Background/Purpose: Filgotinib (FIL), a selective, oral JAK1 inhibitor, has shown efficacy and safety in 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 populations^1-3 and herein conducted a similar study in RA patients (pts) with prior inadequate response to methotrexate (MTX-IR; FINCH1; ClinicalTrials.gov NCT02889796).

Methods: RA pts with MTX-IR were enrolled and randomized to receive either stable dose of MTX with placebo (PBO+MTX), adalimumab (ADA+MTX), or one of two doses of FIL (FIL 100mg+MTX, FIL 200mg+MTX) once daily. Whole blood samples were collected using PAXgene tubes at baseline, weeks 4, and 12. RNA were extracted and sequenced on Illumina HiSeq 2500 platform following globin RNA depletion. Correlations between baseline gene expression and disease measurements were performed using Spearman’s rank partial correlation with covariates. Differentially expressed genes (DEGs) were identified using voom-limma. Pathway analysis was 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 more rapid transcriptional kinetics for FIL-treated pts compared to ADA+MTX-treated pts. No significant DEGs were observed in PBO-treated pts. More significant DEGs were observed in FIL 200mg+MTX arm compared to FIL 100mg+MTX arm, consistent with superior clinical efficacy of 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 both FIL arms and timepoints, but not in ADA+MTX arm. RA disease activity associated genes^2-3 FAM20A and METTL7B were significantly reduced at both 4 and 12 weeks only in the FIL 200mg+MTX arm. 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. The most prominently down-regulated KEGG pathways included JAK-STAT signaling and leukocyte transendothelial migration.

Conclusion: More rapid and sustained changes of transcriptional activity were observed in the whole blood transcriptional profile of RA pts following FIL 200mg+MTX compared to ADA+MTX treatment. 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.  

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

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/whole-blood-transcriptional-changes-following-selective-inhibition-of-janus-kinase-1-jak1-by-filgotinib-in-adults-with-moderately-to-severely-active-rheumatoid-arthritis-with-prior-inadequate-respon/