Filgotinib With Methotrexate for Rheumatoid Arthritis

The addition of the janus kinase 1 inhibitor filgotinib produced rapid improvement in symptoms in patients with active rheumatoid arthritis who did not achieve adequate results with methotrexate alone.[[{"type":"media","view_mode":"media_crop","fid":"61140","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_588431883147","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"7733","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"height: 210px; width: 210px; border-width: 0px; border-style: solid; margin: 5px; float: right;","title":" ","typeof":"foaf:Image"}}]]

Filgotinib orally administered in doses of 50 mg, 100 mg, and 200 mg was well tolerated by the patients taking methotrexate for rheumatoid arthritis.

Because conventional disease-modifying antirheumatic drugs (DMARDs) are often slow acting and biological DMARDs require injections, a fast-acting oral medication for symptomatic relief of active rheumatoid arthritis could provide an attractive alternative.

Alternatives to conventional and biologic disease-modifying agents also may reduce the need for steroid-bridging treatment.

To date, the FDA has approved only one other JAK1 inhibitor, tofacitinib, which is approved only as second-line rescue treatment after methotrexate has failed.

Dr. Westhovens and colleagues in Belgium presented the findings of the DARWIN 1 study in a recent Annals of the Rheumatic Diseases article.

The study

DARWIN 1, a 24-week, multicenter, randomized, double-blind, placebo-controlled, phase IIb, dose finding study, examined oral filgotinib at doses of 50 mg, 100 mg, and 200 mg added to methotrexate treatment either once daily or twice daily in adults with active rheumatoid arthritis refractory to methotrexate monotherapy.

In the study, 594 patients were randomized and received at least one dose of study drug. The primary outcome was achievement of an American College of Rheumatology (ACR) 20 response. ACR 50 and 70 scores were key secondary end points.

Results

At 12 weeks, significantly more patients who received filgotinib 100 mg once daily, 200 mg once daily, or 100 mg twice daily achieved ACR 20 scores than those who received placebo (64% [p=0.0435], 69% [p=0.0068], and 79% [p=0.0001], respectively).

No difference was found between once-daily dosing and twice-daily dosing of filgotinib at any dose.

A dose response was found; 200 mg filgotinib once a day and 100 mg twice a day achieved the earliest onset of ACR 20 responses.

ACR 20, 50, and 70 responses were achieved with statistically greater frequency in the treatment groups when compared with placebo.

Treatment-emergent adverse event frequencies were not statistically different among treatment groups. However, treatment-emergent adverse events did occur more frequently in the treatment groups when compared with placebo (20.9% verses 10.7%). There was one death resulting from pneumonia in the treatment arm.

The rate of discontinuation prior to completion of the study was 10.3% and was not statistically different from that of placebo participants.

Dose-dependent rises in hemoglobin were seen in the treatment group, as were decreases in neutrophil counts.

Dose-dependent increases in mean creatinine concentration occurred in the treatment groups, with a mean elevation of 11.5% from baseline.

Implications for physicians

• Adding filgotinib to methotrexate treatment in patients with rheumatoid arthritis who have failed methotrexate monotherapy can produce a rapid, dose-dependent improvement in symptoms.

• The effects of combination therapy with methotrexate and filgotinib on laboratory values, including hemoglobin, creatinine, and liver function tests, are modest.

• Although well tolerated, combination therapy with filgotinib and methotrexate in active rheumatoid arthritis led to some infections and one death in the treatment group.

• A 200 mg, once-daily dose of filgotinib with methotrexate appears to produce the most rapid and effective response when methotrexate therapy alone fails.

Disclosures:

Galapagos NV provided funding for the DARWIN 1 study.

References:

R Westhovens, PC Taylor, R Alten, et al. “Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1).” Ann Rheum Dis. 2017;76:998-1008. doi: 10.1136/annrheumdis-2016-210104. Epub 2016 Dec 19.