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Abstract Number: 2616

The JAK1-Selective Inhibitor Filgotinib Displays an Anti-Inflammatory Biomarker Signature in Rheumatoid Arthritis Patients

Peter C. Taylor1, R Westhovens2, Luc Meuleners3, Birgen Meuleman4, Yang Pan5, Veerle Vyncke3, Annegret Van der Aa3, Pille Harrison3, Chantal Tasset3 and René Galien6, 1Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom, 2Rheumatology, University Hospitals Leuven, Leuven, Belgium, 3Galapagos NV, Mechelen, Belgium, 42Bridge, Turnhout, Belgium, 5Gilead Sciences, Foster City, CA, 6102 Avenue Gaston Roussel, Galapagos SASU, Romainville, France

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: biomarkers and rheumatoid arthritis (RA), Janus kinase (JAK)

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Session Information

Date: Tuesday, November 15, 2016

Title: Rheumatoid Arthritis – Small Molecules, Biologics and Gene Therapy - Poster III

Session Type: ACR Poster Session C

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

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 TH1 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 TH1 cell expansion. The TH2-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 TH17 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 TH1, TH2 and TH17 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.


Disclosure: P. C. Taylor, Galapagos, Pfizer, Eli Lilly, UCB, GSK, 5; R. Westhovens, Galapagos NV, Roche, BMS, 5; L. Meuleners, Galapagos NV, 3; B. Meuleman, 2Bridge, 3; Y. Pan, Gilead Sciences, 3; V. Vyncke, Galapagos NV, 3; A. Van der Aa, Galapagos NV, 3; P. Harrison, Galapagos NV, 3; C. Tasset, Galapagos NV, 3; R. Galien, Galapagos SASU, 3.

To cite this abstract in AMA style:

Taylor PC, Westhovens R, Meuleners L, Meuleman B, Pan Y, Vyncke V, Van der Aa A, Harrison P, Tasset C, Galien R. The JAK1-Selective Inhibitor Filgotinib Displays an Anti-Inflammatory Biomarker Signature in Rheumatoid Arthritis Patients [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/the-jak1-selective-inhibitor-filgotinib-displays-an-anti-inflammatory-biomarker-signature-in-rheumatoid-arthritis-patients/. Accessed .
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