Filgotinib in Active Noninfectious Uveitis: The HUMBOLDT Randomized Clinical Trial

Abstract

Importance: Noninfectious uveitis is a leading cause of visual impairment with an unmet need for additional treatment options.

Objective: To assess the efficacy and safety of filgotinib, a Janus kinase 1 (JAK1) preferential inhibitor, for the treatment of noninfectious uveitis.

Design, setting, and participants: The HUMBOLDT trial was a double-masked, placebo-controlled, phase 2, randomized clinical trial conducted from July 2017 to April 2021 at 26 centers in 7 countries. Eligible participants (aged ≥18 years) had active noninfectious intermediate uveitis, posterior uveitis, or panuveitis despite at least 2 weeks of treatment with oral prednisone (10-60 mg per day).

Interventions: Participants were randomly assigned 1:1 to receive filgotinib, 200 mg, or placebo orally once daily for up to 52 weeks.

Main outcomes and measures: The primary end point was the proportion of participants experiencing treatment failure by week 24. Treatment failure was a composite end point represented by assessment of the presence of chorioretinal and/or retinal vascular lesions, best-corrected visual acuity, and anterior chamber cell and vitreous haze grades. Safety was assessed in participants who received at least 1 dose of study drug or placebo.

Results: Between July 26, 2017, and April 22, 2021, 116 participants were screened, and 74 (mean [SD] age, 46 [16] years; 43 female [59.7%] of 72 participants, as 2 participants did not receive treatment doses) were randomly assigned to receive filgotinib (n = 38) or placebo (n = 36). Despite early termination of the trial for business reasons ahead of meeting enrollment targets, a significantly reduced proportion of participants who received filgotinib experienced treatment failure by week 24 vs placebo (12 of 32 participants [37.5%] vs 23 of 34 participants [67.6%]; difference vs placebo -30.1%; 95% CI, -56.2% to -4.1%; P = .006). Business reasons were unrelated to efficacy or safety. Adverse events were reported in 30 of 37 participants (81.1%) who received filgotinib and in 24 of 35 participants (68.6%) who received placebo. Serious adverse events were reported in 5 of 37 participants (13.5%) in the filgotinib group and in 2 of 35 participants (5.7%) in the placebo group. No deaths were reported during the trial.

Conclusions and relevance: Results of this randomized clinical trial show that filgotinib lowered the risk of treatment failure in participants with active noninfectious intermediate uveitis, posterior uveitis, or panuveitis vs placebo. Although the HUMBOLDT trial provided evidence supporting the efficacy of filgotinib in patients with active noninfectious uveitis, the premature termination of the trial prevented collection of additional safety or efficacy information of this JAK1 preferential inhibitor.

Trial registration: ClinicalTrials.gov Identifier: NCT03207815.

Figure 1.. Consolidated Standards of Reporting Trials (CONSORT) Flow Diagram

Two participants (one from each treatment group) were randomized but discontinued the trial before administration of the study drug owing to protocol violations. ^aSafety analysis set included participants who received at least 1 dose of study drug. ^bEvaluable analysis set included all participants who received at least 1 dose of study drug and did not permanently discontinue the trial before week 6. ^cTrial completion was defined as the participant completing the week 52 visit or having met the criteria for treatment failure.

Figure 2.. Probability of Treatment Failure on or After Week 6

Treatment failures on or after week 6 were counted as events (marked by vertical lines in the Kaplan-Meier curves); participants who were not observed to have treatment failure by the time of trial completion or by the time of discontinuation from the trial were censored at the date of their last available assessment.

Figure 3.. Probability of Treatment Failure Due to Presence of a New Active Lesion, Increased Anterior Chamber Cell (ACC) Grade or Vitreous Haze (VH) Grade, or Worsening Best-Corrected Visual Acuity (BCVA)

A, Presence of a new active lesion. B, Increased ACC grade. C, Increased VH Grade. D, Worsening BCVA. Treatment failures on or after week 6 were counted as events (marked by vertical lines in the Kaplan-Meier curves); participants who were not observed to have treatment failure by the time of trial completion or by the time of discontinuation from the trial were censored at the date of their last available assessment.