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Mohamed A. Ibrahim, Anthony Watters, Zubir Rentiya, Yasir J. Sepah, Henry A. Leder, Elham Hatef, Joel Naor, Naveed K. Shams, James P. Dunn, Quan D. Nguyen; Sirolimus as Therapeutic Approach to Uveitis: A Randomized Study to Assess the Safety and Bioactivity of Intravitreal and Subconjunctival Injections of Sirolimus in Patients with Non-Infectious Uveitis (The Save Study). Invest. Ophthalmol. Vis. Sci. 2011;52(14):4295.
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To evaluate safety and bioactivity of sirolimus as an immunomodulatory therapeutic (IMT) agent, delivered as subconjunctival (SCJ) or intravitreal (ITV) injections, in patients with non-infectious posterior, intermediate, or panuveitis.
In the SAVE Study, a randomized open-label clinical trial, 30 patients were enrolled and stratified at baseline (BL) into 3 categories (1) active disease and receiving no treatment; (2) active disease and receiving prednisone ≥10 mg/day and/or at least 1 other IMT; (3) inactive disease and receiving prednisone <10 mg/day and/or at least 1 other IMT. Patients in each category were randomized into SCJ or ITV arm in a 1:1 ratio. Study eyes received mandatory SCJ (1320 µg) or ITV (352 µg) injections at days 0, 60, and 120, with primary endpoint at day 180 (M6). Beyond safety, other study parameters include change in visual acuity (VA), vitreous cells and haze, and reduction in dosage of systemic corticosteroid (CS) compared to BL.
19 subjects have completed the 6-month primary endpoints. Both SCJ (10 subjects) and ITV (9 subjects) sirolimus injections have been well tolerated. None of the adverse events (AE), regular or serious, ocular or systemic, has been deemed to be related to sirolimus. At M6, VA improved in 47% (SCJ=50% and ITV=44%) and stabilized in 26% of all patients (SCJ=30% and ITV=22%). Vitreous haze and/or cells improved in 84% of patients (SCJ=80% and ITV=89%). All patients, (both SCJ and ITV groups), who were on systemic CS therapy at BL (disease categories 2 and 3), had their doses of systemic CS reduced at M6. In group 2, CS dose was successfully reduced to <10mg/day in 86% of subjects, (median: BL=20mg/day; M6=8mg/day). In group 3, median CS dose was successfully reduced from 7 at BL to 2mg/day at M6.
Local administration of sirolimus, SCJ or ITV, appears to be safe in patients with non-infectious uveitis. No drug-associated ocular or systemic AEs were noted. Sirolimus delivered ocularly, either SCJ or ITV, has demonstrated bioactivity as an IMT and steroid-sparing agent in reducing vitreous haze and cells, improving VA, and in decreasing need for systemic CS. Additional clinical trials are indicated to confirm the role of locally-delivered sirolimus as an IMT agent and to determine its appropriate dosage and frequencies of treatment interval.
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