Background Janus kinases (JAKs) are key proteins in the signal transduction of many cytokines and growth factors. The selective JAK1 inhibitor filgotinib (GLPG0634, GS-6034) has been evaluated in a 24-week phase 2B study (DARWIN 2) as monotherapy in active rheumatoid arthritis (RA) patients with inadequate response to methotrexate and has shown a good safety and efficacy profile1.
Objectives To gain insight into filgotinib mode of action as monotherapy in RA patients by analysing the impact of filgotinib on a broad panel of immune modulators in the serum.
Methods RA patients received either placebo (PBO), or filgotinib monotherapy at 50mg, 100mg or 200mg once daily (QD). Serum samples were collected at baseline, week 4 and week 12 and analysed using the 18-plex bead-based immunoassay (HSTCMAG-28SK Merck-Millipore) on BioPLEX-200 instrument to measure cytokine concentration. Median % change from baseline for biomarkers are reported for week 4 and 12. Wilcoxon rank-sum test assessed the significance of difference between filgotinib treated groups and PBO.
Results Following treatment with filgotinib at 100 mg QD and 200mg QD, there were significant reductions in cytokines important in expansion and activity of multiple T cell subsets and innate immunity compared to PBO (see Table). These changes include decreases in proinflammatory cytokines (IL-6, IL-1β, and TNFα), TH1-related (IL-2, IFN-γ and IL-12), TH2-related (IL-4, IL-5, and IL-13) and TH17-related cytokines (IL-1β, IL-6, IL-17A, IL-21 and IL-23). All doses of filgotinib also reduced the B- and T-cell development cytokine IL-7. In contrast, IL-8 was not affected by filgotinib. Reductions in MIP1α, MIP1β and GM-CSF are in line with a down modulation of innate immune activity.
Conclusions Treatment of RA patients with filgotinib monotherapy resulted in significant reduction in the levels of a broad range of cytokines related to TH1, TH2, TH17 and potentially B cells, as well as innate immunity. This observed anti-inflammatory activity of filgotinib is consistent with its efficacy in RA patients.
Kavanaugh A et al. Ann Rheum Dis 2016;0:1–11.doi:10.1136/annrheumdis-2016–210105.
Disclosure of Interest A. Kavanaugh Consultant for: Galapagos, Pfizer, Abbvie, Amgen, Celgene, Janssen, Novartis, Eli Lilly, UCB, A. Van der Aa Employee of: Galapagos NV, C. Jamoul Employee of: Galapagos NV, W. Li Employee of: Gilead Sciences, L. Goyal Employee of: Gilead Sciences, Y. Pan Employee of: Gilead Sciences, P. Harrison Employee of: Galapagos NV, C. Tasset Employee of: Galapagos NV, J. Tarrant Employee of: Gilead Sciences, R. Galien Employee of: Galapagos SASU