Article

UVEITIS CORNER: Recent and Current Clinical Trials in Uveitis

New targets and mechanisms are being evaluated.

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As the understanding of the pathogenesis of ocular inflammatory disease advances, novel potential targets and mechanisms of action for treatment emerge. Over the last 2 years, several investigational trials have completed for local therapeutics in the treatment of posterior-segment noninfectious uveitis, including studies of the fluocinolone acetonide 0.19 mg sustained-release implant (Alimera Sciences),1,2 the fluocinolone acetonide 0.18 mg sustained-release implant (EyePoint Pharmaceuticals),2 and the suprachoroidal triamcinolone acetonide 4 mg (Clearside Biomedical, Inc.).2-4

A comparative study found intravitreal dexamethasone to be noninferior to intravitreal triamcinolone, and both of these were superior to periocular triamcinolone acetonide without significant intraocular pressure rise, in the treatment of uveitic macular edema.5 A prospective multicenter, randomized, double-masked, positive-controlled phase 3 trial found that iontophoretic dexamethasone phosphate ophthalmic solution did not demonstrate noninferiority to prednisolone acetate ophthalmic suspension (1%) in patients with noninfectious anterior-segment uveitis after 14 days of treatment.6 Another randomized study compared the safety and efficacy of a 5-minute topical dexamethasone sodium phosphate (DSP)-Visulex (8% or 15%) treatment regimen given twice in the first week and then weekly thereafter to daily prednisolone acetate for noninfectious anterior uveitis. This study found that anterior-chamber cell resolution was similar across all 3 groups, and intraocular pressure (IOP) elevation in the DSP-Visulex groups was observed at day 3 and not thereafter, whereas it was sustained in the prednisolone group.7

Additionally, systemic investigational trials have completed that studied intravenous tocilizumab 4 mg/kg and 8 mg/kg (Genentech)2,8,9 as well as subcutaneous sarilumab (Sanofi and Regeneron Pharmaceuticals, Inc.)2,10 for noninfectious posterior uveitis and refractory macular edema.

This review will focus on phase 2-4 noninfectious uveitis clinical trials registered as active, using the following search terms: “uveitis,” “anterior uveitis,” “cystoid macular edema,” “iritis,” “posterior uveitis,” and “retina” on clinicaltrials.gov .

PHASE 4 UVEITIS STUDIES

“Fluocinolone Acetonide Implant for Treating Refractory Ocular Behcet’s Disease” (NCT00720928) is a Korean multicenter, prospective, single-arm study to assess the efficacy and safety of intravitreal fluocinolone acetonide 0.59 mg (Retisert; Bausch + Lomb) in 15 patients with refractory or chronic ocular Behcet disease (affecting the eye for ≥1 year requiring systemic corticosteroid or other equivalent systemic therapy for ≥3 months or ≥2 sub-Tenon steroid injections in the 6 months prior to enrollment, or ≥2 separate recurrences within the prior 6 months requiring systemic corticosteroid therapy or sub-Tenon injections of corticosteroids) with ≤10 anterior-chamber cells/high-power field and vitreous haze of ≤2, visual acuity (VA) ≥1.4 logMAR units. Endpoints will include recurrence at 36 weeks defined as a 2-step increase in anterior-chamber cells or a 2-step increase in vitreous haze, as well as deterioration in VA.

“Study of the Effectiveness of Ozurdex in Lieu of Oral Corticosteroids for the Control of Active Intermediate and Posterior Uveitis Requiring Immunosuppressive Drug Therapy” (NCT02049476) is an interventional, open-label study of 20 patients at Johns Hopkins University with intermediate and/or posterior uveitis in whom immunosuppressive therapy is indicated, to determine if the dexamethasone implant (Ozurdex; Allergan) as a replacement for oral corticosteroids results in ocular inflammation control at 6 months and control of intraocular inflammation at 12 months. Additionally, IOP as well as progression of cataract or need for cataract surgery will be assessed at 3, 6, and 12 months.

“Macular Edema Nepafenac vs Difluprednate Uveitis Trial (MEND)” (NCT01939691) is an interventional, masked trial of 108 patients at Aravind Eye Hospital, randomized to receive difluprednate 0.05%, combination prednisolone acetate 1% with nepafenac, or combination difluprednate 0.05% with nepafenac 0.1% for the treatment of uveitic macular edema. Patients may be treated with stable doses of systemic immunomodulatory agents and have any type of infectious or noninfectious uveitis. Endpoints assessed at 4 weeks include central subfield thickness (CST) by spectral-domain OCT, IOP change, and VA.

