Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Filgotinib, a Selective JAK‐1 Inhibitor, After Short‐Term Treatment of Rheumatoid Arthritis: Results of Two Randomized Phase IIa Trials

Abstract

ObjectiveJAK inhibitors have shown efficacy in rheumatoid arthritis (RA). We undertook this study to test our hypothesis that selective inhibition of JAK‐1 would combine good efficacy with a better safety profile compared with less selective JAK inhibitors.MethodsIn two 4‐week exploratory, double‐blind, placebo‐controlled phase IIa trials, 127 RA patients with an insufficient response to methotrexate (MTX) received filgotinib (GLPG0634, GS‐6034) oral capsules (100 mg twice daily or 30, 75, 150, 200, or 300 mg once daily) or placebo, added onto a stable regimen of MTX, to evaluate safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of filgotinib. The primary efficacy end point was the number and percentage of patients in each treatment group meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 4.ResultsTreatment with filgotinib at 75–300 mg met the primary end point and showed early onset of efficacy. ACR20 response rates progressively increased to week 4, and the Disease Activity Score in 28 joints using the C‐reactive protein (CRP) level decreased. Marked and sustained improvements were observed in serum CRP level and other PD markers. The PK of filgotinib and its major metabolite was dose proportional over the 30–300 mg range. Early side effects seen with other less selective JAK inhibitors were not observed (e.g., there was no worsening of anemia [JAK‐2 inhibition related], no effects on liver transaminases, and no increase in low‐density lipoprotein or total cholesterol). A limited decrease in neutrophils without neutropenia was consistent with immunomodulatory effects through JAK‐1 inhibition. There were no infections. Overall, filgotinib was well tolerated. Events related to study drug were mild or moderate and transient during therapy, and the most common such event was nausea.ConclusionSelective inhibition of JAK‐1 with filgotinib shows initial efficacy in RA with an encouraging safety profile in these exploratory studies.

Population Pharmacokinetics, Efficacy Exposure-response Analysis, and Model-based Meta-analysis of Fenebrutinib in Subjects with Rheumatoid Arthritis

“…RA is an autoimmune disorder, and although several therapeutics are approved for the treatment of patients with an inadequate response to methotrexate (MTX) or tumor necrosis factor inhibitors (anti-TNF) (3)(4)(5)(6)(7)(8)(9), some patients become refractory to currently available therapeutics and may benefit from therapy utilizing a different mechanism of action (6,(8)(9)(10)(11)(12).…”

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“…Results of two other Phase IIa trials showed that filgotinib is generally well‐tolerated in RA subjects that had an insufficient response to MTX (Vanhoutte et al, 2017). This study was continued by two Phase IIb trials: randomized, dose‐finding study (DARWIN1; additive to MTX) and DARWIN2 (Single therapy; Alten et al, 2017).…”

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“…In two 4-week double blind, placebo controlled phase IIa trials [ 8 ], RA patients with an insufficient response to MTX received filgotinib daily, at doses ranging from 30 to 300 mg or placebo on top of MTX, to explore safety, efficacy, pharmacokinetics and pharmacodynamics. Early efficacy was noted from a dose of 75 mg daily upwards, and the pharmacokinetics of filgotinib and its JAK1 selective active metabolite was dose-proportional over the 30–300 mg range.…”