PEER REVIEWED

Emerging Therapies for Noninfectious Uveitis

Solutions are on the way for ocular inflammation.

EMMETT T. CUNNINGHAM, JR., MD, PhD, MPH

Noninfectious uveitis (NIU) refers to a heterogeneous group of ocular inflammatory conditions.^1,2 Any portion of the uveal tract may be affected in NIU, but the inflammation is typically most difficult to control and associated with the highest risk of vision loss in eyes with intermediate, posterior, or panuveitis.

Whereas topical corticosteroids are often the treatment of choice for anterior NIU, topical therapies tend to be much less effective when used to treat inflammation involving the posterior segment. In such patients, treatment often involves the use of periocular, intraocular, or systemic corticosteroids acutely, followed by noncorticosteroid immunosuppressive agents when the inflammation is chronic or recurrent.^3-6

Noncorticosteroid agents include antimetabolites, such as methotrexate, azathioprine, and mycophenolate mofetil (CellCept, Genentech, South San Francisco, CA); leukocyte signaling inhibitors, such as cyclosporine and tacrolimus; and, for refractory cases, either alkylating agents, such as cyclophosphamide (Cytoxan, Baxter Healthcare, Deerfield, IL) and chlorambucil (Leukeran, GlaxoSmithKline, Philadelphia, PA), or injectable biologic agents, including the tumor necrosis factor-α inhibitors infliximab (Remicade, Janssen, Horsham, PA), adalimumab (Humira, AbbVie, North Chicago, IL), and golimumab (Simponi, Janssen). Of these options, only corticosteroids are approved by the FDA or European Medicines Agency for the treatment of NIU.^4-6

The agents summarized in this review were identified as of June 18, 2015, by searching the clinical trials registry run by the US National Library of Medicine and National Institutes of Health (www.clinicaltrials.gov). The search term to identify relevant studies was “uveitis.”

Phase 2 or 3 trials of drugs primarily targeting intermediate, posterior, or panuveitis were selected, while those targeting solely anterior-segment inflammation were not included in the review (Table 1). Industry-sponsored uveitis development programs for the oral calcineurin inhibitor voclosporin (Aurinia, Victoria, Canada)⁷ and the subcutaneously injected interleukin (IL)-17 inhibitor secukinumab (Cosentyx, Novartis, East Hanover, NJ)⁸ for NIU appear to have been discontinued following failed phase 3 trials. Therefore, these agents are not included in this review. The present review updates an earlier summary of investigational therapies for NIU of the posterior segment.⁹

PHASE 3 DEVELOPMENT PROGRAMS

Adalimumab

Adalimumab is a recombinant, fully human, full-length monoclonal antibody that targets the inflammatory cytokine tumor necrosis factor-α (Table 2).¹⁰ The drug is administered via subcutaneous injection at a maintenance dose of 40 mg every other week. Loading and escalation doses are variable and are based on indication and response.

Indications currently approved by the FDA include rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, adult Crohn’s disease and ulcerative colitis, pediatric Crohn’s disease, and plaque psoriasis.

AbbVie recently completed two phase 3 multicenter trials (VISUAL-1 and VISUAL-2) of adalimumab for the treatment of noninfectious intermediate, posterior, or panuveitis. The VISUAL-1 study (NCT01138657) assessed the efficacy and safety of adalimumab in 217 patients with active NIU of the posterior segment, despite at least 2 weeks of high-dose corticosteroid therapy.^11,12 The study patients had one or more of the following: active, inflammatory chorioretinal or retinal vascular lesions; anterior-chamber cell grade ≥2+; and/or vitreous haze grade ≥2+.

In a 1:1 randomization, the patients received either placebo or adalimumab at an 80-mg baseline loading dose, followed by 40 mg every other week for up to 80 weeks; all of the patients received prednisone 60 mg/day, which was tapered to 0 mg by week 15.

The primary efficacy endpoint was time to treatment failure in one or both eyes, defined as one or more of the following: new, active, inflammatory vascular lesions; worsening of best-corrected visual acuity by ≥15 letters at or after week 6; inability to achieve ≤0.5+ anterior-chamber cell grade or ≤0.5+ vitreous haze grade at week 6; or a two-step increase in anterior-chamber cell grade or vitreous haze grade after week 6.

