Background/Purpose : The potent and selective JAK1 inhibitor filgotinib (GLPG0634, GS-6034) has been evaluated in a 24-week phase 2B study in combination with methotrexate (MTX) in active rheumatoid arthritis (RA) patients with inadequate response to MTX (DARWIN 1 study). Significant improvement in signs and symptoms was observed after 12 weeks and efficacy was sustained or improved up to Week 24 with a safety profile overall acceptable. In order to gain insight in filgotinib mode of action in RA patients, we analysed the impact of this treatment on serum cytokines.

Methods : Patients with active RA on stable dose of MTX were randomized 1:1:1:1:1:1:1 in a double blind manner to receive either placebo (PBO) or one of three doses of filgotinib (50mg, 100mg or 200mg) as once (qd) or twice daily (bid) regimen for 24 weeks (DARWIN 1 study). At baseline, Week 4 and Week 12, sera were collected from all patients and analysed using the 18-plex panel kit from Merck-Millipore (HSTCMAG-28SK) on BioPLEX-200 apparatus to measure concentration of GM-CSF, IFNγ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17A, IL-21, IL-23, MIP-1α, MIP-1β and TNF-α. Data are presented as means of changes from the baseline.

Results : Following treatment with filgotinib, IL-6 was the cytokine showing greatest decreases in concentration at all time points and doses analysed. The pro-inflammatory cytokine IL-1β was also decreased at Week 12 at higher doses confirming the potent anti-inflammatory activity of filgotinib. Of interest, serum concentrations of IL-2 and IFN-γ, two T_H1 cell markers, reduced significantly at Week 12 at the higher doses used, suggesting that filgotinib may impact the promotion of this cell subset. Notably, this is consistent with the Week 4 decrease in IL-12 concentration, a cytokine that, together with IFN-γ, promotes T_H1 cell expansion. The T_H2-related cytokine IL-13 was decreased at Week 12 at all doses analysed, in contrast to IL-4 and IL-5 that were not impacted by filgotinib treatment. Of interest, concentration of IL-21 (a cytokine produced by T_H17 cells) was decreased after 12 weeks of treatment with the higher dose of filgotinib. Higher doses of filgotinib also reduced levels of the B and T cell development cytokine, IL-7. Finally, MIP-1β concentration was decreased by high doses of filgotinib after 4 weeks of treatment, in line with the effect observed on GM-CSF at all time points.

Conclusion: Treatment of RA patients with filgotinib led to the decrease of multiple cytokines involved in various aspects of the inflammatory process. Reductions in IL-6 and IL-1β establish the anti-inflammatory activity of filgotinib. Treatment effects on IL-2, IL-6, IL-7, IL-12 and IFN-γ that play a key role in CD4⁺ T-cell differentiation and expansion further highlight the anti-inflammatory effects of filgotinib, likely by limiting the promotion of T_H1, T_H2 and T_H17 cells. Finally, effects on innate immunity, through MIP-1β and GM-CSF decrease, were also mediated by filgotinib. Taken together, these data further demonstrate the anti-inflammatory activity of filgotinib in line with its efficacy observed in RA patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-jak1-selective-inhibitor-filgotinib-displays-an-anti-inflammatory-biomarker-signature-in-rheumatoid-arthritis-patients/