SF0166, a topically administered α_v integrin antagonist, is safe and efficacious in ocular neovascularization models

Abstract

Purpose : Small molecule antagonists of α_vβ₃ and α_vβ₅ have been shown to inhibit retinal neovascularization in animal models when administered by intraperitoneal or periocular injection. SF0166, a small molecule α_vβ₃ antagonist, has physiochemical properties that allow distribution to the posterior segment of the eye after topical administration in an ophthalmic solution. The safety and efficacy of SF0166 were evaluated in ocular neovascularization models.

Methods : In a mouse model of oxygen-induced retinopathy (OIR), mice were subjected to hyperoxia postnatal (PN) Days 7-12. PN Days 13-17, mice received 5% SF0166 or vehicle twice daily (BID). PN Day 18, retinal tissue was analyzed for neovascularization (7 animals [14 eyes]/group). In the Dutch-Belted rabbit model of laser-induced choroidal neovascularization (CNV), CNV was induced by laser treatment on Day -3. Dosing started on Day 1 (vehicle BID, 2.5% SF0166 BID, or single injection of 1.25 mg/eye bevacizumab; 3 animals/group). Post-dose lesion areas were measured weekly starting Day 4. In the Dutch-Belted rabbit model of vascular endothelial growth factor (VEGF)-induced neovascularization, vascular leakage was induced on Day 3 via intravitreal injection of VEGF (2 days after start of study drug dosing on Day 1). Fluorescein imaging was performed after 8 days of dosing with SF0166, bevacizumab, or vehicle (6 animals [12 eyes]/group).

Results : SF0166 significantly decreased neovascularization in the OIR model (p=0.036 vs placebo; unpaired t-test). In the CNV model, topical ocular application of SF0166 decreased lesion area compared with vehicle and was comparable to a bevacizumab injection (Fig 1). In the VEGF-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 bevacizumab injection (Fig 2).

Conclusions : The activity of SF0166 in VEGF-driven models appears similar to that of anti-VEGF biologic drugs (e.g. bevacizumab). Successful clinical development would provide a topically applied ocular treatment that may replace intravitreal injections of anti-VEGF biologic drugs.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

 

Fig 1. Mean (SD) CNV lesion area. Statistical analysis based on ANOVA with Dunnett’s multiple comparison test vs vehicle group.

 

Fig 2. Mean (SD) vascular leakage measured by fluorescein angiography (FA).