Potential New Treatments for Non-infectious Uveitis: A Clinical Trial Review
By Murat Hasanreisoglu MD, FEBO, Carlos Plaza, MD, and Quan Dong Nguyen MD, MSc, FAAO
In the previous Uveitis eUpdate, we reviewed the clinical trials that supported recent FDA approval of new treatment options for non-infectious uveitis. Herein, we highlight trials evaluating potential treatments that are making their way through the approval process.
SAKURA: Phase 3 Evaluation of Sirolimus
Sirolimus, a non-steroidal immunoregulator that acts on the mTOR signaling pathway, is FDA-approved as Rapamune (Pfizer) for treatment of the rare lung disorder lymphangioleiomyomatosis and for use in the prevention of organ rejection in renal transplant patients. Sirolimus is being evaluated by Santen Pharmaceuticals in the treatment of non-infectious uveitis. The SAKURA program for sirolimus included two multinational, randomized, double-masked, active-controlled studies in adult patients with active non-infectious intermediate, posterior or panuveitis. The latest SAKURA results1 are from SAKURA Study 1, a 6-month evaluation in 347 patients who were randomized into three dose groups: An active control group received 44 µm of intravitreal sirolimus; a second group received 440 µm; and a third group received 880 µm. All patients received their doses on days 1, 60, and 120.
At month 5, the 440-µm dose led to the highest proportion of patients (22.8%) meeting the primary endpoint of zero vitreous haze. Its efficacy was greater than that of the 880-µm dose at every assessment interval up to month 5. In addition, the 440-µm dose exhibited the best risk-to-benefit ratio with greater efficacy than the other doses and a numerically lower incidence of events related to ocular inflammation. It should be noted that use of the minimally active 44-µm dose could have led to underestimation of the effect of the 440-µm dose; however, the results were consistent through various subgroup analyses.
SAKURA provides level-1 evidence supporting the strategy of mTOR inhibition in posterior noninfectious uveitis. After reviewing the results, the FDA requested additional data. Thus, another phase 3 study evaluating intravitreal sirolimus in uveitis, the LUMINA study, is currently being conducted in the United States.
STOP-UVEITIS: Tocilizumab Tested in Non-infectious Uveitis
STOP-UVEITIS, a randomized, controlled, multicenter trial, evaluated the safety and efficacy of two different doses (4 mg/kg or 8 mg/kg) of intravenous tocilizumab (TCZ) in eyes with non-infectious intermediate, posterior or panuveitis.2 TCZ is a humanized mouse monoclonal antibody that inhibits interleukin-6 (IL-6), a cytokine that is upregulated during infection and inflammation and associated with variety of autoimmune diseases. In addition, the role of IL-6 in the development of macular edema owing to various causes has been widely reported. TCZ is approved as Actemra (Genentech) for the treatment of rheumatoid arthritis, giant cell arteritis, and polyarticular juvenile idiopathic arthritis. In STOP-UVEITIS, both treatment groups received intravenous infusions of TCZ every 4 weeks until the 6-month endpoint. Both treatment doses were well-tolerated and associated with improved best-corrected visual acuity (BCVA), reduction in vitreous haze, and reduction in central macular thickness. No ocular adverse events related to the study drug were observed, and no new safety signals were detected. Two patients who received the higher dose developed low absolute neutrophil blood counts after the first infusion. One of those patients recovered before the second infusion.
The results of the STOP-UVEITIS trial indicate that an anti-IL-6 therapy may be a reasonable alternative to conventional immunotherapies and tumor necrosis factor alpha inhibitors for uveitis. Also, interestingly, comparison of results between treatment-naive and previously treated eyes in the trial revealed no statistical difference in the efficacy of TCZ, suggesting it may be equally effective in both types of patient.
Other studies, such as the SATURN study of sarilumab,3 have also illustrated the role of IL-6 inhibition in uveitis.
