This randomized clinical trial investigates the efficacy and safety of filgotinib in patients with active noninfectious uveitis.
Key Points
Question
What is the efficacy and safety of filgotinib in patients with active noninfectious uveitis?
Findings
Among 74 participants in the double-masked, placebo-controlled, randomized clinical trial (HUMBOLDT) that was prematurely halted for business reasons ahead of meeting enrollment targets, the filgotinib group had fewer treatment failures by week 24 (the primary efficacy end point) than the placebo group, while differences in safety between groups were not detected.
Meaning
Although the HUMBOLDT randomized clinical trial provided evidence supporting the efficacy of filgotinib in patients with active noninfectious uveitis, the termination of the trial prevented collection of additional safety or efficacy information of this Janus kinase 1 preferential inhibitor.
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
Introduction
Uveitis is characterized by intraocular inflammation of the uvea and adjacent structures1 and is one of the leading causes of blindness in the US and Europe.2,3,4 Diagnosis of uveitis can be challenging, with approximately one-half of cases being idiopathic.1,5 In these patients, uveitis is presumed to be immune mediated, with associated disorders including inflammatory bowel disease (IBD) and sarcoidosis.1,5,6 These conditions have been associated with activation of signaling pathways involving Janus kinase (JAK) and signal transduction and activation of transcription (STAT) signaling proteins.7
Anterior uveitis, the most common form of uveitis, can often be managed acutely with topical corticosteroid therapy.5 Noninfectious intermediate uveitis, posterior uveitis, and panuveitis subtypes are more challenging to control,5,8 requiring systemic or intravitreal corticosteroid therapies such as prednisone and triamcinolone acetonide, respectively.1,5 Long-term use of corticosteroids is associated with potentially serious adverse events (AEs) such as diabetes, glaucoma, and cataracts.1,8,9,10 Immunosuppressants, such as azathioprine and methotrexate, are recommended as a corticosteroid-sparing approach for patients with noninfectious uveitis, although these are not currently licensed for this indication.1,5
Adalimumab, a subcutaneous anti–tumor necrosis factor therapy, is the only noncorticosteroid treatment approved in the US and Europe for noninfectious intermediate uveitis, posterior uveitis, and panuveitis.11,12 Despite this, treatment with adalimumab has been associated with high treatment failure rates.13,14 As such, uveitis is still associated with substantial morbidity and significant unmet therapeutic need.
Filgotinib, an oral preferential JAK1 inhibitor, is indicated for the treatment of rheumatoid arthritis (RA) and ulcerative colitis (UC) in the European Union, the UK, Japan, South Korea, and Taiwan15,16,17; it is not approved for use in the US. Despite the role of the JAK-STAT pathway in inflammation,7,17 there have been no randomized clinical trials of JAK inhibitors in uveitis, to our knowledge, published to date. The phase 2 HUMBOLDT randomized clinical trial was designed to assess a JAK inhibitor for this indication, assessing the efficacy and safety of filgotinib in participants with active noninfectious intermediate uveitis, posterior uveitis, or panuveitis.
Methods
Study Design
HUMBOLDT was a double-masked, placebo-controlled, phase 2, randomized clinical trial conducted at 26 centers (clinics, research centers, and academic hospitals) in 7 countries (Australia, Canada, Germany, Israel, New Zealand, the UK, and the US) between July 26, 2017, and April 22, 2021. The final protocol (Supplement 1) and the 4 amendments were reviewed and approved by the independent ethics committee and/or institutional review board at each trial site. The trial design is shown in eFigure 1 in Supplement 2. All participants provided written informed consent and were reimbursed for inconveniences related to study participation, such as travel expenses. No financial incentives were offered for study participation. This trial followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.
Participants
Eligible participants were 18 years and older with a history of noninfectious intermediate uveitis, posterior uveitis, or panuveitis. At day 1/baseline, participants had active noninfectious intermediate, posterior, or panuveitis in at least 1 eye despite 2 or more weeks of maintenance therapy with oral prednisone (from ≥10 mg per day to ≤60 mg per day) or oral corticosteroid equivalent. Active uveitis was defined as the presence of at least 1 of the following: an active, inflammatory, chorioretinal, and/or inflammatory retinal vascular lesion; 2+ or greater anterior chamber cell (ACC) grade (based on the Standardization of Uveitis Nomenclature [SUN] criteria); and 2+ or greater vitreous haze (VH) grade (based on the National Eye Institute/SUN criteria). Both of the participants’ eyes were clinically evaluable for the purpose of determining eligibility and for assessment throughout the study.
