Background The 4 Janus kinases (JAK1, JAK2, JAK3 and TYK2) are cytoplasmic tyrosine kinases that mediate intracellular signaling of cytokines (e.g. certain interleukins and interferons) and growth factors (e.g. erythropoietin). Filgotinib (formerly GLPG0634) is the first JAK inhibitor that displays a high selectivity for JAK1 over the 3 other JAK family members in biochemical and cellular assays. It showed a favorable safety and efficacy profile in two 4-week Phase 2a studies in rheumatoid arthritis (RA) patients.
Objectives To assess the effect of RA disease effects, characterize the disease-relevant treatment responses to filgotinib and identify response biomarkers, we compared the gene expression profile of circulating leukocytes of RA patients, before and after up to 4 weeks of once-daily treatment with 200mg of filgotinib, with healthy volunteers.
Methods RA patients participated in the Phase 2a Proof of concept, a randomized, double-blind, placebo-controlled study enrolling 24 patients with insufficient response to MTX. They were orally treated with placebo or 200 mg QD filgotinib for 4 weeks. Blood was sampled in PAXgene tubes at pre-dose and at the last day of treatment. Non-matched healthy volunteers were also sampled. mRNA was extracted, labeled and profiled using Affymetrix U219 micro-arrays. Data analysis was performed in R/BioConductor using linear regression models (limma).
Results The leukocyte gene signature of 12 healthy subjects was first compared to the one obtained from the 24 RA patients prior to placebo or filgotinib treatment. Genes showing differential expression compared to healthy subjects allowed for definition of a disease signature, which includes novel players as well as genes already described in RA (TFPI or ITGA2B). Four weeks of treatment with filgotinib impacted the signal levels for 1005 probes (254 downregulated, 751 upregulated) in RA patient samples (p-value <0.05 and absolute log2-fold change >0.5 compared to pre-dose), while the signal levels of only 161 probes (86 down- and 75 upregulated) were impacted to the same extent in the placebo group. Several disease-relevant genes (CETP, CTSD, FSTL1, HTRA1, MYL9) were affected by filgotinib treatment. This was confirmed by qPCR. Response biomarkers could be identified by comparing strong responders and weaker responders based on percentage change in disease activity score 28 (DAS28). Functional classification of these biomarkers showed enrichment towards key RA pathways including regulation of immune cells, neutrophil recruitment, inositol phosphate metabolism and phosphatidylinositol signaling (PI3K). In addition, in the best responders, ECM-receptor interaction and focal adhesion pathways were enriched in the genes affected by filgotinib while in the weaker responders, regulation of actin cytoskeleton and TGF-beta signalling were affected by filgotinib.
Conclusions Blood transcriptome analysis showed that 4-week filgotinib treatment partially reverses the disease effect and allows for the identification of treatment response biomarkers in circulating leukocytes of RA patients. Additional information to be obtained from the Darwin studies currently ongoing should provide more insights.
Disclosure of Interest M. Ongenaert Grant/research support from: AbbVie, Employee of: Galapagos, S. Dupont Grant/research support from: AbbVie, Employee of: Galapagos, B. Vayssière Grant/research support from: AbbVie, Employee of: Galapagos, L. Meuleners Grant/research support from: AbbVie, Employee of: Galapagos, R. Brys Grant/research support from: AbbVie, Employee of: Galapagos, R. Galien Grant/research support from: AbbVie, Employee of: Galapagos
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.