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Intravitreal sirolimus 400 mcg (Ospiria, Santen) demonstrated positive results in pivotal trials investigating it as a treatment for non-infectious uveitis of the posterior segment. A New Drug Application is under FDA review.
Reviewed by Raj Maturi, MD
Results from an integrated analysis of data from the SAKURA (Sirolimus study Assessing double masKed Uveitis tReAtment) program support the efficacy and safety of intravitreal sirolimus 440 mcg (Opsiria, Santen) as a novel local treatment for non-infectious uveitis of the posterior segment.
Data showed sirolimus 440 mcg had a more favorable benefit:risk profile than the 44 mcg active control, was associated with a very low incidence of IOP elevation, and facilitated successful tapering of existing systemic corticosteroid therapy. The FDA is reviewing the New Drug Application for intravitreal sirolimus and has set an action date of Dec. 24, 2017 to complete its review, according to the company.
“Based on the efficacy and safety of intravitreal sirolimus, I look forward to its approval and the ability to use it to treat patients with non-infectious posterior segment uveitis,” said Raj Maturi, MD, Midwest Eye Institute, Indianapolis, an investigator in the SAKURA program. “Sirolimus, unlike corticosteroids, does not appear to be associated with an increased risk for glaucoma or cataract formation.”
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.
“The data from SAKURA showing that intravitreal sirolimus allows patients to taper their oral corticosteroid to a safer dose without experiencing significant recurrence of their uveitis is quite promising,” Dr. Maturi said.
Serious ocular adverse events in the SAKURA program were generally manageable and have been observed with intravitreal therapy. Rates of increased IOP in the sirolimus 440- and 44-mcg groups were 1.5% and 1.0%, respectively, and rates of cataract were 0.5% and 1.0%, respectively.
Raj Maturi, MD
This article was adapted from a presentation at the 2017 meeting of the Association for Research in Vision and Ophthalmology. Dr. Maturi is a consultant to Santen.