: 0.39 - 0.59). The predicted ratio between acyclovir in vivo concentrations in the umbilical vein plasma and the maternal plasma ranged from 0.37 - 0.77, whereas the observed ratios were slightly higher and ranged from 0.61 - 1.1.1 The previously published, and CLpl (1.49 1/h) parameters2 were applied to the emtricitabine maternal-fetal PBPK model, and the emtricitabine concentrations in the umbilical cord were adequately predicted. Conclusion These results increase the confidence in applying PBPK models to predict maternal and fetal drug exposure. Improved maternal-fetal PBPK models may streamline and accelerate the performance of pharmacokinetic and safety studies for drugs in pregnant women. References Frenkel LM, et al. Pharmacokinetics of acyclovir in the term human pregnancy and neonate. Am J Obstet Gynecol 1991;164:569–76. De Sousa Mendes M, et al. Prediction of human fetal pharmacokinetics using ex vivo human placenta perfusion studies and physiologically based models. Brit J Clin Pharmacol 2016;81:646–57. Disclosure(s) The opinions expressed in this article are those of the authors and should not be interpreted as the position of the U.S. Food and Drug Administration or of the National Institutes of Health. The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

https://adc.bmj.com/content/archdischild/104/6/e16.1.full.pdf

O36 Physiologically based pharmacokinetic models to predict fetal exposure to antiviral drugs

Recently DNA sequencing analysis has played a vital role in the unambiguous diagnosis of clinically suspected patients with Duchenne Muscular Dystrophy (DMD) DMD is a monogenic, X-linked, recessive, degenerative pediatric neuromuscular disorder affecting males, invariably leading to fatal cardiopulmonary failure Early and precise diagnosis of the disease is an essential part of an effective disease management strategy as care guidelines and prevention through counseling need to be initiated at the earliest particularly since therapies are now available for a subset of patients In this manuscript we report the DMD gene mutational profiles of 961 clinically suspected male DMD patients, 99% of whom were unrelated We utilized a molecular diagnostic approach which is cost-effective for most patients and follows a systematic process that sequentially involves identification of hotspot deletions using mPCR, large deletions and duplications using MLPA and small insertions/ deletions and point mutations using an NGS muscular dystrophy gene panel Pathogenic DMD gene mutations were identified in 84% of patients Our data compared well with the frequencies and distribution of deletions and duplications reported in the DMD gene in other published studies We also describe a number of rare in-frame mutations, which appeared to be enriched in the 5' proximal hotspot region of the DMD gene Furthermore, we identified a family with a rare non-contiguous deletion mutation in the DMD gene where three males were affected and two females were deemed carriers A subset of patients with mutations in the DMD gene who are likely to benefit therapeutically from new FDA and EMA approved drugs were found in our cohort Given that the burden of care for DMD patients invariably falls on the mothers, particularly in rural India, effective genetic counseling followed by carrier screening is crucial for prevention of this disorder We analyzed the carrier status of consented female relatives of 463 probands to gauge the percentage of patients with familial disease Our analysis revealed 437% of mothers with DMD gene mutations Our comprehensive efforts, involving complete genetic testing coupled with compassionate genetic counseling provided to DMD patients and their families, are intended to improve the quality of life of DMD patients and to empower carrier females to make informed reproductive choices to impede the propagation of this deadly disease

/pdf/comprehensive-genetic-analysis-of-961-unrelated-duchenne-2347ho0ang.pdf

Comprehensive genetic analysis of 961 unrelated Duchenne Muscular Dystrophy patients: Focus on diagnosis, prevention and therapeutic possibilities.

Endocrinology of bone and growth disorders

ABSTRACT We report a first‐in‐patient study of vamorolone, a first‐in‐class dissociative steroidal anti‐inflammatory drug, in Duchenne muscular dystrophy. This 2‐week, open‐label Phase IIa multiple ascending dose study (0.25, 0.75, 2.0, and 6.0 mg/kg/day) enrolled 48 boys with Duchenne muscular dystrophy (4 to <7 years), with outcomes including clinical safety, pharmacokinetics and pharmacodynamic biomarkers. The study design included pharmacodynamic biomarkers in three contexts of use: 1. Secondary outcomes for pharmacodynamic safety (insulin resistance, adrenal suppression, bone turnover); 2. Exploratory outcomes for drug mechanism of action; 3. Exploratory outcomes for expanded pharmacodynamic safety. Vamorolone was safe and well‐tolerated through the highest dose tested (6.0 mg/kg/day) and pharmacokinetics of vamorolone were similar to prednisolone. Using pharmacodynamic biomarkers, the study demonstrated improved safety of vamorolone versus glucocorticoids as shown by reduction of insulin resistance, beneficial changes in bone turnover (loss of increased bone resorption and decreased bone formation only at the highest dose level), and a reduction in adrenal suppression. Exploratory biomarkers of pharmacodynamic efficacy showed an anti‐inflammatory mechanism of action and a beneficial effect on plasma membrane stability, as demonstrated by a dose‐responsive decrease in serum creatine kinase activity. With an array of pre‐selected biomarkers in multiple contexts of use, we demonstrate the development of the first dissociative steroid that preserves anti‐inflammatory efficacy and decreases steroid‐associated safety concerns. Ongoing extension studies offer the potential to bridge exploratory efficacy biomarkers to clinical outcomes.

Phase IIa trial in Duchenne Muscular Dystrophy shows vamorolone is a firs-in-class dissociative steroidal anti-inflammatory drug.

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Phase IIa trial in Duchenne Muscular Dystrophy shows vamorolone is a firs-in-class dissociative steroidal anti-inflammatory drug.