Participants were excluded from the trial if they had clinically significant (in the opinion of the investigator) active or chronic recurring infection, opportunistic infection, or immunodeficiency syndromes; intraocular pressure of greater than 25 mm Hg if they were receiving 1 or fewer glaucoma medications or intraocular pressure of greater than 21 mm Hg if they were receiving 2 or more glaucoma medications; and/or evidence of glaucomatous optic nerve injury or glaucomatous field loss involving, encroaching on, or having the potential to split fixation or cause visual acuity loss during the trial, regardless of intraocular pressure or number of glaucoma medications. Full inclusion and exclusion criteria are listed in eMethods 1 in Supplement 2.
Eligible participants were enrolled and randomly assigned in a 1:1 ratio to receive filgotinib, 200 mg, daily or placebo. Participants, site investigators, and all personnel directly involved in the conduct of the trial were masked to treatment assignment. Details of randomization and permitted concomitant medications are provided in eMethods 2 in Supplement 2. All participants received 60 mg per day of oral prednisone at day 1/baseline, followed by a mandatory protocol-defined taper requiring prednisone discontinuation by week 15 (eTable 1 in Supplement 2). Those who entered the trial while receiving topical ocular corticosteroid treatment underwent a standardized taper schedule until discontinuation by week 9.
Procedures
Participants received filgotinib, 200 mg (Rottendorf Pharma), or placebo, orally once daily for up to 52 weeks. Beginning at week 6, and at all subsequent visits, participants were examined for evidence of treatment failure (eTable 2 in Supplement 2). Participants were considered in treatment failure if they fulfilled at least 1 of the composite criteria in at least 1 eye. Those with evidence of treatment failure on or after week 6 discontinued the trial and were treated at the discretion of the investigator.
Participants were considered to have completed the trial if they completed the week 52 visit, met the criteria for treatment failure, or discontinued for any other reason before week 52. Participants were considered to have completed treatment if they completed the protocol-specified study drug regimen. End-of-treatment (EOT) visits were conducted at week 52 for participants who completed the study or at the time of trial discontinuation for those with treatment failure. Early termination (ET) visits were conducted at the time of trial discontinuation for those who discontinued for any reason other than treatment failure before week 52. All participants were required to complete a follow-up visit 4 weeks after the last dose of study drug.
Outcomes
Definitions of efficacy end points are given in eTable 2 in Supplement 2. The primary objective was to evaluate the efficacy of filgotinib vs placebo for the treatment of active noninfectious uveitis, as measured by the proportion of participants with treatment failure by week 24.
A key secondary objective was to evaluate the efficacy of filgotinib in terms of time to treatment failure on or after week 6. Other secondary objectives were to evaluate changes from best state in VH grade, ACC grade, logMAR best-corrected visual acuity (BCVA), and central retinal thickness, as well as time to development of macular edema on or after week 6. Central retinal thickness was defined as the thickness of the retina in micrometers in the center of the foveal pit (1-mm subfield). Macular edema was determined by central reader evaluation of optical coherence tomography (OCT) images and defined as central retinal thickness greater than 300 μm or greater than 315 μm (as measured by Cirrus HD-OCT [Carl Zeiss Meditec] or Spectralis [Heidelberg Engineering] systems, respectively). Exploratory efficacy end points were to evaluate the efficacy of filgotinib on time to treatment failure that was due to the presence of a new active lesion, increased VH grade, increased ACC grade, and worsening of BCVA.
The safety and tolerability of filgotinib were assessed by comparing the incidence of AEs between treatment groups (coded according to the Medical Dictionary for Regulatory Activities, or MedDRA, version 24.0). The severity of AEs was graded and defined by the Common Terminology Criteria for Adverse Events, version 4.03.
