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P. U. Dugel, H. Quiroz-Mercado, D. M. Kleinman, D. A. Weber, G. A. Williams, J. A. Haller, M. S. Blumenkranz; Interim Analysis of a Randomized Dose-Escalation Trial of Locally-Administered Sirolimus to Treat Choroidal Neovascularization Secondary to Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2008;49(13):582. doi: https://doi.org/.
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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-angiogenic, anti-fibrotic, anti-proliferative, and anti-inflammatory effects and has shown efficacy in multiple preclinical choroidal neovascularization (CNV) models. 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 sub-foveal CNV due to age-related macular degeneration (AMD).
A multi-center, open-label Phase 1 dose-escalation study was conducted in 30 patients with newly diagnosed, treatment-naïve CNV having best-corrected visual acuity (BCVA) of 20/40 - 20/200. Patients were randomly assigned (five per dose group) to receive either a single intravitreal (IVT) (44, 110, 176 µg) or a single subconjunctival (SCJ) (220, 440, 880 µg) sirolimus injection. BCVA was assessed by ETDRS at 4 meters and central retinal lesion thickness as determined by OCT was interpreted by an independent reading center at 14 and 45 days.
No dose-limiting toxicities were encountered and no systemic adverse events probably or possibly related to the study drug were reported. CNV lesion characteristics at baseline were 17% predominantly classic, 50% minimally classic, and 33% occult with no classic component. The mean baseline BCVA was 48 letters and mean baseline OCT thickness was 457 µm. Interim results showed mean BCVA improvements of 7.6 ± 9.9 and 4.0 ± 12.6 letters and mean OCT reductions of 126 ± 229 and 77 ± 112 µm at 14 and 45 days, respectively, following a single 44 µg IVT injection. Mean BCVA improvements of 5.2 ± 6.3 and 2.4 ± 5.2 letters and mean OCT reductions of 58 ± 107 and 54 ± 130 µm were observed at 14 and 45 days, respectively, following a single 440 µg SCJ injection.
No safety issues and promising efficacy signals were observed following a single subconjunctival or intravitreal injection of sirolimus in patients with treatment-naïve CNV secondary to AMD.
Clinical Trial: :
- FDA Phase 1 Study
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