Session Title: Uveitis
Session Date/Time: Saturday 19/09/2015 | 11:00-12:30
Paper Time: 11:00
First Author: : K.Spataro UNITED STATES
Co Author(s): :
PURPOSE:Intravitreal sirolimus is a novel immunoregulatory therapy currently being investigated in SAKURA Study 1 for the treatment of NIU of the posterior segment. Results from the double-masked phase showed that significantly more subjects receiving bimonthly 440 µg injections achieved resolution of inflammation on the Vitreous Haze (VH) scale at Month 5 compared with an active control dose. Because of the chronic nature of NIU of the posterior segment, longer-term efficacy is essential to prevent the development of cumulative, irreversible structural damage and permanent vision loss. Here, we describe the safety and efficacy results from SAKURA Study 1 through Month 12.
SAKURA Study 1 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 phase, and a 12-month retreatment phase.
347 subjects with active NIU of the posterior segment (VH score of ≥1.5+ in the study eye) were randomized at baseline in 1:1:1 fashion to receive injections of intravitreal sirolimus 440 μg (n=114) or 880 μg (n=116), or an active-control dose of 44 μg (n=117). 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 outcomes, including several assessments of VH score and changes in best corrected visual acuity (BCVA), were assessed at Month 5, with safety assessed at Month 6. At Month 6, subjects were then transitioned to 880 µg doses every 2 months (Months 6-10, the open-label treatment phase). Long-term VH, BCVA, and safety assessments were conducted through Month 12.
The efficacy in the double-masked phase was most favorable with the 440 µg dose: 52% of subjects achieved resolution of inflammation (VH 0 or 0.5+) at Month 5 with 440 µg compared with 35% with the active control dose of 44 µg (p=.008). Intravitreal sirolimus preserved vision over the double-masked phase: The median BCVA at Month 5 was 75 letters for 440 µg vs 71 letters for 44 µg, and 46.7% of subjects receiving 440 µg 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 440 µg and transitioned to 880 µg, the mean VH change from baseline was –1.05 at Month 6 and –1.29 at Month 12. Visual benefits were maintained with long-term dosing: The median BCVA was 73 letters in the 440/880 µg dose group at Month 12. Through Month 12 (combined double-masked/open-label treatment periods), 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 (ie, transient drug depot in the visual axis; 2.3%).
In SAKURA Study 1, the statistically significant improvements in posterior-segment inflammation and clinically relevant vision-related benefits achieved in the double-masked phase were maintained over 12 months in the open-label phase. These findings are consistent with the unique mechanism of action of intravitreal sirolimus, an mTOR inhibitor that is believed to interrupt the inflammatory cascade leading to T-cell activation and proliferation in NIU of the posterior segment. The low incidence of serious ocular adverse events over the long term in this trial, especially those events associated with corticosteroid use (eg, cataract, glaucoma, and increased ocular pressure), highlights the benefits of intravitreal sirolimus as a potential long-term treatment option for this chronic sight-threatening disease.