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Abstract Number: 1239

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

Peter Taylor1, Amer Mirza2, Bryan Downie2, Jinfeng Liu2, Rachael Hawtin2 and Emon Elboudwarej2, 1Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom, 2Gilead Sciences, Inc., Foster City

Meeting: ACR Convergence 2020

Keywords: ,

Session Information

Date: Sunday, November 8, 2020

Title: RA – Treatments Poster III: PROs, Biomarkers, Systemic Inflammation & Radiographs

Session Type: Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: Filgotinib (FIL), an oral selective JAK1 inhibitor, has shown efficacy and safety in phase 3 studies in adults with moderately-to-severely active rheumatoid arthritis (RA), including those naïve to methotrexate (MTX) (FINCH3; NCT02886728). A longitudinal study of protein biomarkers related to JAK signaling1, bone biology2, immune cell migration2 and inflammation2 was conducted in FINCH3 patients (pts) to identify disease-relevant biomarkers altered by FIL vs MTX.

Methods: MTX-naive RA pts enrolled in FINCH3 received a stable dose of MTX (MTX), FIL200mg monotherapy (FIL200mg), FIL100mg+MTX, or 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 from BL to weeks (wks) 4, 12 and 24 were compared  using MTX-adjusted estimates from a linear mixed effects model. A false discovery rate of 5% was applied.

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-naïve 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 >0.3).

Relative to MTX, 23 biomarkers exhibited significant early responses (any arm, wk 4). The strongest treatment effect observed at wk 4 was a reduction for CXCL13 (FIL100mg+MTX: -28.2%; FIL200mg+MTX: -40%; FIL200mg: 34%). This reduction was sustained 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 produced a greater effect on 18 biomarkers vs MTX, significant through wk 24. The greatest effects in FIL200mg were reductions by wk 24 in CTX1 (-29.1%), CXCL13 (-33.2%), and IL6 (-29.5%); biomarkers associated with DAS28CRP at BL. Four biomarkers were different between FIL200mg 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 FIL200 alone. 

Conclusion: Treatment through 24 weeks with FIL200mg ±MTX reduced many disease-relevant biomarkers tested; markers related to JAK signaling1, bone biology2, inflammation2, and immune cell migration2 in MTX-naïve 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 unique to FIL mono, supporting the FIL mechanism of action in RA treatment.

  1. Front Immunol. 2017;8:29
  2. J Clin Invest. 2008;118:3537-45
Disclosure: P. Taylor, Eli Lilly, 2, 5, 8, Celgene, 2, 5, 8, AbbVie, 2, 5, 8, Biogen, 2, 5, 8, Bristol-Myers Squibb, 2, 5, 8, Celltrion, 2, 5, 8, Fresenius, 2, 5, 8, GlaxoSmithKline, 2, 5, 8, Janssen, 2, 5, 8, Nordic Pharma, 2, 5, 8, Roche, 2, 5, 8, Sanofi, 2, 5, 8, UCB, 2, 5, 8, Pfizer, 2, 5, 8, Gilead, 2, 5, 8, Galapagos, 2, 5, 8; A. Mirza, Gilead Sciences, Inc., 3, Gilead Sciences, Inc., 1; B. Downie, Gilead Sciences, Inc., 3, Gilead Sciences, Inc., 1; J. Liu, Gilead Sciences, Inc., 3, Gilead Sciences, Inc., 1, Roche, 1; R. Hawtin, Gilead Sciences, Inc., 3, Gilead Sciences, Inc., 1; E. Elboudwarej, Gilead Sciences, Inc., 3, Gilead Sciences, Inc., 1.

To cite this abstract in AMA style:

Taylor P, Mirza A, Downie B, Liu J, Hawtin R, Elboudwarej E. 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 [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/peripheral-protein-biomarker-changes-following-selective-inhibition-of-janus-kinase-1-jak1-by-filgotinib-in-methotrexate-naive-adults-with-moderately-to-severely-active-rheumatoid-arthritis/. Accessed .

ACR Meeting Abstracts - https://acrabstracts.org/abstract/peripheral-protein-biomarker-changes-following-selective-inhibition-of-janus-kinase-1-jak1-by-filgotinib-in-methotrexate-naive-adults-with-moderately-to-severely-active-rheumatoid-arthritis/