The primary endpoint, time to treatment failure, was a median of 24 weeks for adalimumab vs 13 weeks for placebo.¹² There was a 50% decreased risk of treatment failure with adalimumab compared with placebo (hazard ratio 0.5; 95% confidence interval 0.36-0.70; P<.001).

Adalimumab was also associated with significantly less worsening of anterior-chamber cell grade (P=.011), vitreous haze grade (P<.001), and BCVA (P=.003; each comparing the best state achieved before week 6 with the final visit). Adverse event rates were similar for adalimumab and placebo (1,046 and 952 events/100 patient-years, respectively).

The results of the VISUAL-2 study (NCT01124838), which was conducted in patients with inactive posterior-segment NIU, are expected this month.¹³ VISUAL-3, an open-label extension study of patients previously enrolled in VISUAL-1 or VISUAL-2, is under way to evaluate long-term efficacy and safety in posterior-segment NIU (NCT01148225).¹⁴

Color fundus and fluorescein angiographic photomontages of a patient with birdshot chorioretinopathy showing characteristic yellow-white chorioretinal lesions and diffuse retinovascular leakage, including cystoid macular edema
COURTESY EMMETT T. CUNNINGHAM, JR., MD, PhD, MPH

Gevokizumab

Gevokizumab (XOMA 052, XOMA Corporation, Berkeley, CA) is a recombinant humanized antibody targeting the proinflammatory cytokine IL-1β. It is being studied in multiple inflammatory conditions, including uveitis, in which IL-1β appears to play a key pathophysiologic role.¹⁵ Unlike traditional inhibitors, gevokizumab binds to the allosteric site on the IL-1 ligand, downregulating IL-1β signaling while still allowing the ligand to bind to its receptor.

Two phase 2 proof-of-concept studies examined the tolerability and efficacy of gevokizumab in patients with Behçet’s uveitis. The first trial studied seven patients with acute posterior or panuveitis associated with Behçet’s disease.¹⁶ In all of the patients, uveitis was resistant to azathioprine or cyclosporine.

An intravenous infusion of gevokizumab 0.3 mg/kg led to complete resolution of ocular inflammation in all patients at a median of 14 days, with a median duration of response of 49 days. Five patients received a second intravenous infusion, after which they were attack-free for a median of 115 days. There were no treatment-related adverse events.

A second study enrolled 21 patients with history of Behçet’s uveitis with posterior-segment involvement who were experiencing acute ocular exacerbation or were considered at risk for subsequent exacerbation.¹⁷

Patients were randomly assigned to one of three open-label treatment groups receiving different combinations of gevokizumab 30 or 60 mg, intravenously or subcutaneously, every month beyond stable standardized immunosuppressive therapy and ≤20 mg/day of prednisone equivalent.

Seventeen patients were experiencing acute exacerbations at study entry; 15 were evaluable (two withdrew early), all of whom responded to gevokizumab. The first signs of improvement were observed as early as day 1. Most adverse events were related to Behçet’s uveitis, and no serious adverse events related to gevokizumab were reported.

XOMA announced on July 22, 2015, that its phase 3 study in patients with Behçet’s disease (NCT01965145) failed to meet its primary endpoint of time to first acute ocular exacerbation, although signals of drug activity, such as preserved VA, less severe ocular exacerbations, and a reduced incidence of reported macular edema were observed.¹⁸ Two additional phase 3 studies, one study each in patients with active (NCT01684345) and inactive (NCT017477538) NIU of the posterior segment, are ongoing.^19,20

Sirolimus

Santen Inc. (Emeryville, CA) is developing a novel intravitreal formulation of sirolimus (DE-109), which is believed to exert a T-cell immunoregulatory effect by inhibiting mammalian target of rapamycin (mTOR). Intravitreal sirolimus forms a slowly dissolving depot in the vitreous humor. The local route of administration allows for delivery of therapeutic doses to target intraocular tissues, and it minimizes systemic exposure, thus avoiding the adverse effects of systemic administration.

