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Philip A Petrou, Katherine Shimel, Catherine A Cukras, Frederick L Ferris, Emily Y Chew, Wai T Wong; Intravitreal Sirolimus for the Treatment of Bilateral Geographic Atrophy Associated with Age-Related Macular Degeneration: Results of a Phase I/II Trial. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5892.
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To investigate the safety and effects of intravitreal sirolimus, an mTOR inhibitor and immunosuppressive agent, for the treatment of bilateral geographic atrophy (GA).
The study was a single-center, open-label phase I/II trial, with intravitreal injections of sirolimus (440 µg) every 2 months in a randomly assigned eye of each participant for 24 months. Fellow eyes served as untreated controls. Safety and tolerability were evaluated, and efficacy outcome measures included: change in the total GA area as measured by color fundus photography (CFP) and autofluorescence (AF) imaging, visual acuity, central retinal thickness (CRT), and macular sensitivity. Paired t-tests were used to compare measures in treated vs. control eyes.
The study enrolled 6 participants with bilateral GA; 5 participants completed 12 months of follow-up. During the study, drug administration was suspended for all participants after 2-3 doses following the detection of retinal changes in 2/6 participants that were judged inconsistent with the natural progression of GA. These included: 1) accelerated retinal thinning in the study eye in 2 participants, and 2) accelerated GA area expansion in 1 participant. Comparisons of study vs. fellow eyes respectively showed that mean GA area growth on CFP was 2.1 ± 1.4 vs. 0.9 ± 0.5 mm2 at month 6 (n = 5, p = 0.13) and 2.3 ± 0.9 vs. 1.5 ± 0.7 mm2 at month 12 (n = 5, p = 0.15). Similar results were obtained with AF imaging. Mean change in CRT was -27.4 ± 20.1 vs. +1.0 ± 6.6 µm at month 6 (n = 5, p = 0.04) and -23.8 ± 27.7 vs. -13.8 ± 8.5 µm at month 12 (n = 5, p = 0.32). Mean visual acuity change was -15.6 ± 7.2 vs. 0.0 ± 13.5 letters at month 12 (n = 5, p = 0.013). Substantive differences in macular perimetry measurements were not detected between study and fellow eyes. Study drug was otherwise well-tolerated with few related systemic symptoms and adverse events.
No evidence of anatomical or functional benefit was associated with study drug in this small study. In general, intravitreal sirolimus appeared safe, but may potentially be associated with an increase in retinal thinning and GA expansion in a subset of patients. Further data on the effects of intravitreal sirolimus for GA treatment will be available from a larger ongoing phase II trial.
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