THU0216 PERIPHERAL PROTEIN BIOMARKER CHANGES FOLLOWING SELECTIVE INHIBITION OF JANUS KINASE 1 (JAK1) BY FILGOTINIB IN METHOTREXATE NAÏVE ADULTS WITH MODERATELY-TO-SEVERELY ACTIVE RHEUMATOID ARTHRITIS (FINCH3)

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), including those who are naive to methotrexate (MTX) therapy (FINCH3; NCT02886728). Objectives: A longitudinal study of protein biomarkers related to JAK signaling1, bone biology2, immune cell migration2, and inflammation2 was conducted in FINCH3 pts to identify disease relevant biomarkers that are altered by FIL vs MTX. Methods: MTX-naive RA pts enrolled in FINCH3 received a stable dose of MTX (MTX mono), FIL200mg monotherapy (FIL200mg mono) or one of two doses of FIL once daily with MTX (FIL100mg+MTX, FIL200mg+MTX). Up to 27 disease relevant biomarkers were evaluated. Baseline (BL) correlation between biomarkers and clinical response measures were analyzed by Spearman Rank. Multiscale bootstrap resampling was used to evaluate significant intra-cluster biomarker membership. Mean changes in biomarker levels from BL to wks 4, 12 and 24 were compared between arms using MTX-adjusted estimates from a linear mixed effects model, adjusted for age, sex, race and BL biomarker level. A false discovery rate of 5% was applied for all analyses. Results: At BL, distinct clusters (CL) of biomarkers differentiated by JAK signaling were identified. The strongest intra-group correlations were in biomarkers upstream of JAK2 signaling (CL1; Rho range 0.88–0.98) and cytokines associated with JAK1 signaling (CL2; Rho range 0.72–0.77). Within MTX-naive RA pts, there were significant BL correlations between 15 biomarkers and clinical measures. The strongest associations observed were between DAS28CRP and IL6, CXCL10, TNFRI, YKL-40, and CXCL13 (Rho \u003e0.3). Relative to MTX mono, 23 biomarkers exhibited significant early responses to treatment (any arm, wk 4). The strongest treatment effect observed at wk 4 was a reduction by FIL+MTX (regardless of dose) and FIL200mg mono for CXCL13 (FIL100mg+MTX: -28.2%; FIL200mg+MTX: -40%; FIL200mg: -34%). This reduction was sustained in each arm through 24 wks, with the greatest reduction by FIL200mg+MTX (-37.8%). Dose differences were observed relative to FIL100mg+MTX, where FIL200mg+MTX led to an early (wk 4) and significantly greater reduction of 9 biomarkers. There was a significant dose difference as a delayed response (wk 24) with a greater reduction by FIL200mg+MTX for 8 biomarkers. FIL200mg mono produced a greater effect on 18 biomarkers vs MTX mono, remaining significant through wk 24. The greatest effect in FIL200mg mono were reductions by wk 24 in CTX1 (-29.1%), CXCL13 (-33.2%), and IL6 (-29.5%), all of which were biomarkers associated with DAS28CRP at BL. Effects observed at any time point were largely similar between FIL200mg as a mono or in combination with MTX. Four biomarkers were uniquely different between FIL200mg mono and FIL200mg+MTX arms by wk 24: greater increase of MMP7 and decrease of GMCSF in FIL200mg+MTX; greater decrease of TRACP5B and ICAM1 in FIL200mg alone. Conclusion: Treatment through 24 weeks with FIL200mg (mono or with MTX) reduced many of the disease-relevant biomarkers tested; markers related to JAK signaling1, bone biology2, inflammation2, and immune cell migration2 in the MTX-naive RA setting. Changes were significantly reduced relative to MTX mono at wk 4, supporting the rapid onset of FIL clinical efficacy. The current study identified significant reductions of RA-associated disease markers that were unique to FIL mono, supporting the FIL mechanisms of action in the treatment of RA. References: [1]Majoros A, et al. Front Immunol. 2017;8:29 [2]Brennan F, and McInnes I. J Clin Invest. 2008;118:3537-45 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, Amer M. Mirza Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Bryan Downie Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Jinfeng Liu Shareholder of: Gilead Sciences Inc., Roche, Employee of: Gilead Sciences Inc., Rachael E. Hawtin Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Emon Elboudwarej Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc.