SAKURA is a 24-month phase III study investigating the efficacy and safety of intravitreal sirolimus for treatment of noninfectious posterior segment uveitis. Data were reported from the primary endpoint visit at 5 months.
Take-home message: SAKURA is a 24-month phase III study investigating the efficacy and safety of intravitreal sirolimus for treatment of noninfectious posterior segment uveitis. Data were reported from the primary endpoint visit at 5 months.
By Cheryl Guttman Krader; Reviewed by Sunil Srivastava, MD
Cleveland-Intravitreal sirolimus (DE-109, Santen) significantly reduces vitreous haze in eyes with noninfectious uveitis of the posterior segment, preserves vision, and has an acceptable safety profile.
These were among the results from the primary endpoint visit in a 24-month phase III clinical trial, according to Sunil Srivastava, MD.
The three-arm multicenter Study Assessing double-masKed Uveitis tReAtment (SAKURA) study 1 included 347 patients randomly assigned to intravitreal sirolimus 440 mcg, 880 mcg, or 44 mcg (active control) every 2 months.
The primary endpoint visit was at month 5. Thereafter, all patients continued on open-label treatment with intravitreal sirolimus 880 mcg through month 12, and then dosing was switched to a p.r.n regimen through month 23.
“There is an unmet need in the treatment of noninfectious uveitis of the posterior segment for a local therapy that can control the disease without causing significant side effects,” said Dr. Srivastava, a retina and uveitis specialist, Cole Eye Institute, Cleveland Clinic, Cleveland.
“The initial clinical and safety results from SAKURA lend support to the use of intravitreal sirolimus as a therapeutic option for this disease,” he said. “Data from the 1-year visit will help further define its role in managing these complex patients. Additional information is needed to identify which patients are good candidates for this therapy.”
Sirolimus is a novel non-corticosteroid, immunoregulatory agent that is associated with negligible systemic exposure after intravitreal administration. It is an mTOR inhibitor that interrupts T-cell proliferation and release of interleukin-2 and other proinflammatory cytokines.
Patients entered into SAKURA had to be 18 or older and have an investigator-determined diagnosis of active noninfectious uveitis of the posterior segment, a vitreous haze score (modified Standardization of Uveitis Nomenclature scale) ≥1.5 in the study eye, and best-corrected visual acuity (BCVA) ≥20/400 in the study eye and ≥20/200 in the fellow eye. Key exclusion criteria included active infectious uveitis, uncontrolled glaucoma, and previous vitrectomy.
Any existing immunotherapy had to be discontinued at least 30 days prior to the first study injection. In addition, patients had to be tapered off topical steroids, and systemic steroids were allowed in those already receiving them at baseline but had to be rapidly tapered after study start.
The study population was predominantly female (60%), had chronic uveitis, and mean BCVA of 20/50. About 20% of patients were on a systemic corticosteroid at entry, and ~5% of patients discontinued their participation before the primary endpoint visit at month 5.
The primary efficacy endpoint was vitreous haze score of 0, and that was achieved by a significantly higher proportion of patients treated with sirolimus 440 mcg compared with both the 880 mcg and 44 mcg doses (22.8% versus 16.4% and 10.3%).
Sirolimus 440 mcg also was significantly superior to the 44-mcg dose in secondary endpoints, which included % of patients with inactive disease (vitreous haze score of 0 or 0.5+; 52.6% versus 35%) and success of tapering systemic corticosteroids (≤5 mg/day prednisone equivalent) (76.9% versus 63.6%).
BCVA data showed that overall patients maintained vision during the first 5 months of the study. Stratification of patients by entry vision showed there was little improvement in patients who entered with BCVA of 20/40 or better.
Patients whose BCVA was worse than 20/40 gained about 5 letters, whether they were treated with sirolimus 440 mcg or 44 mcg. However, in those with BCVA worse than 20/100 at baseline, there was greater improvement in eyes treated with sirolimus 440 mcg compared with the controls (10.5 versus 4.5 letters).
About one-third of eyes had macular edema at baseline. In that subgroup, central retinal thickness changed minimally, but there appeared to be a greater benefit of sirolimus 440 mcg in eyes without versus with an epiretinal membrane.
“These analyses are based on small numbers of eyes, and so we should be cautious in interpreting the efficacy of sirolimus for reducing macular edema,” Dr. Srivastava said.
The safety review showed few severe ocular adverse events. In the sirolimus 440-mcg group there was 1 case of culture-negative endophthalmitis, and there were single cases of increased IOP, glaucoma, and cataract in both the sirolimus 440- and 44-mcg groups.
“Overall, patients did well systemically as there were only rare systemic side effects in any arm,” Dr. Srivastava said.
Sunil Srivastava, MD
This article was adapted from Dr. Srivastava’s presentation during Retina Subspecialty Day at the 2014 meeting of the American Academy of Ophthalmology. Dr. Srivastava is a consultant to Bausch + Lomb, Clearside, Regeneron, Sanofi, and Santen, and receives research support from Allergan and Bausch + Lomb.