Local and systemic corticosteroids constitute first-line therapy for virtually all patients with noninfectious uveitis.1 Prolonged corticosteroid use can produce toxic effects, however, and so corticosteroid-sparing immunomodulatory therapies (IMTs) have assumed an increasingly important role in the management of chronic ocular inflammation.2,3 The more commonly used noncorticosteroid immunosuppressive agents include antimetabolites, such as mycophenoloate mofetil, methotrexate, and azathioprine; leukocyte signaling inhibitors, such as cyclosporine and tacrolimus; tumor necrosis factor (TNF)-α inhibitors, such as infliximab (Remicade, Janssen), adalimumab (Humira, Abbott Laboratories), and golimumab (Simponi, Janssen); and the alkylating agents cyclophosphamide and chlorambucil, which are reserved for the most severe vision- or life-threatening conditions.2,4 These and other currently available agents are summarized in Table 1.
Each of the currently available treatments for chronic noninfectious uveitis has its own issues, however.3,4 All have drug-associated toxicities and, even in quite experienced hands, limited efficacy in 30-40% of patients. Fortunately, no fewer than 12 therapies are now in clinical development for chronic noninfectious uveitis (Table 2). These therapies represent both novel agents and established drugs utilizing innovative drug delivery systems. This review provides a summary of these emerging treatments for uveitis. All of these agents were identified through a search of http:// www.clinicaltrials.gov and Pubmed at http://www.ncbi.nlm. nih.gov/pubmed.
Therapies in Late-Stage Development (Phase 3)
DE-109 (Santen Pharmaceutical Co.): DE-109 is a novel intravitreal formulation of the immunosuppressant sirolimus, which blocks leukocyte activation and the production of inflammatory cytokines (including IL-2, IL-4, and IL-5) by inhibiting mammalian target of rapamycin (mTOR). DE-109 has been administered both subconjunctivally and intravitreally in clinical studies. 5,6 When given intravitreally, DE-109 forms a slowly dissolving depot in the vitreous humor. This limits the immunosuppressive effects of DE-109 to the eye, thereby minimizing systemic exposure.7
DE-109 has been studied in conditions including dry eye syndrome, age-related macular degeneration, and diabetic macular edema (DME). In a phase 1 trial involving 50 DME patients, no dose-limiting toxicities were seen with intravitreal doses as high as 352 μg and subconjunctival doses as high as 1760 μg.5 The most common adverse event was mild conjunctival hemorrhage, in 80% of patients. Early studies involving a limited number of patients with chronic noninfectious uveitis have suggested that sirolimus and DE-109 may improve signs and symptoms related to intraocular inflammation and reduce the burden associated with steroids and systemic immunosuppression.6,8 In a phase 2 study of 30 patients with noninfectious uveitis who were given subconjunctival or intravitreal injections of sirolimus on days 0, 60 and 120, visual acuity improved after 6 months in 39% of patients and stabilized in another 39%, while vitreous haze improved in 82%. Moreover, all 20 patients receiving corticosteroid therapy at the beginning of the study were able to have their doses decreased at 6 months. Of reported serious adverse events, none were judged to be the result of DE-109 administration.8
DE-109 is currently being evaluated in a randomized, double-masked, multinational phase 3 trial in patients with active noninfectious uveitis. Enrollment is under way. An estimated 500 patients will be randomized to DE-109 intravitreal doses of 44 μg, 440 μg, or 880 μg every 2 months. The primary end point is the percentage of patients with a vitreous haze score of 0 at month 5. Secondary end points include the percentage of patients on ≤5 mg/day of prednisone at this time point.9
Adalimumab (Abbott Laboratories): The TNFα inhibitors have significantly altered the treatment landscape for systemic autoimmune diseases over the past two decades, and have been increasingly used off-label in the management of refractory uveitis. Three of these agents—infliximab, adalimumab, and etanercept—have been used to treat a range of uveitic disorders, with particularly promising results seen in Behçet disease and juvenile idiopathic arthritis.10-13
Adalimumab a fully humanized, full-length monoclonal antibody given as a subcutaneous (SC) injection every 2 weeks, is currently being evaluated in 2 phase 3 clinical trials of noninfectious posterior-segment uveitis. Visual I in active uveitis and Visual II in inactive uveitis (both N=250)14,15 are 80-week studies comparing adalimumab, 40 mg SC every other week (after an initial 80 mg loading dose) to a matching placebo with all subjects receiving a standardized prednisone induction and taper schedule. The primary outcome is time to treatment failure, as defined by worsening in retinal lesions, anterior chamber cells (ACC), vitreous haze, or visual acuity. The percentage of patients successfully tapering down to a prednisone dosage of 5 mg/day is a secondary outcome. Both trials are currently recruiting. Patients from both trials will be enrolled in a single long-term (up to 282 weeks) open-label follow-up.
EGP-437 (Eyegate Pharmaceuticals, Inc.): EG)-437 is a dexamethasone phosphate 40 mL solution that is delivered to the eye via iontophoresis, a technique whereby a small electrical field is applied to the ocular surface to effect delivery of charged particles across the ocular surface. Dexamethasone phosphate, a prodrug of dexamethasone, was selected for iontophoresis because it possesses the necessary electrical charge and aqueous solubility at physiologic pH levels. EGP-437 has been evaluated in both phase 2 and phase 3 trials for the treatment of dry eye and although delivery of dexamethasone phosphate via the Eyegate II iontophoresis platform appears to be well tolerated16 detailed safety and efficacy results from the most recent phase 3 trial have yet to be published.17
The safety and efficacy of dexamethasone phosphate delivered via the Eyegate II iontophoresis platform was evaluated in a phase 1/2 trial in patients with noninfectious anterior uveitis. Subjects were randomized to 1 of 4 iontophoresis dose groups—1.6, 4.8, 10.0, and 14.0 mA-min.18 The primary endpoint was time to an ACC score of zero. Sixty percent of participants achieved zero anterior chamber cells by day 28.
The 1.6-mA-min dose was found to be most effective, with an ACC score of zero being achieved in this group at a median of 11.5 days, vs 31 days for the 14.0 mA-min group.18 Based on these findings, a phase 3 trial is currently under way comparing EGP-437 at a dose of 4.0 mA-min with topical 1% prednisolone acetate. This 8-week trial will enroll an estimated 200 patients.19 The primary outcome measure is the percentage of patients who achieve an ACC count of zero by day 14.
Gevokizumab (XOMA 052; XOMA Corporation): Gevokizumab is a recombinant humanized antibody targeting the proinflammatory cytokine interleukin (IL)-1β. Gevokizumab was initially studied for the treatment of type 2 diabetes, due to the role that IL-1β plays in β-cell failure. Although the phase 2 study in diabetes showed statistically significant and dose-dependent inhibition of C-reactive protein, a validated marker for inflammation, the clinical trial failed to show significant improvement in hemoglobin A1c levels at higher doses and so the program was halted.20
A phase 2 proof-of-concept study examined the safety and efficacy of gevokizumab in 7 patients with acute posterior or panuveitis associated with Behçet's disease (monocytes in Behçet's disease patients produce high levels of IL-1β).21 In all patients, the 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. IL-1β production was reduced by 97%. There were no treatment-related adverse events.21 A phase 3 program, expanded to include patients with other forms of noninfectious, nonanterior uveitis, has been initiated for gevokizumab.22
Voclosporin (LX211; Lux Biosciences): Voclosporin is an orally active calcineurin phosphatase inhibitor with potent immunosuppressive activity. Voclosporin has been evaluated in a series of phase 2/3 trials that included 558 patients with active or quiescent posterior uveitis or active anterior uveitis. In active posterior disease, voclosporin reduced vitreous haze by 50% and prolonged the time to recurrence by twofold; while in quiescent patients, it reduced the frequency of exacerbations by 50%.23 Importantly, the reduction of inflammation by voclosporin in active posterior uveitis was observed in important subpopulations of patients including those patients with the highest degree of inflammation; patients for whom systemic corticosteroids were determined to be medically inappropriate by the investigator; and in patients with best corrected visual acuity of less than 20/200 in the study eye. In all 3 studies, 96% to 98% of posterior uveitis patients were able to reduce their oral prednisolone dosage to ≤5 mg/d.23 In these trials, hypertension (15%), impaired renal function (8%), and hirsutism (5%) were observed. An additional phase 3 safety and efficacy trial is currently ongoing,24 the results of which are anticipated in the first quarter of 2013.
