THU0194 SELECTIVE INHIBITION OF JANUS KINASE 1 (JAK1) BY FILGOTINIB MODULATES THE DISEASE-ASSOCIATED WHOLE BLOOD TRANSCRIPTIONAL PROFILE OF PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS
ANNALS OF THE RHEUMATIC DISEASES(2019)
摘要
Background Filgotinib (FIL), an oral selective JAK1 inhibitor, was safe and efficacious in FINCH2, a randomized, double-blind, placebo-controlled, phase 3 study in patients with active rheumatoid arthritis (RA) who had an inadequate response to biologic disease-modifying anti-rheumatic drugs (bDMARDs).1 The whole blood transcriptional profile of patients was evaluated. Objectives Identify RA-associated gene transcripts and biological pathways that are altered in response to FIL treatment and interrogate FIL-modulated biomarkers correlated with disease activity. Methods RA patients enrolled in FINCH2 (n=449) were randomized 1:1:1 and received FIL (100 mg, 200 mg) or placebo (PBO) once daily plus a stable background dose of methotrexate. Whole blood samples from enrolled patients were collected at baseline (BL) and weeks 4 and 12 for RNA sequencing. Spearman’s rank correlation of BL disease activity (DAS28[CRP]) was calculated to define disease-associated genes (DAGs) and pathways (DAPs). Differential expression of 5155 genes and FIL-specific changes were determined after subtracting gene expression changes in the PBO group. Biological pathways (910 total) were analyzed by Gene Set Enrichment Analysis (GSEA) or single-sample GSEA. A false-discovery rate of 5% was applied for all analyses. Results At weeks 4 and 12, more genes were significantly differentially expressed in the FIL 200 mg arm vs the 100 mg arm; and, consistent with increased clinical efficacy, the average magnitude of change in gene expression was larger. No single gene reached a threshold of significance for differential expression in PBO-treated patients. FIL treatment induced a stronger reversal of DAG expression (rho range: –0.35 to –0.59) compared to PBO (rho ∼ –0.3) at weeks 4 and 12. DAGs most prominently reversed by FIL included FAM20A and METTL7B. Top-ranked pathways associated positively with disease activity at BL included inflammatory response, complement activity, and cell cycle. Hallmark pathways most significantly reduced following FIL treatment included IL-6/JAK/STAT, inflammatory, and interferon response, consistent with observed effects of FIL in preclinical models and phase 2 DARWIN studies. In contrast, IL-6/JAK/STAT signaling increased at weeks 4 and 12 with PBO. DAPs showed a similar reversal of gene expression (rho range: –0.43 to –0.58) with FIL at weeks 4 and 12 compared to PBO (rho range: –0.007 to –0.024) suggesting that FIL treatment may attenuate RA-mediated IL-6/JAK/STAT signaling, inflammation, and other RA-associated pathways correlated with clinical outcome measures. Conclusion The whole blood transcriptional profile of patients following FIL treatment showed a dose-dependent reduction in the expression of JAK/STAT signaling and inflammation genes. No significant changes in the expression of DAGs were observed in PBO-treated patients. FIL also broadly reversed DAGs and DAPs, and ongoing research is exploring the relationship between changes in gene and pathway modulation across a range of clinical endpoints. Reference [1] Genovese MC, et al. ACR 2018. Abstract L06. Disclosure of Interests Peter C. Taylor Grant/research support from: Celgene, Galapagos, Eli Lilly, UCB, Consultant for: AbbVie, Galapagos, Gilead, Eli Lilly, Pfizer Inc, Bryan Downie Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Luting Zhuo Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Rachael E. Hawtin Shareholder of: Gilead, Employee of: Gilead, Jinfeng Liu Shareholder of: Gilead Sciences, Inc., Roche, Employee of: Gilead Sciences, Inc., Amer M. Mirza Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc.
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