An Update on Intravitreal Sirolimus
Santen is currently conducting the SAKURA 2 study, a second phase 3 prospective, randomized clinical trial of a proprietary formulation of intravitreal sirolimus (DE-109) for the treatment of active, noninfectious posterior, intermediate, or panuveitis. Sirolimus is an mTOR inhibitor, an immunomodulator, which is the same active pharmaceutical ingredient in two products approved by the US Food and Drug Administration (FDA): Rapamune (Pfizer), an immunosuppressive agent approved for use in renal transplant patients, and the Cypher Sirolimus-eluting Coronary Stent (Cordis), approved for improving coronary luminal diameter in patients with symptomatic coronary ischemic disease.
In SAKURA 1, three doses of sirolimus were compared; 44 µg, 440 µg, and 880 µg. All three doses were administered every two months, with primary and secondary outcomes ascertained at month 5. The highest efficacy results were seen in the 440-µg dose treatment arm for primary and secondary outcomes. The primary outcome of the study was patients achieving zero vitreous haze at month 5: 22.8% of patients achieved total resolution of inﬂammation (vitreous haze [VH] score 0) with 440 µg dosing compared with 10.3% of patients with the active control dose of 44 µg (P = .025, adjusted for multiplicity).1 The secondary outcome was patients achieving 0 or 0.5+ VH at month 5: 53% of patients in the 440-µg arm achieved this level of resolution of inflammation at month 5 compared with 35% of patients in the arm receiving 44-µg doses (P = .008).
After the 5 month primary endpoints, patients were allowed to continue to receive open-label 880-µg sirolimus injections every two months. A total of 287 patients completed the month 12 VH assessment. In patients originally randomized to receive a 440-µg dose who transitioned to an open-label treatment with an 880-µg dose, inflammation continued to improve, with mean change in VH from baseline –1.05 at month 6 and –1.29 at month 12.
The most common study medication–related adverse event (AE) in SAKURA 1 was intraocular pressure (IOP) increase (11.3% of subjects), followed by medication residue (transient drug depot in the visual axis, 6.4%), and iridocyclitis (5.5%). The most common injection procedure-related AEs were conjunctival hemorrhage (15.9%), IOP increase (6.6%), eye pain (5.5%), and conjunctival hyperemia (4.3%). Analysis of AEs per injection revealed low rates of AEs per intravitreal injection, especially in the 440-µg treatment arm. Out of 327 injections of the 440-µg dose, one case of infectious endophthalmitis and one case of sterile endophthalmitis were observed.
Until recently, all available FDA-approved intravitreal therapies for posterior segment noninfectious uveitis were steroids (triamcinolone, fluocinolone, and dexamethasone). The recent FDA approval of adalimumab (Humira, AbbVie) marks the first time patients have access to an FDA-approved nonsteroidal option for systemic therapy. Intravitreal sirolimus potentially adds another steroid-sparing alternative to the intravitreal armamentarium. This is especially welcome given the well-known complications of local steroids, particularly cataract and glaucoma.
1. Lescrauwaet B, Duchateau L, Verstraeten T, Thurau S. Improved visual function is associated with inflammation reduction in subjects with non-infectious uveitis (NIU) of the posterior segment treated with intravitreal sirolimus: results from SAKURA Study 1. Value Health. 2015;18(7):A426.
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