Filgotinib versus placebo or adalimumab in patients with rheumatoid arthritis and inadequate response to methotrexate: a phase III randomised clinical trial

Abstract

ObjectiveTo evaluate the efficacy and safety of the Janus kinase-1-preferential inhibitor filgotinib versus placebo or tumour necrosis factor-α inhibitor therapy in patients with active rheumatoid arthritis (RA) despite ongoing treatment with methotrexate (MTX).MethodsThis 52-week, multicentre, double-blind, placebo-controlled and active-controlled phase III trial evaluated once-daily oral filgotinib in patients with RA randomised 3:3:2:3 to filgotinib 200 mg (FIL200) or filgotinib 100 mg (FIL100), subcutaneous adalimumab 40 mg biweekly, or placebo (through week 24), all with stable weekly background MTX. The primary endpoint was the proportion of patients achieving 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Additional efficacy outcomes were assessed sequentially. Safety was assessed from adverse events and laboratory abnormalities.ResultsThe proportion of patients (n=1755 randomised and treated) achieving ACR20 at week 12 was significantly higher for FIL200 (76.6%) and FIL100 (69.8%) versus placebo (49.9%; treatment difference (95% CI), 26.7% (20.6% to 32.8%) and 19.9% (13.6% to 26.2%), respectively; both p<0.001). Filgotinib was superior to placebo in key secondary endpoints assessing RA signs and symptoms, physical function and structural damage. FIL200 was non-inferior to adalimumab in terms of Disease Activity Score in 28 joints with C reactive protein ≤3.2 at week 12 (p<0.001); FIL100 did not achieve non-inferiority. Adverse events and laboratory abnormalities were comparable among active treatment arms.ConclusionsFilgotinib improved RA signs and symptoms, improved physical function, inhibited radiographic progression and was well tolerated in patients with RA with inadequate response to MTX. FIL200 was non-inferior to adalimumab.Trial registration numberNCT02889796.

Filgotinib, a novel JAK1-preferential inhibitor for the treatment of rheumatoid arthritis: An overview from clinical trials

“…In terms of disease activity, the filgotinib 200 mg group had higher percentages of patients with DAS28-CRP 3.2 (49.7% vs. 43.4%, p< .001 for non-inferiority test) and DAS28-CRP <2.6 (34.1% vs. 23.7%, nominal p< .01 for superiority test) compared with the adalimumab group. As for filgotinib 100 mg, the ACR20/50/70 response rates and the percentages of patients with LDA or remission by DAS28-CRP were mostly similar to those with adalimumab (Table 2) [19]. Similar trends of relative efficacy were observed among the three active treatment groups up to week 52 [19].…”

“…In the 52-week phase 3 study of FINCH 1, in addition to demonstrating superior efficacy over placebo, filgotinib 100 and 200 mg regimens were compared to the active comparator of adalimumab (40 mg Q2W), a standard-of-care TNFi in RA treatment [19]. At week 12 (primary analysis), higher percentages of patients in the filgotinib 200 mg group achieved ACR20/50/70 responses than in the adalimumab group, with the numerical improvements being 6.1-12.1% points, but statistical significance could not be demonstrated for these differences with only exploratory p values available (Table 2).…”

Exposure-Response Relationships for Efficacy and Safety of Filgotinib and its metabolite GS-829845 in Subjects with Rheumatoid Arthritis Based on Phase 2 and Phase 3 Studies

“…All studies were conducted according to the principles of the Declaration of Helsinki and the Good Clinical Practice Guidelines of the International Conference of Harmonisation. The study design, patient eligibility, dose administration statistical analyses, and study outcome details for the studies included in this report have been previously published (FINCH 1: NCT02889796, FINCH 2: NCT02873936, FINCH 3: NCT02886728, DARWIN 1: NCT01888874, DARWIN 2: NCT01894516) [9], [10], [16], [17], [18].…”

“…FINCH 3 was a randomized, double-blind, placebo-and active-controlled study in adult male and female subjects with moderately to severely active RA who were naïve to MTX therapy. 1252 subjects were randomized in a 2:1:1:2 ratio to filgotinib 200 mg with MTX, filgotinib 100 mg with MTX, filgotinib 200 mg alone, or MTX alone for up to 52 weeks [9], [10], [16]. DARWIN 1 and DARWIN 2 were the two Phase 2 studies included in this analysis.…”

“…GS-829845, the major circulating metabolite of filgotinib, is also a JAK1 preferential inhibitor and approximately 10-fold less potent than the parent compound [8], [14], [15]. This report describes exposure-efficacy and exposure-safety analyses for filgotinib and its major active metabolite, GS-829845, based on population pharmacokinetic (PopPK) model-derived PK exposures and efficacy and safety data from three Phase 3 studies (FINCH 1, FINCH 2, and FINCH 3) and two Phase 2 studies (DARWIN 1 and DARWIN 2) in patients with moderate to severe RA to support dose recommendation [9], [10], [16], [17], [18].…”