“Efficacy and Safety of H.P. Acthar Gel in Subjects With Severe Noninfectious Intermediate Uveitis Posterior Uveitis or Panuveitis” (NCT03656692) is a multicenter, interventional, unmasked, single-group assignment study, sponsored by Mallinckrodt Pharmaceuticals, of 30 patients with active severe noninfectious intermediate uveitis, posterior uveitis, or panuveitis treated with 80 units of Acthar subcutaneously twice weekly for 36 weeks and then tapered to 80 units subcutaneously once weekly for 2 weeks followed by 40 units subcutaneously once weekly for 2 weeks. Patients may be treated with stable doses of immunomodulatory agents or prednisone for 2 weeks prior to baseline examination but then are tapered to a minimum effective dose. Endpoints include improvement of vitreous haze, aqueous flare, and aqueous cells measured at week 36; systemic and ocular adverse events; and IOP change.

PHASE 3 UVEITIS STUDIES

“A Phase 3 Study to Evaluate ADX-102 Ophthalmic Solution in Subjects With Noninfectious Anterior Uveitis (SOLACE)” (NCT03131154)11 is an Aldeyra Therapeutics-sponsored interventional, randomized, quadruple-masked study of 100 participants with solely anterior uveitis that began within 2 weeks prior to baseline visit, to assess the efficacy of ADX (a novel aldehyde trap) ophthalmic solution administered for 4 weeks. Endpoints include reduction in anterior-chamber cell count and flare.

“Interferon α2a Versus Cyclosporine for Refractory Behcet’s Disease Uveitis” (NCT03209219) is a Chinese interventional, randomized study of 36 participants with refractory (requiring ≥10mg/day oral prednisone with at least 1 IMT agent) Behcet disease posterior or panuveitis. Patients are randomized to receive interferon alpha-2a subcutaneously or intramuscularly daily for 4 weeks followed by every other day thereafter or cyclosporine 100 mg twice daily. Endpoints include relapse rate and severity of inflammation based on the Behcet disease ocular attack score,12 at 12 months.

“Macular Edema Ranibizumab vs Intravitreal Anti-Inflammatory Therapy Trial (MERIT)” (NCT02623426) is an interventional, randomized, single-masked study sponsored by the National Eye Institute and Johns Hopkins University studying 240 participants with inactive or minimally active noninfectious uveitis with macular edema and normal IOP and clear media. Patients are randomized to dexamethasone intravitreal implant 0.7 mg, intravitreal methotrexate 400 micrograms, or intravitreal ranibizumab 0.5 mg (Lucentis; Genentech). Endpoints include percentage change in CST from baseline OCT at 12 weeks and 24 weeks, IOP at 24-week follow-up, VA, and injection-related safety parameters.

PHASE 2 UVEITIS STUDIES

“Randomized Trial Comparing Efficacy of Adalimumab, Anakinra, and Tocilizumab in Noninfectious Refractory Uveitis (RUBI)” (NCT02929251) is a French prospective, randomized study comparing adalimumab (Humira; AbbVie) 40 mg every 14 days for 16 weeks to either anakinra (Kineret; Sobi) 100 mg per day subcutaneously for 16 weeks, or tocilizumab (Actemra; Genentech) 162 mg per week for 16 weeks in 120 participants with currently uncontrolled noninfectious intermediate, posterior, or panuveitis. Patients must be receiving ≥10 mg per day of prednisone and at least 1 other systemic immunomodulatory drug, be receiving interferon alpha, or be intolerant to immunosuppressive agents. Endpoints include change in ocular inflammation, VA, central macular thickness on OCT, retinal vessel leakage by fluorescein angiography, ability to taper prednisone, time to response or relapse, remission of systemic disease, and adverse event monitoring.

“Intravitreal Adalimumab Versus Subcutaneous Adalimumab in Noninfectious Uveitis (IVAS)” (NCT02706704) is a Lebanese interventional, randomized, single-masked study of 32 participants with active noninfectious intermediate, posterior, or panuveitis treated with adalimumab 40 mg subcutaneously every other week vs intravitreal adalimumab 1.5 mg/0.03 mL given at baseline, week 2, and then every 4 weeks for 26 weeks. Endpoints include change in ocular inflammation, VA, macular edema, angiography score, and ability to taper steroids at 26 weeks.

“LUMINA Phase III Study Assessing the Efficacy and Safety of Intravitreal Injections of 440 µg DE-109 Sirolimus for the Treatment of Active, Noninfectious Uveitis of the Posterior Segment of the Eye” (NCT03711929) is a Santen-sponsored, phase 3, multicenter, sham-controlled, randomized, double-masked study assessing the efficacy and safety of intravitreal injections of 44, 440, or 880 micrograms of sirolimus every 2 months in 200 participants with noninfectious uveitis of the posterior segment. Endpoints include vitreous haze and best-corrected VA.

