Date: Sunday, November 8, 2020
Session Type: Poster Session C
Session Time: 9:00AM-11:00AM
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 RA. Previously, we described molecular response to FIL in large-scale RNA sequencing studies of gene expression in other RA populations1-3.We conducted a similar study in methotrexate (MTX)-naïve RA patients (pts) (FINCH3; ClinicalTrials.gov NCT02886728) to identify gene transcripts and biological pathways associated with RA and altered in response to FIL.
Methods: MTX-naïve RA pts received stable dose of MTX+placebo (PBO+MTX), FIL 200mg alone (FIL 200mg), FIL 100mg+MTX, or FIL 200mg+MTX. Whole blood samples were collected using PAXgene tubes at baseline (BL), weeks 4, 12, and 24. RNA was extracted and sequenced on Illumina HiSeq 2500 platform following globin RNA depletion. Correlations between BL 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 Molecular Signature Database v6.1 using single sample gene set enrichment analysis with focus on immune signaling pathways from Kyoto Encyclopedia of Genes and Genomes (KEGG). A false-discovery rate of 5% was applied.
Results: Differential gene expression analyses comparing BL samples with after-treatment samples showed rapid onset of transcriptional changes in FIL pts. Fewer DEGs were observed in PBO+MTX patients with peak number at week 24, an observation consistent with MTX clinical response kinetics.4 Up to 3x as many significant DEGs were observed in FIL 200mg+MTX compared to FIL 100mg+MTX arm, a finding consistent with superior clinical efficacy of FIL 200mg. 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 arms and timepoints, but not PBO+MTX. RA disease activity-associated genes2-3 FAM20A and METTL7B were significantly reduced at all timepoints in FIL pts, but only at week 24 in PBO+MTX. While no significant changes in KEGG immune signaling pathways were observed in PBO+MTX arm, a dose-dependent effect on pathway modulation was observed in 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 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 KEGG JAK-STAT signaling pathway. These observations confirm an inhibition of JAK-STAT signaling by FIL and are consistent with observed clinical efficacy of FIL in these pts.
- Taylor PC, et al. (EULAR 2018). http://dx.doi.org/10.1136/annrheumdis-2018-eular.3759
- Taylor PC, et al. (ACR 2018). https://doi.org/10.1093/rheumatology/kez105.001
- Taylor PC, et al. (EULAR 2019). http://dx.doi.org/10.1136/annrheumdis-2019-eular.2509
- Taylor PC, et al. J Clin Med. 2019;8(4): pii: E515. doi: 10.3390/jcm8040515
To cite this abstract in AMA style:Taylor P, Downie B, Elboudwarej E, Kim S, Hertz A, Mirza A, Siegel J, Hawtin R, Liu J. Whole Blood Transcriptional Changes Following Selective Inhibition of Janus Kinase 1 (JAK1) by Filgotinib in MTX-Naïve Adults with Moderately-to-Severely Active Rheumatoid Arthritis (RA) [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/whole-blood-transcriptional-changes-following-selective-inhibition-of-janus-kinase-1-jak1-by-filgotinib-in-mtx-naive-adults-with-moderately-to-severely-active-rheumatoid-arthritis-ra/. Accessed January 23, 2022.
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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-mtx-naive-adults-with-moderately-to-severely-active-rheumatoid-arthritis-ra/