DOGWOOD and PEACHTREE: Suprachoroidal Drug Delivery
The DOGWOOD and PEACHTREE trials evaluated CLS-TA (Clearside Biomedical) for the treatment of macular edema due to non-infectious uveitis.4,5 CLS-TA is a proprietary suspension of triamcinolone acetonide formulated for administration to the back of the eye via the suprachoroidal space.
In DOGWOOD, a randomized, controlled, masked phase 2 study, a single 4.0-mg suprachoroidal injection of CLS-TA reduced mean central subfield thickness by 164 µm from baseline at the month 2 endpoint. In 65% of patients who received the 4.0-mg dose, BCVA improved by ≥5 ETDRS, with a mean improvement of 9.2 letters. No steroid-related increases in intraocular pressure occurred. In PEACHTREE, a randomized, masked, sham-controlled phase 3 trial, CLS-TA was given every 12 weeks and compared with sham. The primary endpoint was met at 24 weeks, with 46.9% of patients in the treatment group gaining at least 15 ETDRS letters of BCVA from baseline compared with 15.6% in the sham group. Also, at week 24, 40.9% of patients in the treatment group who had baseline vitreous haze scores of 2+ (SUN scale) experienced resolution compared with 0% of patients in the control group. CLS-TA was efficacious against macular edema in anterior, intermediate, posterior, and panuveitis.
The DOGWOOD and PEACHTREE results show that suprachoroidal injection may maximize the positive effect of triamcinolone on the retina, while minimizing negative effects, particularly on the lens and trabecular meshwork.
Progressing Toward a Brighter Future
A wide variety of treatment options, those highlighted here as well as IL-23 inhibitors, complement-directed therapies, signal transduction inhibitors and more, are currently moving through the translational and developmental pipelines, heralding as bright a future as ever for patients with non-infectious uveitis and ocular inflammatory disease.
1. Nguyen QD, Merrill PT, Clark WL, et al.; Sirolimus study assessing double-masked uveitis treatment (SAKURA) Study Group. Intravitreal sirolimus for noninfectious uveitis: a phase III sirolimus study assessing double-masked uveitis treatment (SAKURA). Ophthalmology. 2016;123(11):2413-2423.
2. Sepah YJ, Sadiq MA, Chu DS, et al. Primary (month-6) outcomes of the STOP-Uveitis study: evaluating the safety, tolerability, and efficacy of tocilizumab in patients with noninfectious uveitis. Am J Ophthalmol. 2017;183:71-80.
3. Heissigerová J, Callanan D, de Smet MD, et al. Efficacy and safety of sarilumab for noninfectious uveitis of posterior segment: outcomes from the phase 2 SATURN trial. Ophthalmology. E-pub ahead of print: Oct. 11, 2018.
4. Yeh S, Kurup SK, Wang RC, et al.; DOGWOOD Study Team. Suprachoroidal injection of triamcinolone acetonide, CLS-TA, for macular edema due to noninfectious uveitis: a randomized, phase 2 study (DOGWOOD). Retina. E-pub ahead of print: Aug. 15, 2018.
5. Khurana R. Phase 3 efficacy data of suprachoroidally injected CLS-TA for macular edema due to noninfectious uveitis. Paper PA034, annual meeting of the American Academy of Ophthalmology, Oct. 29, 2018, Chicago, IL.
Dr. Hasanreisoglu is a visiting scholar in ocular immunology and uveitis at the Byers Eye Institute at Stanford University School of Medicine in Palo Alto, Calif., and is also an associate professor in the Department of Ophthalmology at Gazi University School of Medicine in Ankara, Turkey.
Dr. Plaza is a visiting scholar in ocular immunology and uveitis at the Byers Eye Institute at Stanford University School of Medicine in Palo Alto, Calif., and is also a resident physician in the Department of Ophthalmology, Hospital Universitario de León, Spain.
Dr. Nguyen is a professor of ophthalmology at the Byers Eye Institute at Stanford University School of Medicine in Palo Alto, Calif., where he has an active uveitis, ocular inflammatory disease, and medical and surgical retina practice. He also serves as principal investigator on multiple clinical trials and teaches students, residents and fellows.