“Efficacy and Safety of Filgotinib in Adults With Active Noninfectious Uveitis (Humboldt)” (NCT03207815)2 is an interventional placebo-controlled, double-masked study of 110 participants with active noninfectious intermediate, posterior, or panuveitis treated either with filgotinib (Gilead Sciences) 200 mg orally once daily or placebo. All patients also receive 60 mg per day of prednisone at baseline followed by a protocol-defined taper schedule to week 15. Endpoints include proportion of participants failing treatment by week 24, time to treatment failure, change in ocular inflammation, change in VA, time to development of macular edema, and pharmacokinetic plasma concentrations of filgotinib and its metabolite.

“ACTH as a Re-emerging Therapy for Uveitis (The ACTHAR Study)” (NCT02931175) is an open-label, multicenter, randomized study of 36 participants to evaluate subcutaneous ACTH (Mallinckrodt Pharmaceuticals) 80 units per day twice weekly vs 3 times per week in patients with active non-infectious intermediate, posterior, or panuveitis over 6 months, with “active” defined as active disease not on therapy, active disease while on ≥10mg per day of prednisone and another systemic immunosuppressant, or inactive disease and receiving ≥10 mg per day of prednisone and/or at least 1 other systemic immunosuppressant. Outcome measures include ocular and systemic adverse effects, change in ocular inflammation, best-corrected VA, inflammation degree, disc leakage, macular thickness, ability to taper prednisone, and angiographic leakage.

“Tocilizumab for the Treatment of Refractory Behcet’s Uveitis” (NCT03554161) is a single-center, open-label study of 9 patients with treatment-refractory Behcet disease uveitis (difficulty tapering corticosteroids while being treated with at least 1 other systemic immunosuppressant) treated with tocilizumab in addition to their current treatment. Endpoints assessed at each visit up to 6 months include remission of uveitis based on intraocular inflammation, ability to taper corticosteroids, frequency or severity of uveitis recurrence, quality of life, and adverse effects.

“Ustekinumab (STELARA) for the Treatment of Active Sight-Threatening Uveitis (STAR Study)” (NCT02911116)2 is a prospective, nonrandomized, uncontrolled, 2-arm open-label study to evaluate ustekinumab (Janssen) in the treatment of 11 participants with active intermediate, posterior, or panuveitis treated with either 90 mg subcutaneous ustekinumab at baseline, week 4, and week 8 vs high, weight-dependent intravenous injection of ustekinumab at baseline followed by a single 90 mg subcutaneous injection at week 8. Endpoints include treatment response by week 16, change in VA, presence or extent of macular edema on OCT and FA, time to recurrence, time to quiescence, ability to taper concomitant immunosuppressants, ocular and systemic adverse events or toxicities, and IOP rise.

PHASE 1/2 UVEITIS STUDIES

“Evaluation of EYS606 in Patients With Noninfectious Posterior, Intermediate or Panuveitis” (NCT03308045)2 is an interventional, open-label, single-arm trial of 24 participants with noninfectious intermediate, posterior, or panuveitis to study the safety and tolerability of EYS606 (Eyevensys), a DNA plasmid solution administered by electrotransfection into the ciliary muscle. The maximum study duration per patient is 27 weeks and the study will be conducted in 2 parts: a dose escalation phase of lower, intermediate, and higher dose over 3 cohorts and a phase that will confirm safety of maximum tolerated dose from part 1 and assessment of efficacy. Endpoints will include assessment of adverse events, concomitant medications, IOP, electroretinogram, electrocardiogram, vital signs, physical exam, routine blood labs, urinalysis, VA, anterior-chamber cells, vitreous haze, central retinal thickness, and corticosteroid dose.

“A Safety Study of Intravitreal PP-001 in Patients With Chronic Noninfectious Uveitis” (NCT03634475) is a study to assesses the safety and efficacy of PP-001 (a novel, small-molecule inhibitor of the enzyme dihydroorotate dehydrogenase) after intravitreal injection in patients diagnosed with noninfectious chronic uveitis. Endpoints include adverse events over ascending doses, change in inflammation measured by slit lamp and by OCT, and systemic pharmacokinetics.

Infectious uveitis trials at this time are primarily viral, examining the effect of topical 2% ganciclovir for CMV anterior uveitis and endotheliitis (NCT02943057) as well as the Zoster eye disease study (ZEDS, NCT03134196), which is a multicenter, randomized, double-masked, placebo-controlled trial of suppressive (1g per day) valacyclovir (Valtrex; GlaxoSmithKline) for 1 year in 1,050 immunocompetent participants with an episode of dendriform epithelial keratitis, stromal keratitis, endothelial keratitis, and/or iritis due to herpes.

While we await the results of these ongoing trials, long-term data from completed studies mentioned previously are also becoming available. These will continue to improve our pathophysiologic understanding of complicated uveitic entities. RP

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