Filgotinib for non-infectious uveitis: a new frontier in treatment

Uveitis is an inflammatory disease affecting the uvea, which includes the iris, ciliary body and choroid (1). Non-infective uveitis is more prevalent in developed countries and primarily impacts individuals of working age, with a mean onset of around 40 years. It accounts for 5–10% of severe vision impairment globally (1,2). This form of uveitis is often associated with systemic diseases, such as ankylosing spondylosis, juvenile idiopathic arthritis, sarcoidosis and Behcet’s disease (2,3).

Immunosuppressive therapy is the cornerstone of care in non-infectious uveitis. Corticosteroids (local or systemic) are first-line therapy, with disease-modifying anti-rheumatic drugs (DMARDs) as the second-line treatment to control inflammation (3,4). Long-term corticosteroid use has significant sequelae, with systemic steroids associated with diabetes, osteoporosis, mood disturbance, weight gain and hypertension, and local steroid treatment associated with increased risk of cataract and glaucoma. Individuals are, thus, switched to DMARD therapy if there is an inability to taper prednisone below 5–7.5 mg/day, if there are unacceptable side effects of prednisone, or if long-term high-dose therapy is required (3,4).

Traditional DMARDs, such as methotrexate and mycophenolate, have shown limited success in controlling inflammation, with reported success rates at six months of 66.7% for methotrexate and 57.1% for mycophenolate. These treatments are also associated with significant side effects, including fatigue, headache, gastrointestinal upset, hepatotoxicity and cytotoxicity as well as teratogenicity, which further limit their use (4,5).

Biologic agents are typically employed in patients with refractory disease and persistent symptoms or signs of inflammation despite high-dose corticosteroid or DMARD therapy. Adalimumab is frequently the first choice among anti-tumour necrosis factor (anti-TNF) agents, supported by robust evidence from the efficacy and safety of adalimumab in patients with active uveitis (VISUAL I), adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II) and Safety and Cost Effectiveness of Adalimumab in Combination with Methotrexate for the Treatment of Juvenile Idiopathic Arthritis Associated Uveitis (SYCAMORE) trials demonstrating its efficacy in reducing inflammation and preserving vision (6-8). Adalimumab is a monoclonal antibody to TNF alpha, thereby limiting the downstream cytokines and reducing inflammatory changes. Infliximab, another anti-TNF agent, is often used as a second-line option, especially in cases where adalimumab is not tolerated or ineffective. For patients who fail anti-TNF therapy, other biologics, such as tocilizumab, an interleukin-6 (IL-6) receptor inhibitor, have shown promise in treating refractory uveitis (9). Anti-TNF drugs are associated with potential side effects, including increased susceptibility to infections (e.g., tuberculosis, opportunistic infections), injection site reactions, and less commonly, demyelinating diseases, heart failure exacerbation, or autoimmune phenomena such as drug-induced lupus (6).

Due to the limitations of existing therapy options, there has been a search for a suitable alternative. Janus kinase (JAK) inhibitors have emerged as a promising therapeutic option for uveitis, especially in cases where conventional immunosuppressive therapies are ineffective or poorly tolerated. JAK inhibitors target the JAK-signal transducer and activator of transcription (JAK-STAT) pathway. It is a transmembrane tyrosine kinase protein that leads to the immune activation pathway by potentiating the transcription of genes in the nucleus of the cell. Over-expression of this gene is associated with many autoimmune conditions. By blocking this pathway, JAK inhibitors can reduce the production of pro-inflammatory cytokines such as IL-6, TNF-α, and interferon-γ (IFN-γ), which are often elevated in uveitis (10).

There have been previous case reports, chart reviews and a prospective cohort study reporting success with the use of JAK inhibitors (tofacitinib, baricitinib and upadacitinib) in the treatment of uveitis in patients who have failed conventional immunosuppressive therapy (11-20). No significant side effects were noted other than one report of myalgia (20).

Although the first generation of non-specific JAK inhibitors has shown efficacy in the treatment of chronic pro-inflammatory conditions, adverse effects such as cytopenia associated with nonselective pan-JAK blockade have led to the development of second-generation JAK inhibitors with selective inhibitory activity. Fligotinib is a second-generation JAK inhibitor that preferentially blocks the JAK1 pathway (21). It has been approved for use in the treatment of rheumatoid arthritis and ulcerative colitis (22).

Study to Evaluate the Efficacy and Safety of Filgotinib in Adults with Active Noninfectious Uveitis (HUMBOLDT) randomized clinical trial is a double-masked, phase 2 randomized clinical trial, which investigated the efficacy and safety of filgotinib, a JAK1 preferential inhibitor, for treating active noninfectious uveitis. It was conducted at 26 centres in 7 countries from July 2017 to April 2021 (23).