Therapies in Early-Stage Development (Phases 1 and 2)
ESBA105 (ESBA105, Alcon Research): ESBA105 is a topically administered TNFα inhibitor25 with highly favorable pharmacokinetic properties. In animal models, ESBA105 in a sodium citrate buffer was administered via eyedrops either in a high frequency (1 drop/hr for up to 10 hours) or multiday (5 drops/d) regimen. ESBA 105 penetrated all ocular compartments in a concentrationdependent manner, reaching therapeutic levels within several hours, with low systemic exposure. Total systemic exposure was approximately 25 000-fold lower when ESBA105 was administered topically as compared to systemic administration. Vitreous ESBA105 concentration was 4.6-fold higher following topical vs systemic administration. 25 A phase 2 pilot study of ESBA105, applied to the eye in hourly dosing intervals with subsequent dose tapering, has been completed in 9 patients with acute anterior uveitis (results were not available as of the publication of this article).26
LFG316 (Novartis Pharmaceuticals): LFG316 is a complement inhibitor that targets the complement system at C5. A phase 1 study of intravitreal LFG316 has been completed in patients with advanced age-related macular degeneration.27 (Results were not available as of the publication of this article.) A phase 2 study to assess intravitreal LFG316 for the treatment of multifocal choroiditis and panuveitis has been planned, but is not yet open for recruitment.28
Peptide B27PD (Optiquel; Enzo Biochemical): Peptide B27PD is an HLA class I antigen that mimics ocular S-antigen, thereby directing an immune response toward these antigens in the eye.29 In a small pilot trial in 9 chronic autoimmune uveitis patients who were treated with peptide B27PD, 4 mg tid for 12 weeks and followed for 5 years, treatment had an ameliorating effect (ie, patients required less immunosuppressive/ anti-inflammatory medication for relapses). A decrease in inflammation suggested that tolerance was reinduced. No treatment-related adverse effects were observed (4 patients were retreated over the course of the study.29 Peptide B27PD is being evaluated in a 52-week, phase 1/2 trial as a corticosteroid-sparing treatment in chronic noninfectious uveitis. The primary end point is time to uveitis recurrence; a key secondary end point is the reduction in total systemic exposure to corticosteroids.30
Sotrastaurin (AEB071; Novartis Pharmaceuticals): Sotrastaurin acts as a potent inhibitor of early T-cell activation and β2-integrin-mediated T-cell adhesion. In a 2-week proof-of-concept study involving 32 plaque psoriasis patients, oral sotrastaurin at dosages of 25, 100, 200, or 300 mg bid (cumulative 2-week dosages of 50, 200, 400, and 600 mg/day) improved clinical disease severity as measured on the Psoriasis Area and Severity Index.31 Adverse effects were generally mild, occurring in 45.8% of the 24 patients receiving sotrastaurin vs 37.5% of the 8 patients receiving placebo.31 A phase 2 trial in 13 patients with uveitis-associated macular edema was completed in May 2012 (results were not available as of the publication of this article).32
At least 3 additional biologic therapies are currently in phase 1 or 2 trials for noninfectious posterior-segment uveitis. Ustekinumab (Janssen Biotech) is an IL-12 inhibitor that is being evaluated in a 52-week pilot trial (N=7) in active, sight-threatening uveitis. Dosing is 90 mg subcutaneous 3 times through week 4 and every 12 weeks thereafter. The primary outcome is the number of participants who experience at least a 2-step (or down to grade 0) reduction in inflammation on the Standardization of Uveitis Nomenclature (SUN) criteria by week 8.33
A small, open-label, 2-year, phase 2 study of abatacept (Bristol-Myers Squibb) is examining changes in visual acuity and vitreous haze, as well as corticosteroid dosage reduction, in patients with steroid-refractory, visionthreatening autoimmune uveitis. Starting doses of 5 mg/ kg or 10 mg/kg are being compared with open-label doses of 5-10 mg/kg.34
Finally, 5 children and adolescents with uveitis associated with juvenile idiopathic arthritis are being studied in a phase 1/2 trial of tocilizumab (Genentech). The primary outcome is the level of anterior chamber cell control at week 16.35
Although current treatments for chronic noninfectious uveitis are effective and well-tolerated in many patients, a sizable minority are either suboptimally controlled and/or intolerant of these agents.4 Fortunately, a number of novel anti-inflammatory agents are currently in clinical development for the treatment of this serious condition.
Editorial support was provided by Bioscience Communications (Harrold P. Schombert) and was funded by Santen, Inc.
