Article
Sirolimus Showed Improvements in Patients with Active Noninfectious Posterior Uveitis
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In the SAKURA study, a greater proportion of those in the intravitreal sirolimus treatment groups than those in the active control group met the primary endpoint, a vitreous haze score of zero at Month 5 without the use of rescue therapy.
Because inflammation of the uvea in noninfectious uveitis (NIU) is mediated by T cells and perpetuated by proinflammatory cytokines, NIU treatment targets inflammation. Although systemic corticosteroids are effective in most patients with NIU, its long-term use may result in diabetes, myopathy, or pancreatitis. And local corticosteroids are not effective for all types of NIU and may cause elevated intraocular pressure, glaucoma, and cataract.
These and other limitations of corticosteroid therapy have led to the evaluation of an intravitreal form of the immunoregulatory agent sirolimus for NIU. This agent inhibits the activity of a protein kinase mammalian target of rapamycin (mTOR) pathway, which contributes to autoimmune inflammation by promoting T cell activation, proliferation, and differentiation and producing inflammatory cytokines. By inhibiting this pathway, sirolimus suppresses the response of lymphocytes to interleukin-2 and promotes the development and function of regulatory T cells.
Although oral sirolimus (Rapamune/PR Prism CV) is effective for severe NIU, it requires regular monitoring for systemic toxicity. So an intravitreal formulation of sirolimus (Opsiria/Santen) was recently developed and is currently being investigated. This agent reduced ocular inflammation in patients with active or quiescent NIU in the Phase I Sirolimus as a Therapeutic Approach for Uveitis, or SAVE, study.
Based on these results as well as preliminary results of the ongoing SAVE-2 study, an international team of investigators initiated the first Sirolimus Study Assessing Double-masked Uveitis Treatment, or SAKURA. The team included investigators from Hokkaido University Graduate School of Medicine in Sapporo, Pitie-Salpetriere Hospital in Paris, and Rush University Medical Center in Chicago, among other centers.
SAKURA was a Phase III, multicenter, randomized, double-masked study of the efficacy and safety of intravitreal sirolimus in patients with active NIU of the posterior segment, including intermediate uveitis, posterior uveitis, or panuveitis. A vitreous haze score of more than 1+ was considered to indicate active disease. At baseline, patients discontinued all medications except systemic corticosteroids, which were rapidly tapered thereafter.
The investigators randomized 347 patients in equal numbers to either an active control group or one of two treatment groups. Those in the active control group received intravitreal sirolimus, 44 μg. Those in the treatment groups received intravitreal sirolimus, 440 μg or 880 μg. Patients took these doses on Days 1, 60, and 120.
The team found that a greater proportion of those in the treatment groups than those in the active control group met the primary endpoint, a vitreous haze score of zero at Month 5 without the use of rescue therapy. In the low-dose treatment group, 23% met this endpoint, and in the high-dose group, 16% did, compared with 10% in the active-control group (P = 0.025 for low dose vs. active control; P = 0.182 for high dose vs. active control).
The team noted similar results for a secondary endpoint, a vitreal haze score of zero or 0.5+, indicating no or minimal ocular inflammation, at Month 5. Whereas 53% of those in the low-dose treatment group and 43% of those in the high-dose treatment group met this endpoint, only 35% of those in the active-control group did (P = 0.008 for low dose vs. active control; P = 0.228 for high dose vs. active control).
Each group maintained mean best-corrected visual acuity throughout the study. Moreover, most patients who had been taking a systemic corticosteroid (>5 mg/day of prednisone or its equivalent) before the study could be tapered to ≤5 mg/day of prednisone or its equivalent at Month 5. Furthermore, the incidence of adverse events was similar between the treatment groups and the active control group, and all doses of intravitreal sirolimus were well tolerated.
As a result, the investigators concluded that intravitreal sirolimus at a dose of 440 μg improved ocular inflammation and preserved visual acuity in patients with active NIU of the posterior segment.
The study “Intravitreal sirolimus for noninfectious uveitis: a phase III Sirolimus study Assessing double-masKed Uveitis tReAtment (SAKURA),” was published in the November, 2016, issue of Ophthalmology.
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