Date: Sunday, November 8, 2020
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.
- Front Immunol. 2017;8:29
- J Clin Invest. 2008;118:3537-45
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 January 20, 2022.
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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/