Preclinical studies demonstrated that near steady-state concentrations of sirolimus were maintained in the vitreous for ~2 months after injection.²¹ Intravitreal sirolimus doses of 440 and 880 μg injected every two months are being evaluated in phase 3 trials. Intravitreal sirolimus is an investigational therapy and has not received regulatory approval, although an application for approval has been filed with the European Medicines Agency.

In a phase 1/2 study of 30 patients with NIU given subconjunctival or intravitreal injections of sirolimus on days 0, 60, and 120, VA improved after six months in 39% of patients and stabilized in another 39%, and vitreous haze improved in 82%.²²

All 20 patients receiving corticosteroids at baseline were able to have the dosage reduced at six months. No serious adverse events were considered attributable to sirolimus. An open-label extension of this study to one year from baseline reported continued benefit from treatment over 12 months.²³

Two multinational phase 3 trials (SAKURA 1 and 2) are evaluating intravitreal sirolimus in patients with active NIU of the posterior segment in the United States, India, Latin America, the European Union, and Japan.²⁴

An estimated 600 patients will be randomized to intravitreal sirolimus at a dose of 44 μg (active control), 440 μg, or 880 μg every two months. The studies both have monotherapy designs: patients are being discontinued from all systemic immunosuppressive agents and topical corticosteroids prior to baseline. Oral corticosteroids are allowed only for those already receiving them at baseline but are being rapidly tapered per protocol.^24-26

The primary endpoint is the proportion of patients with a vitreous haze score of 0 at month 5 without the use of rescue therapy; secondary endpoints include the proportion of patients with a vitreous haze score of 0 or 0.5+, the percentage of patients successfully tapered to prednisone ≤5 mg/d (ie, corticosteroid-tapering success), and the mean change from baseline in BCVA.

Analysis of SAKURA 1 showed that intravitreal sirolimus 440 μg met its primary endpoint, with VA maintained over five months.²⁶ The majority of patients were successfully tapered off corticosteroids.

Fluocinolone Acetonide Intravitreal Implant

pSivida Corp (Watertown, MA) is developing a novel 0.18-mg fluocinolone intravitreal implant for the treatment of NIU of the posterior segment.²⁷ The implant represents a refinement of the company’s Retisert fluocinolone intravitreal insert (licensed to Bausch + Lomb, Rochester, NY).

The new implant is designed to release fluocinolone for 36 months, compared to 30 months with Retisert, and to be injected as an in-office procedure. A version of the new product has been approved for the treatment of diabetic macular edema, and it is marketed as Iluvien by pSivida’s licensing partner Alimera Sciences, Inc. (Alpharetta, GA).²⁷

pSivida, which plans to develop and market the new technology independently for a potential uveitis indication, is currently evaluating the implant vs a sham injection in two phase 3, randomized, masked multicenter studies in patients with NIU involving the posterior segment (NCT01694186).^28-30 The primary endpoint of the phase 3 studies is the recurrence rate of uveitis at one year, and data from the first study are anticipated by mid-2016.

The results of a small, randomized, investigator-sponsored study of the implant in posterior NIU were recently reported at the ASRS meeting in Vienna, Austria, by Glenn Jaffe, MD.³¹ In this study, the eyes of patients with NIU were randomized to receive the implant or sham.

At one year, there were no recurrences in eyes receiving the implant vs an average of 2.6 recurrences in sham-treated eyes (P=.01), and VA in implanted eyes improved by 17 letters from baseline. At the last follow-up between one and two years, there were no recurrences in implanted eyes, and VA increased by an average of >20 letters. In sham-treated eyes, in contrast, VA decreased by 10 letters.

PHASE 2 DEVELOPMENT PROGRAMS

Abatacept

Abatacept (Orencia, Bristol-Myers Squibb, New York, NY) is a fusion protein composed of the extracellular domain of human cytotoxic T-lymphocyte antigen 4, linked to the modified Fc domain of human immunoglobulin-G1.³² Abatacept, which blocks the binding of CD80 and CD86 with CD28 and thereby inhibits the costimulatory activation of T lymphocytes, may be given either intravenously or, in adults only, subcutaneously.

