Ocular Distribution and Pharmacodynamics of SF0166, a Topically Administered αvβ3 Integrin Antagonist, for the Treatment of Retinal Diseases

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Abstract
SF0166, a small molecule αvβ3 antagonist, has physiochemical properties that allow distribution to the posterior segment of the eye after topical administration in an ophthalmic solution. The pharmacodynamics and pharmacokinetics of SF0166 were evaluated in several cell lines, chick chorioallantoic membrane assays, and models of ocular neovascularization in mice and pigmented rabbits. SF0166 inhibited cellular adhesion to vitronectin across human, rat, rabbit, and dog cell lines with IC50 values of 7.6 pM to 76 nM. SF0166 inhibited integrin-ligand interactions at IC50 values of 0.6 nM to 13 nM for human αvβ3, αvβ6, and αvβ8. SF0166 significantly decreased neovascularization in the oxygen-induced retinopathy mouse model. SF0166 distributed to the choroid and retina after topical ocular administration in amounts that substantially exceeded the cellular IC50 for adhesion to vitronectin; drug concentrations were maintained for >12 hours. In the laser-induced choroidal neovascularization model, topical ocular administration of SF0166 decreased lesion area compared with vehicle and was comparable to a bevacizumab injection. In the vascular endothelial growth factor-induced early neovascularization and vascular leakage model, topical ocular application of SF0166 resulted in a dose-dependent reduction in vascular leakage; the highest ocular doses tested showed comparable activity to a bevacizumab injection. In summary, SF0166 was safe and efficacious in animal models of ocular neovascularization and Phase I/II clinical trials in patients with diabetic macular edema (NCT02914613) and neovascular age-related macular degeneration (NCT02914639) have recently completed.

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