Statistical Analyses
Sample size calculations were based on published data from the VISUAL I trial.13 Assuming the observed proportion of participants with treatment failure by week 24 was 70% in the placebo group, 107 participants per treatment group would provide at least 85% power to detect a 20% reduction in the proportion of participants with treatment failure by week 24 in the filgotinib group using a 2-sided significance level of .05. Given an expected attrition rate of 15%, a total of 248 participants would need to be randomized into the trial. By the time of study termination, the number of participants enrolled was fewer than planned; therefore, all hypothesis testing was exploratory, and all P values reported are nominal, 2-sided, and not adjusted for multiple analyses. All CIs were calculated based on the nominal level of 95%. Two data monitoring committee safety data review meetings took place before early termination of the trial; no interim analyses of efficacy and futility had been performed at this point.
Efficacy end points were analyzed using the evaluable analysis set (all randomized participants who received at least 1 dose of study drug and did not permanently discontinue the trial before week 6). Safety end points were analyzed using the safety analysis set (all participants who received at least 1 dose of study drug).
Full details of statistical analyses are given in eMethods 2 in Supplement 2. In brief, the Cochran-Mantel-Haenszel approach, adjusting for the stratification factors, was used for the hypothesis testing of the primary end point, and the repeated measures analyses of covariance were used for continuous end points. A stratified log-rank test was used to compare time to treatment failure or development of macular edema on or after week 6 between treatment groups. Safety data were summarized using descriptive statistics. Statistical analyses were performed using SAS, version 9.4 (SAS Institute Inc).
Results
Patient Flow and Baseline Characteristics
Between July 26, 2017, and April 22, 2021, 116 participants were screened. Of a planned 248 participants, 74 (mean [SD] age, 46 [16] years; 43 female [59.7%]; 29 male [40.3%]; these data were from 72 participants, as 2 participants did not receive treatment doses) were enrolled and randomized to either filgotinib, 200 mg (n = 38), or placebo (n = 36) (Figure 1). On December 15, 2020, the trial was halted ahead of meeting its enrollment target due to reasons related to a business decision to discontinue development efforts across all disease indications in the US. Business reasons were unrelated to the efficacy or safety of filgotinib. Participants enrolled in the trial at the time of termination were allowed to continue participation through all protocol-specified safety and efficacy evaluations.
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.
In total, 72 participants (filgotinib, 37 [51.4%]; placebo, 35 [48.6%]) received at least 1 dose of study drug. Of these, 55 participants completed treatment (filgotinib, 29 [52.7%]; placebo, 26 [47.3%]), and 17 participants prematurely discontinued the study drug. The most common reasons for discontinuation were AEs (filgotinib, 2 [5.4%]; placebo, 4 [11.4%]) and loss to follow-up (filgotinib, 1 [2.7%]; placebo, 2 [5.7%]).
Of the 72 participants treated, 66 participants (filgotinib, 32 [48.5%]; placebo, 34 [51.5%]) did not permanently discontinue the trial before week 6, and 59 participants completed the trial (filgotinib, 30 [50.8%]; placebo, 29 [49.2%]). Thirteen participants discontinued the trial; the most common reasons for premature discontinuation were AEs (filgotinib, 1 [2.7%]; placebo, 2 [5.7%]) and loss to follow-up (filgotinib, 1 [2.7%]; placebo, 2 [5.7%]). Each treatment group had 1 participant who discontinued the trial before administration of the study drug owing to protocol violations.
Baseline characteristics were generally similar across treatment groups (Table 1). Most cases of uveitis were idiopathic in etiology, observed in 56.8% of participants (21 of 37) in the filgotinib group and 57.1% of participants (20 of 35) in the placebo group. At random, baseline immunosuppressant use was more frequent in participants treated with filgotinib than placebo (9 [24.3%] vs 4 [11.4%], respectively). Other characteristics were similar between groups (Table 1).
