LAUSR

Background: Filgotinib (FIL), an oral selective JAK1 inhibitor, has shown efficacy and safety in multiple phase 3 studies in adults with moderately-to-severely active rheumatoid arthritis (RA). We have previously described the molecular response to FIL in large-scale RNA sequencing studies of gene expression in other RA populations1-3 and conducted a similar study in methotrexate (MTX)-naive RA patients (pts) (FINCH3). Objectives: Identify gene transcripts and biological pathways associated with RA and those altered in response to FIL treatment. Methods: MTX-naive RA pts who were enrolled in FINCH3 (ClinicalTrials.gov NCT02886728) received a stable dose of MTX with placebo (PBO+MTX), FIL 200mg alone (FIL 200mg monotherapy), or one of two doses of FIL once daily (QD) together with MTX (FIL 100mg+MTX, FIL 200mg+MTX). Whole blood samples were collected from pts using PAXgene tubes at baseline, week 4, week 12, and week 24. RNA from these samples was extracted and sequenced on the Illumina HiSeq 2500 platform following globin RNA depletion. Correlations between baseline gene expression and disease measurements were performed using Spearman’s rank partial correlation to account for covariates. Differentially expressed genes (DEGs) were identified using voom-limma. Biological pathway analyses were performed on v6.1 of the Molecular Signature Database using single sample gene set enrichment analysis (GSEA) with the focus on immune signaling pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG). A false-discovery rate of 5% was applied for all analyses. Results: Differential gene expression analyses comparing baseline samples with after-treatment samples revealed rapid onset of transcriptional changes in FIL-treated pts, most notably for the two FIL 200mg arms. Fewer DEGs were observed at all timepoints in PBO+MTX treated patients with a peak number at week 24, an observation consistent with the clinical response kinetics of MTX.4 Up to 3x as many significant DEGs were observed in the FIL 200mg+MTX arm compared to the FIL 100mg+MTX arm, a finding consistent with the superior clinical efficacy of the FIL 200mg dosage. As with other FIL clinical trial RNA-seq studies and consistent with the selective MoA of FIL, JAK-STAT pathway-induced genes SOCS2 and CISH were significantly downregulated across FIL treatment arms and timepoints, but not for PBO+MTX. RA disease activity-associated genes2-3 FAM20A and METTL7B were significantly reduced at all timepoints in FIL-treated pts, but only at week 24 in PBO+MTX pts. While no significant changes in KEGG immune signaling pathways were observed in the PBO+MTX arm, a dose-dependent effect on pathway modulation was observed in the FIL arms, including reductions in JAK-STAT, toll-like receptor, chemokine, and RIG-I like receptor signaling. Conclusion: More rapid and sustained changes of transcriptional activity in the whole blood transcriptional profile of RA pts after FIL treatment were found compared to PBO+MTX. Dose-dependent changes were observed in FIL-treated pts, most notably in the KEGG JAK-STAT signaling pathway. These observations confirm an inhibition of JAK-STAT signaling by FIL and are consistent with the observed clinical efficacy of FIL in these pts. References: [1]Taylor PC, et al. (EULAR 2018). http://dx.doi.org/10.1136/annrheumdis-2018-eular.3759 [2]Taylor PC, et al. (ACR 2018). https://doi.org/10.1093/rheumatology/kez105.001 [3]Taylor PC, et al. (EULAR 2019). http://dx.doi.org/10.1136/annrheumdis-2019-eular.2509 [4]Taylor PC, et al. J Clin Med. 2019;8(4): pii: E515. doi: 10.3390/jcm8040515 Acknowledgments: This study was funded by Gilead Sciences, Inc. Editorial support was provided by Fishawack Communications Inc and funded by Gilead Sciences, Inc. Disclosure of Interests: Peter C. Taylor Grant/research support from: Celgene, Eli Lilly and Company, Galapagos, and Gilead, Consultant of: AbbVie, Biogen, Eli Lilly and Company, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer Roche, and UCB, Bryan Downie Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Emon Elboudwarej Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Sam Kim Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Angie Hertz Shareholder of: Gilead Sciences Inc, Employee of: Gilead Sciences Inc, Amer M. Mirza Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Jeffrey Siegel Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Rachael E. Hawtin Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Jinfeng Liu Shareholder of: Gilead Sciences Inc., Roche, Employee of: Gilead Sciences Inc.