Eligible participants were 18 years and older, and at baseline had active non-infectious intermediate, posterior, or panuveitis in at least 1 eye despite 2 or more weeks of maintenance therapy with oral prednisone (10–60 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). Participants were excluded from the trial if they had a clinically significant active or chronic recurring infection, opportunistic infection, or immunodeficiency syndromes; high intraocular pressure 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 (23).

There were a total of 74 participants with active non-infectious intermediate uveitis, posterior uveitis, or panuveitis (mean age 46 years; 59.7% female) who were randomized to receive either filgotinib (200 mg oral daily) or placebo (1:1 ratio). The primary endpoint was to determine the efficacy of treatment with filgotinib, specifically the proportion of participants experiencing treatment failure by week 24. Secondary endpoints in the study included: the efficacy of filgotinib in terms of time to treatment failure on or after week 6, changes from the best state achieved before week 6 to week 52/end of trial visits in ACC grade, best-corrected visual acuity (BCVA), central retinal thickness, VH grade, time to development of macular oedema on or after week 6 and safety and tolerability of filgotinib by comparing adverse events between treatment groups (23).

The early results from the HUMBOLDT trial showed that filgotinib reduced treatment failure at both week 6 and week 24 compared to the placebo. Treatment failure at week 24 of filgotinib was 37.5% compared to 67.6% in the placebo group (21). The treatment group also showed reduced changes in ACC grade, BCVA, and central retinal thickness. However, there was no significant difference in VH grade or the time to development of macular oedema between the two groups (23). However, owing to the small sample size, the study sample is underpowered. All hypothesis testing undertaken by the study team was exploratory, and all P values reported are nominal, 2-sided, and not adjusted for multiple analyses.

In terms of drug safety and tolerability, adverse events were more common in the treatment group, reported in 81.1% and 68.6% of participants in the filgotinib and placebo groups, respectively. There were serious adverse events in 13.5% and 5.7% of participants in the filgotinib and placebo groups, respectively. The documented serious adverse events included bladder prolapse, epilepsy, coronavirus disease 2019 (COVID-19), spinal stenosis, suicidal ideation, uveitis and inflammatory bowel disease (IBD). The only event considered by the trial investigator to be related to filgotinib was the flare of IBD. The incidence of infection was 32.4% (12 of 37 participants) in the filgotinib group and 25.7% (9 of 35 participants) in the placebo group, with the most common infections noted being urinary tract infections. Serious infections occurred once in each group. No arterial or venous thromboembolic events, major adverse cardiovascular events, gastrointestinal perforations, nonmelanoma skin cancers, opportunistic infections, cases of tuberculosis, or cases of herpes zoster were reported in either treatment group (23). However, the need for future studies with a larger, more diverse study population are needed to confirm these findings.

Commentary

The HUMBOLDT trial (23) showed that filgotinib presents itself as an alternative option in the treatment of patients with uveitis. Filgotinib is available orally, which has advantages over other biological agents (e.g., adalimumab) as it avoids local injection site reactions and is more acceptable to patients.

However, the results of the study should be interpreted with caution, as the statistical significance might not be fully reliable due to the small sample size and the exploratory nature of the analysis. Further research with a larger sample size and adjusted statistical methods would be necessary to confirm the findings. Further research is also needed to determine if it has efficacy comparable to the other treatments currently available to use in the treatment of patients with uveitis. Further data comparing its effectiveness and safety to conventional DMARDs or anti-TNF agents would be beneficial before its widespread clinical use.

Future studies could consider including the impact on fertility as an adverse event of interest (as the target population are young patients who may also need long-term therapy to control their disease). So far, there have been results from animal studies suggesting an impact on male fertility, but no clinical data from clinical trials (phase 2 MANTA and MANTA-RAy, n=240) to suggest that there is a clear impact in humans (22).

Filgotinib is approved for use with rheumatoid arthritis patients, and there is potential to expand its use to other inflammatory ocular diseases, such as scleritis, if future studies with a larger sample size and adjusted statistical methods could confirm the findings.

Conclusions

Current treatments for uveitis have their limitations, such as the poor side effect profile of long-term corticosteroids and conventional DMARDs, and that anti-TNF agents may be ineffective in a select group of patients. Furthermore, the currently utilised first-line biologic agents, adalimumab and infliximab, are available as subcutaneous or intravenous infusion, respectively. Therefore, an oral agent, such as filgotinib, may provide a more tolerable therapy for patients with uveitis. Further research is needed to confirm the safety and efficacy of this medication as well as the potential to expand its use to the treatment of other non-infective inflammatory ocular diseases such as scleritis.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Eye Science. The article has undergone external peer review.

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Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aes.amegroups.com/article/view/10.21037/aes-24-37/coif). The authors have no conflicts of interest to declare.

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