Table 1. Baseline Characteristics of Participantsa.
| Characteristic | Filgotinib, 200 mg (n = 37) | Placebo (n = 35) |
|---|---|---|
| Age, mean (SD), y | 48 (15.1) | 43 (15.7) |
| Sex at birth, No. (%) | ||
| Male | 14 (37.8) | 15 (42.9) |
| Female | 23 (62.2) | 20 (57.1) |
| Etiology of uveitis, No. (%) | ||
| Birdshot chorioretinopathy | 5 (13.5) | 5 (14.3) |
| Idiopathic | 21 (56.8) | 20 (57.1) |
| Multifocal choroiditis and panuveitis | 0 | 1 (2.9) |
| Rheumatoid arthritis | 2 (5.4) | 0 |
| Sarcoidosis | 5 (13.5) | 5 (14.3) |
| Spondyloarthritis | 1 (2.7) | 0 |
| Tubulointerstitial nephritis and uveitis syndrome | 0 | 1 (2.9) |
| Vogt-Koyanagi-Harada disease | 1 (2.7) | 3 (8.6) |
| Other | 2 (5.4) | 0 |
| Anatomic type of uveitis, No. (%) | ||
| Intermediate | 5 (13.5) | 5 (14.3) |
| Intermediate and posterior | 3 (8.1) | 0 |
| Posterior | 7 (18.9) | 9 (25.7) |
| Panuveitis | 22 (59.5) | 21 (60.0) |
| Eye affected by uveitis flare, No. (%) | ||
| Left | 3 (8.1) | 4 (11.4) |
| Right | 4 (10.8) | 3 (8.6) |
| Both | 30 (81.1) | 28 (80.0) |
| Duration of uveitis from first symptoms, mo | ||
| No. | 35 | 35 |
| Mean (SD) | 48.6 (60.1) | 59.5 (74.0) |
| Time since last uveitis flare at baseline, mo | ||
| No. | 26 | 27 |
| Mean (SD) | 12.9 (22.5) | 24.5 (50.3) |
| Number of uveitis flares in the past 12 mo | ||
| No. | 37 | 35 |
| Mean (SD) | 2 (2.0) | 2 (0.8) |
| Uveitis attributed to sarcoidosis, No. (%) | 5 (13.5) | 5 (14.3) |
| Baseline immunosuppressant use, No. (%) | 9 (24.3) | 4 (11.4) |
| Prior immunosuppressant use during screening, No. (%) | ||
| Azathioprine | 7 (18.9) | 3 (8.6) |
| Methotrexate | 2 (5.4) | 1 (2.9) |
| Prior use of anti-TNF therapy, No. (%) | 2 (5.4) | 1 (2.9) |
| OCT evidence of macular edema, No. (%) | 21 (56.8) | 20 (57.1) |
Abbreviations: OCT, optical coherence tomography; TNF, tumor necrosis factor.
Denominator for percentages was the number of patients in the safety analysis set. Safety analysis set included patients who received at least 1 dose of study drug.
Efficacy
Primary End Point
A significantly lower proportion of participants who received filgotinib than placebo experienced treatment failure by week 24 (12 of 32 [37.5%] vs 23 of 34 [67.6%]; treatment difference vs placebo, −30.1%; 95% CI, −56.2% to −4.1%; P = .006). This corresponded to an absolute risk reduction of 30.1% (95% CI, 4.1%-56.2%). Three participants (25.0%) who received filgotinib and 6 participants (26.1%) who received placebo had missing values for the primary efficacy end point (and were, therefore, considered as having treatment failure by week 24). A consistent result was obtained using a logistic regression analysis adjusted for stratification factors (odds ratio, 0.23; 95% CI, 0.08-0.69; P = .008).
Key Secondary End Points
In the time to event analysis, participants who received filgotinib were less likely to have treatment failure on or after week 6 compared with those who received placebo (stratified hazard ratio [HR], 0.31; 95% CI, 0.14-0.66; P = .003). The treatment failure Kaplan-Meier curve for the filgotinib group separated early from the placebo group, a change that persisted through the treatment period (Figure 2). Median time to treatment failure was 22.0 (95% CI, 16.0-36.1) weeks for the placebo group and was not calculable for the filgotinib group because fewer than 50% of participants (12 of 32) met treatment failure criteria by the time they completed the trial. The 25th percentile for time to treatment failure was 12.1 weeks for the placebo group and 24.1 weeks for the filgotinib group.
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.
