Can Sirolimus Solve the Taper Puzzle?

SAKURA results point the way to successful tapering of steroids in noninfectious posterior uveitis.

Richard Mark Kirkner
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One of the clinical challenges of treating noninfectious posterior uveitis with systemic corticosteroids is tapering patients without risk of flare ups, but two ongoing trials of intravitreal sirolimus have reported significant reduction of vitreous haze as patients were successfully tapered off their systemic corticosteroids, according to results of Phase III trials presented as posters at the Association for Research in Vision and Ophthalmology meeting.1,2

SAKURA—it stands for Sirolimus study Assessing double-masKed Uveitis tReAtment—is the largest clinical program to date evaluating patients with noninfectious posterior uveitis. The program comprises two multinational, randomized, double-masked Phase III trials that are evaluating intravitreal sirolimus 440 μg and 880 μg vs. 44 μg as the comparator. The ARVO reports involved the intent-to-treat (ITT) population comparing the 44 μg and 440 μg treatment arms.

How Sirolimus Works
Sirolimus has been used systemically as an anti-rejection agent in patients who have had kidney transplants. Raj K. Maturi, MD, of Midwest Eye Institute in Indianapolis, one of the SAKURA investigators, explains how sirolimus works in noninfectious posterior uveitis. “Essentially it has multiple mechanisms of action where it uses this unique system called TOR, or target of rapamycin, and it inhibits the mammalian target of rapamycin, or mTOR, which is a very central mechanism for inhibition of leukocyte activation and certain processes affecting regulated T cells, as well as decreasing vascular endothelial growth factor to reduce edema in uveitis,” he says.

Dr. Maturi also explains why clinical trials of uveitis are lacking. “A uveitis trial is very difficult to run because patients are so different and the disease is so heterogeneous.”

The SAKURA studies include 592 patients—347 in Study 1 and 245 in Study 2. Subjects from both studies comprised the ITT population with 208 in each the sirolimus 440 μg and 44 μg active control groups, with 46 from the 440 μg and 32 from the active controls designated for the intent-to-taper group. The studies define tapering success as achieving an overall prednisone-equivalent dose of ≤5 mg/day at month five without rescue therapy.

Tapering success with vitreous haze reduction was higher in the 440-μg vs. the active controls (43.5 percent vs. 28.1 percent), although the small sample size precludes a declaration of any statistically significant difference (p=0.1676).

The Nature of the Taper
“There’s good tapering success with the drug,” Dr. Maturi says. “If you look at the combined data of the two trials, they’ve clearly reached their primary endpoints in getting patients to no inflammation. It also shows that a higher proportion of patients end up being successfully tapered off of oral steroids.”

While the numbers are small, the take-home for Dr. Maturi was the nature of the tapering that was not reported in the data. “On a majority of patients we were able to literally taper their oral steroids quite successfully over just a few weeks after beginning sirolimus,” he says. “We didn’t have any patients we had to go back and add steroids to either orally or systemically because their drug did not work.”

Commercialization on Track
Santen is on track with its commercialization program for sirolimus, which it has labeled DE-109 in its Food and Drug Administration filing. Santen filed the New Drug Application in February and received word of its acceptance in April. At the company’s annual meeting in May, Chief Scientific Officer Naveed Shams, MD, PhD, told shareholders launch is expected in the first half of next year, pending approval.  RS

REFERENCES
1. Nguyn QD, Merrill PT, Clark L. Efficacy and safety results from the SAKURA program: Two phase III studies of intravitreal sirolimus every other month for non-infectious uveitis of the posterior segment. Poster presented at: Association for Research in Vision and Ophthalmology 2017; May 6-11, 2017; Baltimore, MD.
2. Maturi R. Corticosteroid tapering success with every-other-month intravitreal sirolimus for non-infectious uveitis of the posterior segment: Results of the SAKURA program. Poster presented at: Association for Research in Vision and Ophthalmology 2017; May 6-11, 2017; Baltimore, MD.