Filgotinib (GLPG0634/GS-6034), an oral selective JAK1 inhibitor, is effective as monotherapy in patients with active rheumatoid arthritis: results from a randomised, dose-finding study (DARWIN 2)

Objectives:
The primary objective of this study was to assess the efficacy and safety of various doses of filgotinib, an oral selective Janus kinase 1 (JAK1) inhibitor, as monotherapy in patients with active rheumatoid arthritis (RA) who had previously exhibited an inadequate response to methotrexate (MTX).

Methods:
This phase IIb, 24-week randomized controlled trial enrolled patients with moderately to severely active RA. Participants underwent a washout period of at least four weeks following MTX discontinuation before being randomly assigned (1:1:1:1) to receive either 50 mg, 100 mg, or 200 mg of filgotinib once daily, or a placebo. The study’s primary endpoint was the proportion of patients achieving a 20% improvement in RA symptoms, as defined by the American College of Rheumatology (ACR20) criteria, at week 12.

Results:
A total of 283 patients were randomized and received treatment. By week 12, significantly higher percentages of patients in all filgotinib treatment groups achieved an ACR20 response compared to the placebo group (≥65% vs. 29%; p < 0.001). Additional key secondary endpoints at week 12—including ACR50, ACR70, ACR-N, Disease Activity Score-28 with C-reactive protein (DAS28-CRP), Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI), and Health Assessment Questionnaire-Disability Index (HAQ-DI)—also demonstrated significant improvements in the 100 mg and 200 mg filgotinib groups compared to placebo. These benefits were sustained or further enhanced through week 24, with a rapid onset of clinical response observed across multiple efficacy measures.

From a safety perspective, dose-dependent increases in hemoglobin levels were noted. The overall incidence of treatment-emergent adverse events (TEAEs) was comparable across the filgotinib and placebo groups, with approximately 40% of patients experiencing a TEAE. Serious TEAEs occurred in eight patients receiving filgotinib and in one patient receiving placebo. Additionally, four patients in the filgotinib-treated groups developed serious infections. Importantly, no cases of tuberculosis or opportunistic infections were reported during the study period.

Conclusions:
Over the 24-week study period, filgotinib monotherapy demonstrated significant efficacy in reducing the signs and symptoms of active RA, with a rapid onset of therapeutic action. The treatment was generally well tolerated across all tested doses, further supporting its potential as a viable monotherapy option for patients with RA who do not adequately respond to MTX.