The SAKURA program consisted of two sequentially performed, phase III randomized, double-masked, multinational studies. Inclusion/exclusion criteria required patients have a vitreous haze score ≥1.5+, BCVA ≥19 ETDRS letters (≥20/400) in the study eye and ≥20/200 in the fellow eye, and no evidence of active ocular infection.
Topical corticosteroids and nonsteroidal immunosuppressive agents had to be stopped prior to enrollment, whereas existing systemic corticosteroid therapy >5 mg/day prednisone-equivalent was to be rapidly tapered after study entry.
In SAKURA 1, 347 patients were randomly assigned to receive either intravitreal sirolimus 440 mcg, 880 mcg, or 44 mcg once every 2 months. The primary efficacy analysis--which determined the proportion of patients with a vitreous haze score of 0 at month 5--showed superiority of the 440-mcg dose compared with both the 44- and 880-mcg doses. The protocol for SAKURA 2 was amended to eliminate further evaluation of the 880-mcg dose.
SAKURA 2 randomly assigned 245 patients. Consistent with the outcome in SAKURA 1, 19.1% of patients treated with sirolimus 440 mcg achieved a vitreous haze score of 0 at month 5. There was a 17.6% response rate in the sirolimus 44-mcg group and the difference between treatment groups was not statistically significant (p = 0.783).
However, integrated analysis of the SAKURA 1 and 2 data demonstrated statistically significant superiority of sirolimus 440 mcg to the 44-mcg dose.
Similarly, a key secondary endpoint analysis that considered the proportion of patients achieving a vitreous haze score of 0 or 0.5+ at month 5 showed a statistically significant difference favoring sirolimus 440 mcg over sirolimus 44 mcg in SAKURA 1 (52.6% verus 35.0%; p = 0.0008), no significant difference comparing sirolimus 440 mcg and 44 mcg in SAKURA 2 due to a higher response rate in the active control group (47.3% versus 46.8%; p = 0.952), but a statistically significant benefit of sirolimus 440 mcg in the integrated analysis (50.0% versus 40.4%; p = 0.049).
A post hoc efficacy analysis focused on the population of patients with multiple measures of inflammation at baseline as defined by a vitreous haze score ≥1.5+ and at least one of the following characteristics: BCVA ≤75 ETDRS letters, requirement for systemic corticosteroids, or presence of macular edema.
About 80% of patients in both the sirolimus 44- and 440-mcg groups met these criteria. Analyses of the proportion of patients achieving a vitreous haze score of 0 by month 5 showed statistically significant differences favoring sirolimus 440 mcg over the 44-mcg dose in SAKURA 1, 2, and the pooled populations.
In the SAKURA program, 46 patients in the sirolimus 440-mcg group and 32 active control (sirolimus 44 mcg) patients were receiving an oral prednisone-equivalent dose >5 mg at study entry and were included in an Intent-to-Taper corticosteroid population. Corticosteroid tapering success with remission—defined as dose reduction to ≤5 mg prednisone-equivalent at month 5 without the need for rescue medication—was achieved by a higher proportion of patients receiving sirolimus 440 mcg compared with the active controls. Mean prednisone-equivalent dosage in the sirolimus 440- and 44-mcg groups at baseline was 26.2 and 24.2 mg, respectively, and at month 5 it was reduced to 4.4 and 2.7 mcg, respectively.