OBJECTIVE: JAK 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.
METHODS: In 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.
RESULTS: Treatment 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.
CONCLUSION: Selective inhibition of JAK-1 with filgotinib shows initial efficacy 
in RA with an encouraging safety profile in these exploratory studies.