Filgotinib Modulates Inflammation-Associated Peripheral Blood Protein Biomarkers in Adults with Active Rheumatoid Arthritis and Prior Inadequate Response to Methotrexate

Yoshiya Tanaka; Peter C Taylor; Emon Elboudwarej; Angie Hertz; Xiaorong Shao; Vladislav A Malkov; Hironori Matsushima; Kahaku Emoto; Bryan Downie; Tsutomu Takeuchi

doi:10.1007/s40744-023-00583-9

Filgotinib Modulates Inflammation-Associated Peripheral Blood Protein Biomarkers in Adults with Active Rheumatoid Arthritis and Prior Inadequate Response to Methotrexate

Rheumatol Ther. 2023 Oct;10(5):1335-1348. doi: 10.1007/s40744-023-00583-9. Epub 2023 Jul 25.

Authors

Affiliations

¹ The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, 1-1, Iseigaoka, Kitakyushu, 807-8555, Japan. tanaka@med.uoeh-u.ac.jp.
² Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Windmill Road, Headington, Oxford, OX3 7LD, UK. peter.taylor@kennedy.ox.ac.uk.
³ Gilead Sciences, Inc., Foster City, CA, USA.
⁴ Division of Rheumatology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
⁵ Saitama Medical University, Saitama, Japan.

^# Contributed equally.

Abstract

Introduction: Our aim was to evaluate protein biomarker changes related to the administration of filgotinib, a Janus kinase (JAK) 1 preferential inhibitor, in patients with moderately to severely active rheumatoid arthritis (RA) with inadequate response to methotrexate.

Methods: Plasma and serum samples were collected from patients enrolled in FINCH 1 (NCT02889796), a Phase 3 trial. Patients with stable backgrounds of methotrexate were randomly assigned once-daily oral filgotinib 200 or 100 mg, subcutaneous adalimumab 40 mg every 2 weeks (W), or placebo. Up to 35 biomarkers were analyzed at baseline, W4, and W12 with enzyme-linked immunosorbent assays and chemiluminescence and electrochemiluminescence assays.

Results: At baseline, four distinct biomarker clusters were identified. The strongest intragroup correlations were in bone-cartilage resorption/inflammation and JAK/signal transducer and activator of transcription (STAT) signaling activity. At baseline, significant positive correlations were identified for cytokines with patient-reported pain and with patient measures of fatigue. Filgotinib reduced levels of cytokines associated with inflammation and cell migration as early as W4 and through W12. Compared to adalimumab, filgotinib induced significant reductions in bone-related turnover biomarkers, N-telopeptide of type 1 collagen and C-telopeptide 1, as well as biomarkers associated with baseline disease activity. No baseline predictors of therapeutic response to filgotinib were identified.

Conclusions: Filgotinib reduced peripheral protein biomarkers associated with JAK/STAT signaling, inflammatory signaling, immune cell migration, and bone resorption as soon as W4 in FINCH 1. Effects were dose-dependent and consistent with the clinical efficacy of filgotinib observed in FINCH 1. The changes in peripheral biomarkers associated with filgotinib treatment in methotrexate-experienced patients are consistent with changes observed in both methotrexate-naïve and biologic disease-modifying antirheumatic drug-experienced RA populations. These data demonstrate dose-dependent effects of preferential JAK1 inhibition by filgotinib on peripheral blood protein biomarkers in methotrexate-experienced patients with RA.

Trial registration: ClinicalTrials.gov, NCT02889796.

Keywords: Biological therapy; Biomarker; Cytokines; Inflammation; Methotrexate; Rheumatoid factor.

Associated data

ClinicalTrials.gov/NCT02889796