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)

Abstract

ObjectivesTo evaluate the efficacy and safety of different doses of filgotinib, an oral Janus kinase 1 inhibitor, as monotherapy in patients with active rheumatoid arthritis (RA) and previous inadequate response to methotrexate (MTX).MethodsIn this 24-week phase IIb study, patients with moderately to severely active RA were randomised (1:1:1:1) to receive 50, 100 or 200 mg filgotinib once daily, or placebo, after a ≥4-week washout from MTX. The primary end point was the percentage of patients achieving an American College of Rheumatology (ACR)20 response at week 12.ResultsOverall, 283 patients were randomised and treated. At week 12, significantly more patients receiving filgotinib at any dose achieved ACR20 responses versus placebo (≥65% vs 29%, p<0.001). For other key end points at week 12 (ACR50, ACR70, ACR-N, Disease Activity Score based on 28 joints and C reactive protein, Clinical Disease Activity Index, Simplified Disease Activity Index and Health Assessment Questionnaire-Disability Index) significant differences from baseline in favour of filgotinib 100 and 200 mg versus placebo were seen; responses were maintained or improved through week 24. Rapid onset of action was observed for most efficacy end points. Dose-dependent increases in haemoglobin were observed. The percentage of patients with treatment-emergent adverse events (TEAE) was similar in the placebo and filgotinib groups (∼40%). Eight patients on filgotinib and one on placebo had a serious TEAE, and four patients, all of whom received filgotinib, experienced a serious infection. No tuberculosis or opportunistic infections were reported.ConclusionsOver 24 weeks, filgotinib as monotherapy was efficacious in treating the signs and symptoms of active RA, with a rapid onset of action. Filgotinib was generally well tolerated.Trial registration numberNCT01894516.

Janus kinase inhibitors for the treatment of rheumatoid arthritis demonstrate similar profiles of in vitro cytokine receptor inhibition

“…However, these differences do not appear to translate into significant differences in key clinical biomarkers. Although IL‐6 is involved in stimulating CRP production from hepatocytes, reduction of CRP levels from baseline to week 12 does not appear to differ by any clinically meaningful extent for these JAK inhibitors when used to treat RA: tofacitinib 5 mg BID (−10.1 mg/L); baricitinib 4 mg QD (approximately −10 mg/L); upadacitinib 6 mg BID (−8.8 mg/L); and filgotinib 200 mg QD (−14.9 mg/L). Likewise, although IL‐15 is critical for NK cell maintenance, reductions from baseline in NK cell counts do not appear to differ to a meaningful extent for these JAK inhibitors in RA: tofacitinib (−32.5 cells/mm 3 at month 1.5, −63.5 cells/mm 3 at month 6, +6.5 cells/mm 3 at month 22, cross‐sectional analysis in different groups of patients); baricitinib 4 mg QD (−57.0 cells/mm 3 at week 12; −53.4 cells/mm 3 at week 24); upadacitinib 6 mg BID (approximately −50 cells/mm 3 at week 12); sufficient long‐term data are not available for filgotinib.…”

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 diseasemodifying 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 [1,2,20]. Subsequently, efficacy was confirmed in larger, phase IIb studies of filgotinib given as monotherapy [3] and in combination with methotrexate [4]. 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.…”

Filgotinib, a JAK1 Inhibitor, Has No Effect on QT Interval in Healthy Subjects

“…7,8 The metabolite also exhibits selective JAK1 inhibition, with approximately 16-to 20-fold higher exposure and longer half-life (23-27 hours for the metabolite versus 5-6 hours for filgotinib) but ß19-fold lower potency than filgotinib. 7,9,10 In phase 2 studies, filgotinib has shown clinical efficacy, rapid onset of activity, and a favorable safety and tolerability profile both as monotherapy and in combination with methotrexate in subjects with moderate to severe rheumatoid arthritis, [11][12][13] and in subjects with moderate to severe Crohn's disease. 14 Safety pharmacology studies conducted in vitro and in dogs have indicated that filgotinib has a low risk of QTc interval prolongation.…”

“…In phase 2 data from both subjects with rheumatoid arthritis and subjects with Crohn's disease receiving up to a 200-mg once daily dose of filgotinib, no clinically relevant effects on QTcF were noted. 11,12,14 Despite a low predicted risk for filgotinib, the potential for QT/QTc interval prolongation by nonantiarrhythmic drugs remains a serious risk and an important consideration in drug development. The International Conference on Harmonization (ICH) E14 guidance recommends characterization of the effect of a new pharmaceutical agent on the QT/QTc interval to mitigate any serious potential risks.…”