ObjectivesTo evaluate the efficacy and safety of different doses and regimens of filgotinib, an oral Janus kinase 1 inhibitor, as add-on treatment to methotrexate (MTX) in patients with active rheumatoid arthritis (RA) and inadequate response to MTX.MethodsIn this 24-week phase IIb study, patients with moderate-to-severe active RA receiving a stable dose of MTX were randomised (1:1:1:1:1:1:1) to receive placebo or 50, 100 or 200 mg filgotinib, administered once daily or twice daily. Primary end point was the percentage of patients achieving a week 12 American College of Rheumatology (ACR)20 response.ResultsOverall, 594 patients were randomised and treated. At week 12, significantly more patients receiving filgotinib 100 mg once daily or 200 mg daily (both regimens) achieved an ACR20 response versus placebo. For other key end points at week 12 (ACR50, ACR-N, Disease Activity Score based on 28 joints and C reactive protein value, Clinical Disease Activity Index, Simplified Disease Activity Index and Health Assessment Questionnaire-Disability Index), differences in favour of 100  or 200 mg filgotinib daily were seen versus placebo; responses were maintained or improved through to week 24. Rapid onset of action and dose-dependent responses were observed for most efficacy end points and were associated with an increased haemoglobin concentration. No significant differences between once-daily and twice-daily regimens were seen. Treatment-emergent adverse event rates were similar in placebo and filgotinib groups. Serious infections occurred in one and five patients in the placebo and filgotinib groups, respectively. No tuberculosis or opportunistic infections were reported.ConclusionsFilgotinib as add-on to MTX improved the signs and symptoms of active RA over 24 weeks and was associated with a rapid onset of action. Filgotinib was generally well tolerated.Trial registration number:NCT01888874.

BackgroundFilgotinib (GLPG0634) is a novel oral selective JAK1 inhibitor that was evaluated in a 24-week phase 2B study in combination with methotrexate (MTX) in active rheumatoid arthritis (RA) with inadequate response to MTX. The primary endpoint of proportion of patients achieving ACR20 response after 12 weeks of treatment was met.ObjectivesTo present the results of the 24-week analysis.MethodsPatients with active RA on stable dose of MTX were randomized 1:1:1:1:1:1:1 in a double blinded 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 Week 12, patients on placebo and 50mg dose whose tender and swollen joint counts did not improve by 20% (non-responders (NR)) were reassigned to 100mg daily.Results594 randomized and treated patients, mean duration of RA of 7–10 years and mean DAS28(CRP) at baseline 6.0–6.2. At Week 12, statistically significant and dose dependent higher ACR20, ACR50, ACR70, DAS28(CRP) and CDAI responses versus PBO were observed in patients on filgotinib. These responses were maintained or continued to improve through 24 weeks (Table 1). Increase in filgotinib dose from Week 12 lead to improved efficacy in PBO and 50mg NR groups (at Week 24 ACR20 57% and 42% respectively). Serious Adverse Events and Treatment-Emergent Adverse Events (TEAE) were distributed over the groups including PBO: TEAE 51% PBO and 52% filgotinib groups. No opportunistic infections or cancers occurred; one death was reported. Infections occurred in 19% PBO and 25% filgotinib groups. Laboratory parameters remained stable between 12 and 24 weeks. Increase in haemoglobin was noted in patients on filgotinib.Table 1.Summary of the efficacy responses after 12 and 24 weeks treatmentOnce-daily dosingTwice-daily dosingPlacebo50mg100mg200mg25mg50mg100mgn=86n=82n=85n=86n=86n=85n=84Week 12 ACR20, NRI1, %445664*69**576079*** ACR50, NRI, %1533*38**43***28*34*55*** ACR70, NRI, %8162124*141931** DAS28(CRP), mean change from BL2, LOCF3−1.2−1.8**−2.2***−2.5***−1.9**−2.1***−2.8*** CDAI4, mean change from BL, LOCF−17−20−24**−26***−21*−23**−29***Week 24 ACR20, NRI, %425561*73***5660*80*** ACR50, NRI, %1635**47***50***35**35**55*** ACR70, NRI, %922*33**29**21*24*39*** DAS28(CRP), mean change from BL, LOCF−1.2−2.0***−2.7***−2.8***−2.2***−2.4***−3.2*** CDAI, mean change from BL, LOCF−16−21**−29***−29***−24***−27***−32****p<0.05 vs. placebo; **p<0.01 vs. placebo; ***p<0.001 vs. placebo; ACR scores based on ITT analysis. 1Non-responder imputation. 2Baseline. 3Last observation carried forward. 4Clinical Disease Activity Index.ConclusionsSignificant improvement in signs and symptoms of active RA was observed after 12 weeks and sustained or increased up to Week 24 with filgotinib in combination with MTX. The safety profile was overall acceptable.Disclosure of InterestR. Westhovens Grant/research support from: Roche, BMS, Janssen, Galapagos NV: investigator DARWIN 1, R. Alten Grant/research support from: Galapagos NV: investigator ...