Intravenous dosing (500 to 1,000 mg based on body weight) is delivered in a maintenance regimen of once every four weeks, and subcutaneous dosing (125 mg) is available in a once-weekly maintenance regimen with or without an intravenous loading dose. Approved indications include rheumatoid arthritis in adults and juvenile idiopathic arthritis.

A 12-month retrospective study examined the potential for abatacept to induce disease inactivity in children with active anterior uveitis — despite the use of topical or systemic immunosuppressive agents — associated with juvenile idiopathic arthritis.^33,34 Active anterior uveitis was defined as anterior-chamber cell grade ≥1+.

Of the 21 patients (mean age 11.8 ± 3.6 years old) included in the study, 11 achieved inactive uveitis (anterior-chamber cell grade <0.5+) following treatment. Of these 11 patients, uveitis recurred in eight (72.7%). Only three patients taking systemic corticosteroids and noncorticosteroid systemic immunosuppressive agents were able to be tapered from these treatments.

Among these three patients, the level of tapering was described as “good” (ie, decrease ≥50% in both corticosteroid and immunosuppressive use) in one patient and “moderate” (ie, decrease ≥50% in either corticosteroid or immunosuppressive use, but not both) in two patients; uveitis recurred in all three during further follow-up.

An ongoing open-label, two-year, phase 2 study is evaluating the tolerability and efficacy of abatacept 5 or 10 mg/kg every four weeks in adults with noninfectious autoimmune uveitis refractory to previous therapies (NCT01279954).³⁵ The anticipated enrollment is 20 patients. The outcomes include changes in BCVA and vitreous haze, as well as reduction in corticosteroids or noncorticosteroid immunosuppressive agents.

CF101

CF101 (Can-Fite BioPharma, Waltham, MA) is a small-molecule, orally administered, A3 adenosine receptor agonist that modulates key signaling proteins, such as PI3K, PKA, PKB/Akt, IKK, and NF-κB, resulting in inhibition of inflammatory cytokine production.³⁶

In a phase 2 study of patients with moderate-to-severe plaque psoriasis, CF101 1, 2, or 4 mg twice daily was associated with significant improvements in the Psoriasis Area and Severity Index (PASI) score vs placebo.³⁷

A phase 2, 24-week study of CF101 1 mg twice daily in patients with active noninfectious intermediate or posterior uveitis has been planned, with an anticipated population of 45 patients (NCT01905124).³⁸ Enrollment is expected to start by the beginning of 2016. The primary endpoint will be uveitis severity as assessed by fundus photographs.³⁹

LFG316

LFG316 (Novartis) is an investigational monoclonal antibody that inhibits the C5 component of the complement cascade.⁴⁰ A phase 2 study of intravitreal LFG316 has been completed in patients with neovascular age-related macular degeneration, but the results have yet to be published (NCT01535950).⁴¹ A second phase 2 study in geographic atrophy associated with neovascular AMD is ongoing (NCT01527500).⁴²

A phase 2, randomized, 12-week, open-label study to assess the tolerability and efficacy of intravitreal LFG316 for the treatment of active noninfectious intermediate, posterior, or panuveitis is currently recruiting an estimated 24 patients (NCT01526889).⁴³ Vitreous haze will be used as the primary endpoint, with VA and safety as prespecified secondary outcome measurements.

Peptide B27PD

Peptide B27PD (Optiquel, Enzo Biochem, New York, NY) is an orally delivered human leukocyte antigen class I antigen that mimics ocular S-antigen.⁴⁴ Exposure to peptide B27PD is hypothesized to induce immune tolerance to ocular S-antigen in the eye.

In a small pilot trial, eight patients with chronic NIU were treated with peptide B27PD 4 mg three times daily for 12 weeks and followed for five years. The average corticosteroid dosage decreased from 10.4 mg/day prior to oral tolerance induction to 2.9 mg/day at year 2 and 1.9 mg/day at year 5, and average VA remained stable during follow-up. Although relapses occurred in some patients, those who were retreated with oral peptide B27PD for uveitis recurrence responded to treatment, exhibiting decreased inflammation.

