Session Title: Uveitis
Session Date/Time: Saturday 19/09/2015 | 11:00-12:30
Paper Time: 11:56
First Author: : K.Spataro UNITED STATES
Co Author(s): :
PURPOSE:Intravitreal sirolimus is a novel immunoregulatory therapy currently being investigated in the SAKURA Study for treating NIU of the posterior segment. In the double-masked phase, a statistically significantly larger proportion of subjects receiving 440 µg injections every other month versus an active control dose achieved resolution of inflammation on the Vitreous Haze (VH) Scale at Month 5 without the use of rescue therapy. Because of the chronic nature of NIU of the posterior segment, long-term treatment is essential to prevent cumulative structural damage and vision loss. Here, we present safety and efficacy findings from the SAKURA Study through Month 12.
The SAKURA Study is a Phase 3, randomized, multinational, active control, 24-month study that enrolled subjects from 103 sites in the United States, India, Europe, Latin America, and Japan. The study consists of a 6-month double-masked phase, a 6-month open-label treatment phase, and a 12-month open-label retreatment phase.
347 subjects with active NIU of the posterior segment (VH score of ≥1.5+ in the study eye at baseline) were randomized in a 1:1:1 fashion to receive injections of intravitreal sirolimus 440 μg (n=114), 880 μg (n=116), or an active dose of 44 μg (n=117) as the control. Injections were administered every 2 months. The study was designed as a monotherapy study. Immunosuppressants and topical corticosteroids were discontinued prior to baseline, while systemic corticosteroids were allowed only for subjects already receiving them at baseline and were tapered rapidly thereafter. Efficacy was assessed by outcomes including VH and best corrected visual acuity (BCVA) measures at Month 5, and safety was assessed primarily by ocular adverse events. At Month 6, subjects entered the open-label treatment phase and were transitioned to receive open-label 880 µg injections every 2 months up to Month 12. Long-term efficacy and safety assessments were conducted through Month 12.
Efficacy in the double-masked treatment phase was most favorable with the 440 µg dose: 53% of subjects achieved resolution of inflammation (VH 0 or 0.5+) at Month 5 with 440 µg versus 35% with the 44 µg dose (p=.008). Intravitreal sirolimus preserved vision during the double-masked treatment phase: The median BCVA at Month 5 was 75 letters with 440 µg vs 71 letters with 44 µg, and 46.7% of subjects receiving the 440 µg dose achieved a clinically relevant improvement of ≥5 ETDRS letters. 287 subjects completed the Month 12 VH assessment. Inflammation continued to improve with open-label treatment. In subjects originally randomized to receive the 440 µg dose and then transitioned to the open-label 880 µg dose, the mean change in VH from baseline was –1.05 at Month 6 and –1.29 at Month 12. Visual acuity benefits were maintained with long-term dosing: The median BCVA was 73 letters at Month 12 in subjects randomized to receive the double-masked 440 ug dose. Through Month 12 (combined double-masked/open-label treatment phases), the most common serious ocular adverse events occurring in ≥2% of subjects were ocular inflammation (2.9%-5.8%), cataract (2.6%), and medication residue (i.e., transient drug depot in the visual axis; 2.3%).
In the SAKURA Study, the statistically significant improvements in posterior-segment inflammation and clinically relevant vision-related benefits achieved in the double-masked treatment phase were maintained through until the end of the open-label treatment phase (Month 12). These findings are consistent with the unique mechanism of action of intravitreal sirolimus, an mTOR inhibitor that interrupts the inflammatory cascade leading to T-cell activation and proliferation in NIU of the posterior segment. The low incidence of serious ocular adverse events with long-term dosing in this trial, especially those events associated with corticosteroid use (eg, cataract, glaucoma, and increased intraocular pressure) highlights the benefits of intravitreal sirolimus as a potential long-term treatment option for this chronic sight-threatening disease.