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M. S. Blumenkranz, P. U. Dugel, W. A. Solley, D. M. Kleinman, D. A. Weber, G. A. Williams, J. A. Haller; A Randomized Dose-Escalation Trial of Locally-Administered Sirolimus to Treat Diabetic Macular Edema. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1567.
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Sirolimus (rapamycin) is a specific inhibitor of the mammalian target of rapamycin (mTOR), a regulatory protein kinase which regulates cell growth, proliferation, motility, and survival. Sirolimus has broad activity that includes anti-inflammatory, anti-permeability, and anti-proliferative effects. Inhibition of mTOR by sirolimus down-regulates Hypoxia-Inducible Factor 1 (HIF-1), a key regulator of oxygen homeostasis which is elevated in the diabetic eye. The purpose of this study was to evaluate the safety and pharmacological activity of a proprietary liquid depot-forming formulation of sirolimus in patients with clinically-significant diabetic macular edema (DME).
A multi-center, open label Phase 1 dose escalation study was conducted in 50 patients with DME (www.clinicaltrials.gov NCT00401115). Patients were randomly assigned to receive either a single intravitreal (IVT) (44, 110, 176, 264, or 352 µg) or a single subconjunctival (SCJ) (220, 440, 880, 1320, or 1760 µg) sirolimus injection. Best-corrected visual acuity (BCVA) was assessed by ETDRS and central subfield retinal thickness as determined by OCT was interpreted by an independent reading center at 14, 45, 90 and 180 days.
No dose-limiting toxicities were observed and no serious ocular adverse events probably or possibly related to the study drug were reported. A statistically-significant treatment effect (p<0.05) was observed at 14, 45 and 90 days. Mean BCVA improvements were 8.8 ± 4.4, 11.4 ± 7.6, and 7.4 ± 8.6 letters at 14, 45 and 90 days, respectively, following a single 440 µg SCJ injection. Anatomical changes were also observed, with mean OCT reductions of 33 ± 60, 78 ± 50, and 54 ± 93 µm at 14, 45, and 90 days, respectively. Similar changes were observed following a single 352 µg IVT injection, with mean BCVA improvements of 11.6 ± 7.7, 6.4 ± 7.1, and 7.8 ± 2.2 letters, and mean OCT reductions 72 ± 53, 42 ± 39, and 61 ± 47 µm at 14, 45, and 90 days, respectively. These functional and anatomical improvements persisted through 180 days following a single injection.
No safety issues and promising efficacy signals were observed following a single subconjunctival or intravitreal injection of sirolimus in patients with DME.
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