Emmett T. Cunningham Jr., MD, PhD, MPH, is Director of the Uveitis Service at the California Pacific Medical Center, San Francisco, and an Adjunct Clinical Professor of Ophthalmology at Stanford University School of Medicine in California. Dr. Cunningham reports no financial relationships with any product mentioned in this article. He sees patients in the West Coast Retina Medical Group. He can be reached via phone: 415 972 4600; fax: 415 975 0999; or email: email@example.com.
- Cunningham ET Jr, Wender JD. Practical approach to the use of corticosteroids inpatients with uveitis. Can J Ophthalmol. 2010;45:352-358.
- Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol. 2000;130:492-513.
- Esterberg E, Acharya NR. Corticosteroid-sparing therapy: practice patterns among uveitis specialists. J Ophthalmic Inflamm Infect. 2012;2:21-28.
- Cunningham ET Jr, Goldstein DA, Zierhut M. Uveitis treatment trials. A cross-study perspective. Ocul Immunol Inflamm. 2012;20:63-67.
- Dugel PU, Blumenkranz MS, Haller JA, et al. A randomized, dose-escalation study of subconjunctival and intravitreal injections of sirolimus in patients with diabetic macular edema. Ophthalmology. 2012;119:124-131.
- Shanmuganathan VA, Casely EM, Raj D, et al. The efficacy of sirolimus in the treatment of patients with refractory uveitis. Br J Ophthalmol. 2005;89:666-669.
- Mudumba S, Bezwada P, Takanaga H, Hosoi K, Tsuboi T, Ueda K, Kawazu K, Ali Y, Naor J. Tolerability and Pharmacokinetics of Intravitreal Sirolimus. J Ocul Pharmacol Ther. 2012 Jun 4. [Epub ahead of print]
- Nguyen QD, Ibrahim M, Watters A, et al. Safety and efficacy of intravitreal and subconjunctival injections of sirolimus in patients with non-infectious uveitis. Ophthalmology. 2012 [submitted].
- Santen Pharmaceutical Co., Data on file. September 2012.
- Deuter CME, Kotter I, Wallace GR, Murray PI, Stubiger N, Zierhut M. Behçet's disease: ocular effects and treatment. Prog Ret Eye Res. 2008;27:111–136.
- Lee RWJ, Dick AD. Treat early and embrace the evidence in favour of anti-TNF-α therapy for Behçet's uveitis. Br J Ophthalmol. 2010;94(3):269–270.
- Qian Y, Acharya NR. Juvenile idiopathic arthritis-associated uveitis. Curr Opin Ophthalmol. 2010;21(6):468–472.
- Cunningham ET Jr, Zierhut M. TNF inhibitors for uveitis: balancing efficacy and safety. Ocul Immunol Inflamm. 2010;18:421-423.
- Abbott Laboratories. Efficacy and Safety of Adalimumab in Subjects With Inactive Uveitis (Visual II). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). September 27, 2012. Available from: http://www.clinicaltrials.gov/ct2/show/NCT01124838?term=NCT01124838&rank=1.
- Abbott Laboratories. Efficacy and Safety of Adalimumab in Subjects With Active Uveitis (Visual I). In: ClinicalTrials. gov [Internet]. Bethesda (MD): National Library of Medicine (US). October 12, 2012. Available from: http:// www.clinicaltrials.gov/ct2/show/NCT01138657?term=adalimumab+visual+1&rank=1.
- Patane MA, Cohen A, From S, et al. Ocular iontophoresis of EGP-437 (dexamethasone phosphate) in dry eye patients: results of a randomized clinical trial. Clin Ophthalmol. 2011;5:633-643.
- Eyegate Pharmaceuticals, Inc. Safety and efficacy sStudy of EGP-437 (dexamethasone phosphate formulated for ocular iontophoresis) to treat dry eye. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). September 10, 2012. Available from: http://www.clinicaltrials.gov/ct2/show/NCT01129856?term=EGP- 437&rank=1.
- Cohen AE, Assang C, Patane MA, From S, Korenfeld M; Avion Study Investigators. Evaluation of dexamethasone phosphate delivered by ocular iontophoresis for treating noninfectious anterior uveitis. Ophthalmology. 2012;119:66-73.
- Eyegate Pharmaceuticals, Inc. Safety and efficacy study of iontophoretic dexamethasone phosphate ophthalmic solution to treat non-infectious anterior segment uveitis. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). September 4, 2012. Available from: http://www.clinicaltrials.gov/ct2/show/NCT015050 88?term=NCT01505088&rank=1.
