Filgotinib and Methotrexate Combination Therapy Proves Effective Treatment for RA in FINCH 3 Trial

In a new study, investigators set out to discover whether the Janus kinase-1 inhibitor filgotinib is efficacious, either in combination with MTX or as monotherapy, in patients with RA who have had limited or no MTX exposure.

As early intervention is essential in rheumatoid arthritis (RA) treatment, rheumatologists must work quickly to create therapy plans that will yield the best results for their patients. Currently, both the European Alliance of Associations for Rheumatology (EULAR) and American College of Rheumatology (ACR) recommend starting methotrexate (MTX) monotherapy or in combination with glucocorticoids to induce remission by week 24. Unfortunately, only 30% of patients achieve this goal with MTX alone. Previous studies indicate that combination therapies can significantly improve quality of life while preventing disability and joint destruction.

In a new study published in Annals of the Rheumatic Diseases,1 investigators set out to discover whether the Janus kinase-1 inhibitor filgotinib is efficacious, either in combination with MTX or as monotherapy, in patients with RA who have had limited or no MTX exposure. The results of the phase 3 FINCH 3 study (NCT02886728) determined that both once-daily oral filgotinib 200 mg (FIL200) and filgotinib 100 mg (FIL100), combined with MTX, greatly improved the symptoms and physical function of patients.

In earlier phase 2 and phase 3 trials, filgotinib, both used in combination with disease-modifying antirheumatic drugs (DMARDs) or as monotherapy, was proven to be far superior over placebo. Although FIL200 monotherapy did not have a better ACR20 response versus MTX, it was shown to be well-tolerated and safe.

The 52-week, randomized, double-blind, active-controlled, phase 3 trial followed 1252 patients who were randomized 2:1:1:2 to FIL200+MTX (400 of patients), FIL100+MTX group (200 of patients), FIL200 monotherapy (200 of patients), and MTX monotherapy group (400 of patients) between August 8, 2016, and October 5, 2018. All patients were 18 years of age or older, had been diagnosed with RA, and had little to no MTX exposure. Patients had similar demographic baselines and disease characteristics. The median disease duration was 0.4 years and 77.2% of patients were DMARD-naïve at baseline.

Efficacy analysis was based on on-treatment data and safety end points were calculated per treatment by the number/percentage of patients with events for categorical values or summary statistics. A liner mixed-effect model demonstrating change from baseline was created to categorize structural end points: week 24 (campaign A) and week 52 (campaign A and B). A total of 90.5% of patients made it to the primary checkpoint at week 24 and 82% were able to complete the entire 52-sweek trial.

Filgotinib was taken once daily and MTX was taken once weekly, beginning with 10 mg/week and increasing the dosage to 15 mg or 20 mg, depending on each country’s prescribing practices. A dose reduction was available if MTX was not well tolerated and non-steroidal anti-inflammatory drugs or glucocorticoids were allowed. The mean dose of MTX was 18 mg by week 24.

The study aimed to achieve 20% improvement in American College of Rheumatology criteria (ACR20) by week 24. Results showed that 81% of patients taking FIL200+MTX met this goal compared with 71% of patients taking MTX monotherapy (P <0.001). A significantly greater proportion treated with FIL100+ MTX compared with MTX achieved an ACR20 response (80%, p=0.017) at week 24.There were also significant improvements in the Health Assessment Questionnaire-Disability index and in physical function, with higher proportions achieving 28-joint Disease Activity Score (DAS28) C-reactive protein(CRP) for the FIL200+MTX and FIL100+MTX groups. The FIL200 and MTX monotherapy groups had similar ACR20 scores at week 24 (78% and 71%, respectively).

The study was also focused on other responses, including ACR50 and ACR70. “In early RA, separation between 2 active medications can be observed based on the proportion of patients achieving the clinically meaningful threshold such as the ACR20 but also by the depth of response seen by those on treatment,” investigators explained. “Thus, 2 medications can show similar proportions of ACR20 responses, and their true difference in efficacy is only revealed when assessing ACR50 and ACR70 responses...Although ACR20 was chosen as the primary end point, other end points of clinical interest were also evaluated. All filgotinib treatments achieved numerically better disease control versus MTX alone for higher hurdle endpoints such as ACR50/70 and remission.”

Common adverse reactions included nausea, upper respiratory tract infection, nasopharyngitis, headache, and hypertension. Serious reactions occurred in similarly small percentages (between 6-8% for all groups). “The clinical benefits achieved in the study were considered alongside the potential risks of all treatment regimens. Over 52 weeks, rates of infections, serious infections, opportunistic infections, herpes zoster, major adverse cardiovascular events (MACE), and malignancies were similar between filgotinib and MTX arms,” Investigators explained.

Filgotinib, in conjunction with MTX, was found to be more beneficial than MTX monotherapy alone and could be considered as a treatment option for patients with RA who have had limited exposure to MTX. The combination “reduced signs and symptoms of RA and improved physical function, and these effects were sustained through 52 weeks. Both filgotinib doses were well tolerated with an acceptable safety profile,” concluded investigators. The long-term safety of filgotinib is currently being studied in 2 trials (NCT02065700NCT03025308) and “an additional study evaluating early, temporary use of JAK-inhibitors or bDMARDs in patients with a suboptimal early response to initial MTX and tapering glucocorticoids is needed to assess potential benefits of this strategy.”

Reference:

Westhovens R, Rigby WFC, van der Heijde D, et al. Filgotinib in combination with methotrexate or as monotherapy versus methotrexate monotherapy in patients with active rheumatoid arthritis and limited or no prior exposure to methotrexate: the phase 3, randomised controlled FINCH 3 trial [published online ahead of print, 2021 Jan 15]. Ann Rheum Dis. 2021;annrheumdis-2020-219213. doi:10.1136/annrheumdis-2020-219213