OP033 Reduction of tissue pSTAT3 in Crohn's disease patients treated with filgotinib (GLPG0634, GS-6034), a JAK1-selective inhibitor
Vermeire S.*1, De Hertogh G.2, Chen G.3, French D.4, Huntzicker E.4, Van der Aa A.5, Van Kaem T.5, Harrison P.5, Tasset C.5, Galien R.6, Pan Y.4, Feagan B.7, Sandborn W.8
1University Hospitals Leuven, Department of Gastroenterology, Leuven, Belgium 2University Hospitals Leuven, Department of Pathology, Leuven, Belgium 3Gilead Sciences, Department of Biostatistics, Foster City, United States 4Gilead Sciences, Biomarker Sciences, Foster City, United States 5Galapagos NV, Mechelen, Belgium 6Galapagos SASU, Romainville, France 7Robarts Resaerch Institute, Ontario, Canada 8University of California, Division of Gastroenterology, San Diego, United States
Janus kinases (JAK) are a family of tyrosine kinases that play a key role in the signalling of more than 60 cytokines and growth factors. Many of these cytokines display pro-inflammatory activity in Crohn's Disease (CD). The selective JAK1 inhibitor filgotinib blocks cytokine signalling through the inhibition of STAT phosphorylation and has shown clinical efficacy in a double-blind, placebo-controlled Phase 2 study in CD (FITZROY). In order to understand the mechanism of action of filgotinib in CD patients, we measured the level of pSTAT3 in gut biopsies from this study.
CD patients were randomized 3:1 to receive 200mg filgotinib or placebo QD for the first 10 weeks. Two biopsies, one each from the most and least affected mucosa, were collected during screening and at Wk 10 from each of the 6 predefined segments of the lower gastrointestinal tract. Samples from 60 patients with complete set of paired biopsies were selected. pSTAT3 was evaluated by IHC using an antibody specific to phosphorylated Y705. H-Score was quantified using Definiens Tissue Studio software. The mixed effect ANOVA method was used for evaluating the treatment effect and difference between patients achieving clinical remission (defined as CDAI <150) and those who did not.
Basal pSTAT3 level was comparable for the filgotinib and placebo groups. Following filgotinib treatment, pSTAT3 level was significantly reduced in the most affected mucosa from all segments combined: −36% (95% CI: −51%, −17%), whereas reduction in the placebo arm was not significant (although with less subjects): −24% (95% CI: −49%, +14%). In patients with clinical remission at Wk 10, pSTAT3 levels showed a significant reduction from baseline in each group: −62% (95% CI: −83%, −16%) with placebo, and −42% (95% CI: −57%,-21%) with filgotinib. In patients not achieving clinical remission, pSTAT3 from the placebo arm showed an average numerical increase of +12% (95% CI: −21%, +94%) whereas pSTAT3 was on average reduced with filgotinib: −28% (95% CI: −51%, +7%). Similar observations were made in the least affected mucosa of different segments.
Significant reduction of pSTAT3 by filgotinib on inflamed gut of CD patients provides direct evidence of its anti-inflammatory effect. Clinical remission status is associated with a decrease in pSTAT3. In non-remitters, the observed pSTAT3 reduction with filgotinib illustrates its pharmacodynamic effect through JAK1 inhibition. A large phase 3 program in CD and UC is ongoing.