Reduced changes from best state to week 52/EOT/ET visits in ACC grade (per eye: filgotinib, 32 of 32 [100%]; placebo, 34 of 34 [100%]; treatment difference of least squares [LS] mean, −0.4; 95% CI, −0.8 to −0.1; P = .01), BCVA (filgotinib, 32 of 32 [100%]; placebo, 34 of 34 [100%]; treatment difference of LS mean, −0.05; 95% CI, −0.10 to 0; P = .04), and central retinal thickness (filgotinib, 32 of 32 [100%]; placebo, 32 of 34 [94.1%]; treatment difference of LS mean, −0.02; 95% CI, −0.05 to 0; P = .03) were observed in participants who received filgotinib compared with placebo. There was no difference in change to VH grade between treatment groups (filgotinib, 32 of 32 [100%]; placebo, 33 of 34 [97.1%]; treatment difference of LS mean, −0.1; 95% CI, −0.4 to 0.2; P = .36). Best state and week 52/EOT/ET visit data are summarized in eTable 3 in Supplement 2. Of the treatment failure criteria, an increase in ACC grade was the main reason for treatment failure in the placebo group (13 of 34 [38.2%]) (eFigure 2 in Supplement 2). An increase in VH grade and a worsening of BCVA were the main reasons for treatment failure in the filgotinib group (5 of 32 [15.6%] each).
No difference was observed between treatment groups in time to the development of macular edema on or after week 6 (treatment difference vs placebo, 6.8%; 95% CI, −19.6% to 33.2%) (eFigure 3 in Supplement 2). A total of 21 of 32 participants (65.6%) who received filgotinib had macular edema on or after week 6, compared with 20 of 34 participants (58.8%) who received placebo (eTable 4 in Supplement 2). Most participants in the evaluable analysis set who had OCT evidence of macular edema at baseline (filgotinib, 18 of 32 [56.3%]; placebo, 20 of 34 [58.8%]) also had macular edema on or after week 6 (filgotinib, 16 of 18 [88.9%]; placebo, 19 of 20 [95.0%]).
Exploratory End Points
Time to treatment failure due to a new active lesion was improved in the filgotinib group compared with the placebo group (stratified HR, 0.31; 95% CI, 0.09-1.05; P = .06) (Figure 3A). Time to treatment failure due to increased ACC grade was also improved (stratified HR, 0.20; 95% CI, 0.06-0.69; P = .01) (Figure 3B). No differences were observed between treatment groups in time to treatment failure due to increased VH grade (stratified HR, 0.42; 95% CI, 0.11-1.61; P = .21) or worsening of BCVA (stratified HR, 0.33; 95% CI, 0.08-1.42; P = .14) (Figure 3C and 3D).
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.
Safety
Mean (SD) durations of exposure to filgotinib and placebo were 34.0 (19.6) weeks and 22.6 (16.1) weeks, respectively. AEs were reported in 30 of 37 participants (81.1%) who received filgotinib and 24 of 35 participants (68.6%) who received placebo (eTable 5 in Supplement 2). There were 369.1 and 361.8 AEs per 100 participant-years in the filgotinib and placebo groups, respectively.
The majority of AEs were mild or moderate in severity (eTable 5 in Supplement 2). AEs reported in 10% or more participants in the filgotinib group were visual impairment (5 of 37 [13.5%]) and insomnia, urinary tract infection, nausea, and abdominal pain (4 [10.8%] each). In the placebo group, AEs reported in 10% or more of participants were headache (7 of 35 [20.0%]) and insomnia, urinary tract infection, and dry eye (4 [11.4%] each).
Study drug-related AEs (as determined by the investigator) were reported in 15 of 37 participants (40.5%) who received filgotinib and 6 of 35 participants (17.5%) who received placebo. Twelve participants experienced uveitis-related AEs in each treatment group (filgotinib, 32.4%; placebo, 34.3%). The proportion of participants with grade 3 or higher (severe) AEs is detailed in eTable 5 in Supplement 2.
Serious AEs (SAEs) were reported in 5 of 37 participants (13.5%) in the filgotinib group and 2 of 35 participants (5.7%) in the placebo group (Table 2). There were 19.2 SAEs per 100 participant-years in the filgotinib group and 11.2 SAEs per 100 participant-years in the placebo group. Two participants in the filgotinib group each experienced 2 SAEs (spinal stenosis and suicidal ideation; epilepsy and IBD). Of these, only the SAE of IBD was considered related to the study drug. Other treatment-related SAEs reported in the filgotinib group were COVID-19 infection and uveitis (1 [2.7%] each), and 1 participant (2.9%) who was receiving placebo experienced a treatment-related SAE of urinary tract infection. All other reported SAEs occurred in up to 1 participant in each treatment group.
