P535 Effects of the Janus Kinase 1 (JAK1)-selective inhibitor filgotinib on circulating cytokines and whole-blood genes/pathways of patients with moderately to severely active Crohn’s disease (CD)

Background

A Phase 2 study of the JAK1-selective inhibitor filgotinib (FIL) dosed at 200 mg once daily for 10 weeks in moderately to severely active CD (FITZROY, ClinicalTrial.gov #NCT02048618) demonstrated significantly higher clinical remission rates compared with placebo,¹ and early decrease in systemic and mucosal inflammation biomarkers that was more pronounced in endoscopic responders.² We investigated baseline (BL) correlation of whole-blood transcriptome pathway activities with clinical disease indexes and circulating cytokines. The effect of FIL on changes in disease-related pathways in responders and nonresponders was also explored.

Methods

PAXgene blood samples were collected from 104 CD patients at BL and Week 10 (W10). RNA was sequenced (Illumina HiSeq 2500) after globin depletion (ThermoFisher GlobinClear). Differential gene expression analysis was performed using the limma R package,³ and Hallmark pathway⁴ activity scores were calculated using a single-sample Gene Set Enrichment Analysis (ssGSEA).⁵ All correlations were performed using the Spearman method.

Results

At BL, pathways with activity scores positively correlated with Simple Endoscopic Score for Crohn’s Disease (SES-CD) were immune (IL6/JAK/STAT3, inflammatory response), metabolic, and reactive oxygen species (ROS). These were also positively correlated with systemic inflammation (CRP, SAA, IL6, and OSM) and epithelial turnover (IL22, C4M2, and C3M) markers. Ten weeks of FIL treatment led to significant decreases in these pathways in endoscopic responders (50% reduction in SES-CD) (Figure), whereas there were no significant changes by placebo treatment. While interferon (IFN) response pathway scores showed a weak correlation (rho < 0.2) with SES-CD at BL, they are significantly reduced by FIL treatment, particularly in FIL responders.

Figure. Filgotinib treatment effect in whole-blood. The pathway score is standardised using the mean and standard deviation of ssGSEA scores of BL samples. Each dot is coloured by the Spearman correlation coefficient with SES-CD; black encircled dots denote statistically significant (p < 0.05) pathway change from BL. Per cent expr gene is the proportion of genes in the pathway gene list expressed in whole blood (>10% of samples)