- Cavelti-Weder C, Babians-Brunner A, Keller C, et al. Effects of gevokizumab on glycemia and inflammatory markers in type 2 diabetes. Diabetes Care. 2012;35:1654-1662.
- Gül A, Tugal-Tutkun I, Dinarello CA, Reznikov L, Esen BA, Mirza A, Scannon P, Solinger A. Interleukin-1β- regulating antibody XOMA 052 (gevokizumab) in the treatment of acute exacerbations of resistant uveitis of Behçet's disease: an open-label pilot study. Ann Rheum Dis. 2012;71:563-566.
- Gevokizumab (XOMA 052). Available at: http://www.xoma.com/content/pipeline/gevokizumab.htm. Accessed September 10, 2012.
- Roesel M, Tappeiner C, Heiligenhaus A, Heinz C. Oral voclosporin: novel calcineurin inhibitor for treatment of noninfectious uveitis. Clin Ophthalmol. 2011;5:1309-1313.
- Lux Biosciences, Inc. Efficacy and safety of voclosporin to treat active noninfectious uveitis. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). September 10, 2012. Available from: http://www. clinicaltrials.gov/ct2/show/NCT01243983?term=voclosporin&rank=7.
- Furrer E, Berdugo M, Stella C, Behar-Cohen F, Gurny R, Feige U, et al. Pharmacokinetics and posterior segment biodistribution of ESBA105, an anti-TNF-alpha single-chain antibody, upon topical administration to the rabbit eye. Invest Ophthalmol Vis Sci. 2009;50:771-778.
- ESBATech AG. Exploratory study on topical ESBA105 in acute anterior uveitis. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). September 10, 2012. Available from http://www.clinicaltrials. gov/ct2/show/NCT00823173?term=NCT00823173&rank=1.
- Novartis Pharmaceuticals. Intravitreal LFG316 in patients with advanced age-related macular degeneration. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). September 10, 2012. Available from: http://www.clinicaltrials.gov/ct2/show/NCT01255462?term=LFG316&rank=1.
- Novartis Pharmaceuticals. Safety, tolerability and efficacy of intravitreal LFG316 in patients with multifocal choroiditis and panuveitis (MCP). ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). September 10, 2012. Available from: http://www.clinicaltrials.gov/ct2/show/NCT01526889?term=LFG316&ra nk=4.
- Thurau SR, Fricke H, Burchardi C, Diedrichs-Möhring M, Wildner G. Long-term follow-up of oral tolerance induction with HLA-peptide B27PD in patients with uveitis. Ann N Y Acad Sci. 2004;1029:408-412.
- National Eye Institute. Optiquel(Trademark) as corticosteroid-sparing therapy for chronic noninfectious uveitis. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). September 10, 2012. Available from: http://www.clinicaltrials.gov/ct2/show/NCT01195948?term=01195948&rank=1.
- Evenou JP, Wagner J, Zenke G, Brinkmann V, Wagner K, Kovarik J, et al. The potent protein kinase C-selective inhibitor AEB071 (sotrastaurin) represents a new class of immunosuppressive agents affecting early T-cell activation. J Pharmacol Exp Ther. 2009;330:792-801.
- Novartis Pharmaceuticals. Safety, tolerability, and efficacy of AEB071 in the treatment of uveitis. ClinicalTrials. gov [Internet]. Bethesda (MD): National Library of Medicine (US). September 10, 2012. Available from: http:// www.clinicaltrials.gov/ct2/show/NCT00615693?term=NCT00615693&rank=1.
- National Eye Institute. Ustekinumab for active sight-threatening uveitis. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). September 10, 2012. Available from: http://www.clinicaltrials.gov/ct2/ show/NCT01647152?term=Ustekinumab+uveitis&rank=1.
- Suhler EB, Oregon Health & Science University (Bristol-Myers Squibb, Collaborator). Abatacept in the Treatment of Uveitis. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). September 27, 2012. http://www.clinicaltrials.gov/ct2/show/NCT01279954?term=abatacept+uveitis&rank=1.
- Suhler EB, Oregon Health & Science University (Genentech, Collaborator). Tocilizumab in the Management of Juvenile Idiopathic Arthritis Associated Uveitis. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). September 27, 2012. http://www.clinicaltrials.gov/ct2/show/NCT01603355?term=tocilizumab+ AND+uveitis&rank=1.