Filgotinib, a JAK1 Inhibitor, Modulates Disease-Related Biomarkers in Rheumatoid Arthritis: Results from Two Randomized, Controlled Phase 2b Trials

Jacqueline M Tarrant, René Galien, Wanying Li, Lovely Goyal, Yang Pan, Rachael Hawtin, Wangshu Zhang, Annegret Van der Aa, Peter C Taylor, Jacqueline M Tarrant, René Galien, Wanying Li, Lovely Goyal, Yang Pan, Rachael Hawtin, Wangshu Zhang, Annegret Van der Aa, Peter C Taylor

Abstract

Introduction: The Janus kinase (JAK) inhibitor therapeutic class has shown significant clinical benefit in the treatment of rheumatoid arthritis (RA). We sought to gain insight into the mode of action and immunological effects of filgotinib, a JAK1 selective inhibitor, in active RA by analyzing secreted and cell-based biomarkers key to RA pathophysiology in two phase 2b trials of filgotinib in active RA.

Methods: Immune cell subsets and 34 serum biomarkers were analyzed longitudinally over 12 weeks using blood samples collected from patients with active RA receiving filgotinib (100 or 200 mg once daily) or placebo (PBO) in the two phase 2b trials (DARWIN 1, on a background of methotrexate, and DARWIN 2, as monotherapy).

Results: Consistently across both studies, filgotinib treatment decreased multiple immune response biomarkers that have key roles in RA for immune response, and decreased markers that promote matrix degradation, angiogenesis, leukocyte adhesion, and recruitment. Filgotinib did not significantly modulate T and natural killer (NK) lymphoid subsets, but slightly increased B cell numbers after 12 weeks. Multiple correlations were observed for changes in biomarkers with disease activity score 28-CRP. MIP1β showed modest predictivity at baseline for ACR50 response at 12 weeks in the 100 mg filgotinib dose across both studies (AUROC, 0.65 and 0.67, p < 0.05).

Conclusions: Filgotinib regulates biomarkers from multiple pathways, indicative of direct and indirect network effects on the immune system and the stromal response. These effects were not associated with reductions of major circulating lymphoid populations.

Trial registration: ClinicalTrials.gov, NCT01888874, NCT01894516.

Keywords: Biomarkers; Cytokines; DARWIN1; DARWIN2; Filgotinib; Rheumatoid arthritis.

Figures

Fig. 1
Fig. 1
Baseline levels (median, interquartile range) of biomarkers in DARWIN 1 (filgotinib on MTX background therapy) and DARWIN 2 (filgotinib monotherapy)
Fig. 2
Fig. 2
Early and sustained biomarker changes with filgotinib in DARWIN 1 and DARWIN 2 based on a model of estimated percent change from placebo in post-BL ratio of each biomarker
Fig. 3
Fig. 3
Percent change of biomarkers from baseline in filgotinib-treated arms were comparable in DARWIN 1 (filgotinib [FIL] + methotrexate [MTX]) and DARWIN 2 (FIL monotherapy)
Fig. 4
Fig. 4
Box plots of percentage changes from baseline in absolute lymphocyte subpopulation counts at weeks 2 and 12 in the DARWIN 1 and DARWIN 2 studies
Fig. 5
Fig. 5
Overview of the cytokine-mediated regulation of synovial interactions. Adapted from Ref. [37]

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Source: PubMed

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