Table 2. Summary of Serious Adverse Events (SAEs).
| AE type | Filgotinib, 200 mg (n = 37) | Placebo (n = 35) |
|---|---|---|
| Participants with any SAE, No. (%)a | 5 (13.5) | 2 (5.7) |
| Bladder prolapse | 1 (2.7) | 0 |
| COVID-19 infection | 1 (2.7) | 0 |
| Epilepsy | 1 (2.7) | 0 |
| Inflammatory bowel disease | 1 (2.7) | 0 |
| Spinal stenosis | 1 (2.7) | 0 |
| Suicidal ideation | 1 (2.7) | 0 |
| Uveitis | 1 (2.7) | 0 |
| Retinal vasculitis | 0 | 1 (2.9) |
| Urinary tract infection | 0 | 1 (2.9) |
SAEs began on or after the study drug start date up to 30 days after permanent discontinuation of study drug or led to premature study drug discontinuation. Multiple AEs were counted only once per participant for each term and AEs were presented by descending order of the total frequencies for filgotinib participants.
AEs of interest included infections, serious infections, herpes zoster, opportunistic infection, gastrointestinal perforation, thromboembolism, and malignancy. The proportion of participants with infections was 32.4% (12 of 37 participants) in the filgotinib group and 25.7% (9 of 35 participants) in the placebo group (eTable 5 in Supplement 2). The most common infection was urinary tract infection, which was reported in 4 participants in each treatment group (filgotinib, 10.8%; placebo, 11.4%). Serious infections were reported in 1 participant in each treatment group (filgotinib, 2.7%; placebo, 2.9%). No arterial or venous thromboembolic events, major adverse cardiovascular events (MACEs), gastrointestinal perforations, nonmelanoma skin cancers, opportunistic infections, cases of tuberculosis, or cases of herpes zoster were reported in either treatment group. No deaths were reported during the trial.
Discussion
We report a randomized clinical trial to investigate a JAK inhibitor in the treatment of active noninfectious intermediate uveitis, posterior uveitis, or panuveitis. Owing to early termination of this trial (due to business reasons, unrelated to the efficacy or safety of filgotinib), only 74 participants were randomly assigned to a treatment group (29.8% of the planned enrollment). Despite this, a significantly lower proportion of participants treated with filgotinib experienced treatment failure compared with placebo (demonstrated by the primary efficacy end point of treatment failure at week 24). Filgotinib also lowered the risk of treatment failure and loss of visual acuity compared with placebo, suggesting potential efficacy of filgotinib in this indication. The premature termination of the trial prevented collection of additional safety or efficacy information of this JAK1 preferential inhibitor in this disease state.
Participants who received filgotinib had a reduced probability of treatment failure on or after week 6, as well as significantly reduced mean changes in ACC grade and BCVA compared with placebo, findings that are in line with those in participants with active noninfectious intermediate uveitis, posterior uveitis, or panuveitis who received adalimumab in the phase 3 VISUAL I trial.13 VH grade was unchanged between treatment groups, and there was no functional difference in visual acuity on or after week 6 in participants who received filgotinib compared with placebo (the end point that most patients would value). Deterioration in VH grade and BCVA were the main reasons for treatment failure on or after week 6 in those who received filgotinib (31.2% of participants). In comparison, in the VISUAL I trial, 36% of participants in the adalimumab-treated population experienced treatment failure due to the same disease progression parameters, although these were reported over a maximum duration of 80 weeks.13
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 on this JAK1 preferential inhibitor in this disease state. Nevertheless, there were no new safety concerns identified in the immunosuppressed uveitis population in this trial. When adjusted for participant-years of exposure, there was only a slightly higher incidence of AEs in the filgotinib group vs the placebo group in our trial, although this is consistent with the profile of other systemic immune modifying therapies vs their respective placebo groups.14 Most AEs were either mild or moderate (grade 1 or 2) in severity, consistent with findings from the phase 2b/3 SELECTION trial in patients with moderately to severely active UC, as well as the phase 2b/3 DARWIN 1, DARWIN 2, FINCH 1, and FINCH 2 trials in patients with RA.18,19,20,21,22,23 The incidences of uveitis-related AEs, AEs, and SAEs were similar in the filgotinib group and placebo group. The incidence of serious infections was low across treatment groups, similar to findings reported in several previous phase 2b/3 trials of filgotinib in RA (DARWIN 1, DARWIN 2, and FINCH 1-3) and UC (SELECTION).18,19,20,21,22,23,24
Together these data suggest that the safety profile of filgotinib in uveitis is akin to that seen in other inflammatory conditions. Participants who received filgotinib in HUMBOLDT did not experience any AEs of special interest typically reported for JAK inhibitors (eg, thromboembolism, MACEs, malignancies, and gastrointestinal perforations),18,22,25 although this could be due to the small sample size. Alternatively, it could be hypothesized that individuals with uveitis are less susceptible to these events owing to the pathophysiology of the condition or the specific characteristics of this trial’s population.
