The long-term extension (LTE) study DARWIN 3 published in Rheumatic & Musculoskeletal Diseases Open provided significant findings on the safety and efficacy of filgotinib in patients with rheumatoid arthritis (RA). The study followed 739 patients who had completed the 24-week DARWIN 1 and DARWIN 2 trials, evaluating filgotinib either in combination with methotrexate or as monotherapy. Participants received filgotinib 200 mg/day, except for a small subset of men who were given 100 mg/day.
With a total exposure of 3706.3 patient-years, filgotinib demonstrated a consistent safety profile. The exposure-adjusted incidence rate (EAIR) of treatment-emergent adverse events (TEAEs) was 67 per 100 patient-years, while serious TEAEs occurred at a rate of 3.8 per 100 patient-years. Infections remained the most frequent adverse event, with an EAIR of 23.3 per 100 patient-years, including 1.3 per 100 patient-years for serious infections and herpes zoster. Major adverse cardiovascular events (0.19 per 100 patient-years) and malignancies (0.6 per 100 patient-years) were observed at low rates. Efficacy analysis revealed that clinical responses peaked at week 12 of the LTE before gradually declining over time. At week 396, ACR20/50/70 response rates were 26.9%, 20.2%, and 14.7%, respectively. Despite a high discontinuation rate of 67.3%, mainly due to adverse events and patient decisions, the overall benefit-risk profile of filgotinib remained favorable.
Janus kinase (JAK) inhibitors (JAKinibs) represent a significant advancement in oral therapy for RA. While these medications demonstrate comparable clinical efficacy, the incidence rates of certain adverse events of special interest differ among them. The link between JAK isoform selectivity and the inhibition of specific cytokine responses at clinically relevant plasma concentrations may help explain variations in their efficacy and safety profiles. Filgotinib (GS-6034, formerly GLPG0634) is an oral, selective JAK1 inhibitor. By preferentially targeting JAK1, it modulates a distinct subset of proinflammatory cytokines within the JAK–signal transducer and activator of transcription (STAT) pathway, differing from the cytokines influenced by JAK2 or JAK3 inhibition. It provides rapid and sustained improvements in disease activity, with significant ACR20/50/70 response rates and reductions in pain, fatigue, and morning stiffness. It slows radiographic progression, preserving joint structure and function, while improving physical abilities (HAQ-DI score. The drug is rapidly and extensively absorbed following oral administration and is metabolized primarily by carboxylesterase isoform 2, producing its active metabolite, GS-829845.
The findings confirmed that filgotinib is well tolerated over an extended period, maintaining its safety and efficacy in patients previously treated with either monotherapy or combination therapy. These findings represent a significant milestone in RA treatment, providing rheumatologists with robust evidence supporting filgotinib’s role in long-term disease management. The study’s unprecedented duration and comprehensive safety data offer valuable insights for clinical decision-making in chronic RA care.
References
- Westhovens R, Winthrop KL, Kavanaugh A, Greenwald M, Dagna L, Cseuz R, et al. Safety and efficacy of filgotinib in patients with rheumatoid arthritis: final results of the DARWIN 3 long-term extension study. RMD Open. 2025 Jan 30;11(1):e004857.
- Namour F, Anderson K, Nelson C, Tasset C. Filgotinib: A Clinical Pharmacology Review. Clin Pharmacokinet. 2022 Jun;61(6):819-832.
- Traves PG, Murray B, Campigotto F, Galien R, Meng A, Di Paolo JA. JAK selectivity and the implications for clinical inhibition of pharmacodynamic cytokine signalling by filgotinib, upadacitinib, tofacitinib and baricitinib. Ann Rheum Dis. 2021 Jul;80(7):865-875.