THU0194 SELECTIVE INHIBITION OF JANUS KINASE 1 (JAK1) BY FILGOTINIB MODULATES THE DISEASE-ASSOCIATED WHOLE BLOOD TRANSCRIPTIONAL PROFILE OF PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS
Authors: Peter C. Taylor, Bryan Downie, Luting Zhuo, Rachael E. Hawtin, Jinfeng Liu, Amer M. Mirza
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> 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).<sup>1</sup> The whole blood transcriptional profile of patients was evaluated. <h3>Objectives</h3> 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. <h3>Methods</h3> 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. <h3>Results</h3> 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 <i>FAM20A</i> and <i>METTL7B</i>. 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. <h3>Conclusion</h3> 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. <h3>Reference</h3> [1] Genovese MC, et al. ACR 2018. Abstract L06. <h3>Disclosure of Interests</h3> 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.