Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1)

Abstract

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.

Influence of age and renal impairment on the steady state pharmacokinetics of filgotinib, a selective JAK1 inhibitor

“…Clinical efficacy was observed at daily doses of 75–300 mg in a phase IIa study in patients with RA with an insufficient response to methotrexate and naïve to biological disease‐modifying anti‐rheumatic drugs, with similar effects noted for these doses in terms of improvements in C‐reactive protein and disease activity scores based on 28 joints . Subsequently, efficacy was confirmed in larger, phase IIb studies of filgotinib given as monotherapy and in combination with methotrexate . Filgotinib dosed at 100–200 mg once daily is currently being evaluated in pivotal phase III studies in patients across several indications, including RA, CD and ulcerative colitis.…”

JAK inhibition by methotrexate (and csDMARDs) may explain clinical efficacy as monotherapy and combination therapy

“…Finally, given the different JAK targets being inhibited, it can be hypothesized that the combination of baricitinib plus LFN might be of clinical interest considering that LFN inhibits JAK3 and this may explain also the additive effect of LFN when used in combination with MTX . The same should occur with Upadacitinib and Filgotinib . When examining the side effects associated to JAK inhibitors, the major one is represented by the occurrence of Herpes Zoster infection .…”

“…43 The same should occur with Upadacitinib and Filgotinib. 44,45 When examining the side effects associated to JAK inhibitors, the major one is represented by the occurrence of Herpes Zoster infection. 46 Despite discordant results have been described in the literature, 47 yet most recent data suggest that Zoster infection may be a side effect of MTX therapy.…”

Janus Kinase Antagonists and Other Novel Small Molecules for the Treatment of Crohn's Disease

“…31 In a phase 2B clinical trial in rheumatoid arthritis, filgotinib showed a dose-dependent response in combination with methotrexate. 32 …”