A 52-week, phase 1/2 study assessed the efficacy of peptide B27PD as corticosteroid-sparing therapy in 31 patients with chronic NIU (NCT01195948).⁴⁵ Peptide B27PD was administered at oral doses of 1 and 4 mg three times daily, while a third group received placebo. The primary endpoint was the time to recurrence of uveitis during or after tapering the corticosteroid dose to 7.5 mg/day.

The median time to recurrence was 52 months (inter-quartile ranges 52.00-52.00 for 1 mg and 28.29-52.00 for 4 mg) in each of the active treatment groups and 45 months (10.00-52.00) in the placebo group.

Sarilumab

Sarilumab (Sanofi, Bridgewater, NJ) is an investigational, humanized monoclonal antibody that acts as an IL-6 receptor antagonist.⁴⁶ Investigational indications for this subcutaneously injected drug include rheumatoid arthritis (phase 3) and posterior segment NIU (phase 2).⁴⁷

A phase 2 study (NCT01900431) is under way in NIU with an enrollment of 57 patients. The study is assessing changes in BCVA, signs of ocular inflammation, macular edema, and safety. Approximately half of the patients have panuveitis, with intermediate or posterior uveitis comprising the remainder. As of the last study update, 33 patients have been randomized and treated.⁴⁸

Sotrastaurin

Sotrastaurin (AEB071, Novartis) is a small-molecule inhibitor of both protein kinase C-mediated early T-lymphocyte activation and β2-integrin-mediated T-lymphocyte-endothelial cell adhesion.⁴⁹ Orally administered sotrastaurin was studied in a two-week, dose-escalation (50 to 600 mg/day), proof-of-concept study of 32 patients with moderate-to-severe plaque psoriasis. Compared with baseline, the percentage reduction/improvement in PASI score at day 14 of treatment was 68.9% (95% CI 52.3%-85.4%) with sotrastaurin 300 mg twice daily vs 5.3% (-8.8%-19.5%) with placebo.

A phase 2, multicenter, open-label study of 13 patients with macular edema associated with posterior-segment NIU (NCT00615693) has been completed, but the results have yet to be published or presented.⁵⁰ In this study, oral sotrastaurin was administered at a dosage of 1,300 mg twice daily for two weeks, followed by 1,200 mg twice daily for six weeks. The efficacy outcomes included changes in inflammation, BCVA, and macular edema.

Tocilizumab

Tocilizumab (Actemra, Genentech) is a recombinant, humanized, immunoglobulin-G1κ monoclonal antibody that acts to block the IL-6 receptor.⁵¹ Per the US labeling, tocilizumab can be administered intravenously (4 mg/kg every four weeks followed by an increase to 8 mg/kg every four weeks based on clinical response) or subcutaneously (162 mg every week or every other week based on clinical response and weight). It is currently indicated for adult rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, and systemic juvenile idiopathic arthritis.

The long-term safety and efficacy of tocilizumab were examined in a retrospective study of 12 patients (17 eyes) with refractory, noninfectious uveitic macular edema.⁵² The primary outcome measurement was the mean change in central retinal thickness through month 24. From a baseline of 530 µm, the mean central retinal thickness was reduced significantly at month 24 to 274 µm (P<.001). Peak efficacy was observed at months 6 to 9 and plateaued thereafter.

A phase 1/2 trial — the STOP-UVEITIS study (NCT01717170) — is being conducted in 36 adult patients with noninfectious posterior, intermediate, or panuveitis.⁵³ Interim data are anticipated in 2015.

In addition, a small phase 1/2 trial of tocilizumab (NCT01603355) is under way in five patients with inflammation associated with juvenile idiopathic arthritis.^54-56 Three patients have enrolled to date; one has met the primary endpoint of control of inflammation with corticosteroid tapering by week 16.

CONCLUSION

A number of promising therapies are in late-stage clinical trials for NIU of the posterior segment. Both the breadth of targets and the advanced stage of the clinical trials hold promise for the near-term emergence of novel therapies for uveitis.⁵⁷ RP

REFERENCES