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Rafal Farjo, Didier Nuno, Alexander Quiambao, Phillip Vanlandingham, Fadee Mondalek, Eric Phelps, Glenn Stoller, Drew Wassel; Eyedrop application of CLT-005, a Stat3 inhibitor, is efficacious in animal models of Wet and Dry Age-related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1716.
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Activation of Stat3 in the posterior segment is associated with neovascular and inflammatory processes. We assessed the safety, ophthalmic distribution, and efficacy of CLT-005, a selective small molecule inhibitor of Stat3, after topical eyedrop administration to rabbit and rodent animal models.
A custom emulsion consisting of 1% CLT-005 was prepared and dosed daily at QID (9am, 12pm, 3pm, 6pm) for all experiments throughout the study duration. Dutch Belted rabbits were scored daily for tolerability/irritation, and the RPE/choroid was isolated for LC-MS/MS quantification of CLT-005 at Day 5. Brown Norway rats were induced by thermal laser to produce choroidal neovascular lesions on Day 1, and in-vivo fluorescein angiography was used to quantify lesion area on Day 22. The CEP Dry-AMD model (under license from SKS Ocular) was induced by immunization of C57Bl/6 mice with Carboxyethylpyrrole-Mouse Serum Albumin (CEP-MSA). At day 60, contrast sensitivity was evaluated with optokinetic tracking at a spatial frequency of 0.064 cycles/degree.
Topical application of CLT-005 achieved mean drug levels in the RPE/Choroid of >2000 ng/g and did not result in any measurable hyperemia, chemosis, or discharge. In the laser-CNV model, treatment with topical CLT-005 or oral CLT-005 at 500 mg/kg in a soybean oil vehicle significantly reduced lesion size and late-stage leakage from lesions. In the CEP Dry-AMD model at Day 60, mean contrast sensitivity was significantly reduced to 0.0512 in CEP-MSA immunized mice as compared to 0.0841 in normal naïve controls. Daily eyedrop application of 1% CLT-005 prevented the loss of contrast sensitivity in CEP-MSA immunized mice and the mean was 0.0842, as compared to 0.054 in the vehicle control group. CLT-005 also significantly reduced inflammation in the posterior segment of CEP-MSA animals.
Eyedrop application of 1% CLT-005 delivers therapeutic amounts of drug to the RPE/choroid which can reduce neovascularization in the laser CNV model of wet AMD. Inhibition of Stat3 by CLT-005 also prevented the dramatic loss of contrast sensitivity in the CEP Dry-AMD model. These data support future clinical studies of topical CLT-005 as a standalone therapy or in conjunction with other intravitreal-based therapies to treat various forms of Age-related Macular Degeneration and Geographic Atrophy.
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