Limitations
This study has some limitations. It is feasible that the observed activity of filgotinib in this trial occurred by dampening of intraocular inflammation associated with uveitis,5 via inhibition of the JAK-STAT inflammatory pathway.26 Although filgotinib is a JAK1 preferential inhibitor, it is unclear which downstream cytokines might have been impacted. Future studies could evaluate the underlying mechanism of action of filgotinib in uveitis.7 The findings of these studies could also have implications for patients with other diseases that are complicated by uveitis, such as sarcoidosis, IBD, RA, and ankylosis spondylitis.6 The main limitation of this trial was its termination ahead of meeting its prespecified enrollment target. It is also unclear whether filgotinib could offer significant anti-inflammatory control as a monotherapy during an active flare period owing to the protocol-defined prednisone taper, although this is a minor point considering that clinicians typically regard corticosteroids as a bridge to biologics. The potential advantages of a nonsteroidal oral therapy for uveitis control should be considered.
Conclusions
In conclusion, filgotinib lowered the risk of treatment failure after corticosteroid withdrawal in participants with active noninfectious intermediate uveitis, posterior uveitis, or panuveitis vs placebo. On average, the regression in ACC grade, BCVA, and central retinal thickness was reduced in the filgotinib group compared with the placebo group, while there was no difference in VH grade between groups. No functional difference in visual acuity was observed on or after week 6 in participants who received filgotinib compared with placebo (the end point that most patients would value). Treatment with filgotinib was generally well tolerated, with no new safety concerns identified in the immunosuppressed uveitis population treated with filgotinib, compared with other previously studied populations.18,19,20,21,22,23,24 Overall, results of this trial indicate that filgotinib could be efficacious in individuals with active noninfectious intermediate uveitis, posterior uveitis, or panuveitis and may warrant further investigation.
Trial Protocol.
eMethods 1. HUMBOLDT Trial Inclusion and Exclusion Criteria
eMethods 2. HUMBOLDT Trial Design Details
eFigure 1. Trial Design
eFigure 2. Reasons for Treatment Failure on or After Week 6
eFigure 3. Probability of Macular Edema Development on or After Week 6
eTable 1. HUMBOLDT Trial Prednisone Taper Schedule
eTable 2. Efficacy End Point Definitions
eTable 3. Summary of Best State and Week 52/EOT/ET Data for ACC Grade, VH Grade, logMAR BCVA and Logarithm Change in Central Retinal Thickness
eTable 4. Participants With Macular Edema on or After Week 6
eTable 5. Summary of AEs
eReferences
Data Sharing Statement.
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol.
eMethods 1. HUMBOLDT Trial Inclusion and Exclusion Criteria
eMethods 2. HUMBOLDT Trial Design Details
eFigure 1. Trial Design
eFigure 2. Reasons for Treatment Failure on or After Week 6
eFigure 3. Probability of Macular Edema Development on or After Week 6
eTable 1. HUMBOLDT Trial Prednisone Taper Schedule
eTable 2. Efficacy End Point Definitions
eTable 3. Summary of Best State and Week 52/EOT/ET Data for ACC Grade, VH Grade, logMAR BCVA and Logarithm Change in Central Retinal Thickness
eTable 4. Participants With Macular Edema on or After Week 6
eTable 5. Summary of AEs
eReferences
Data Sharing Statement.