VIAN-c4551 delivered in eye drops reaches high therapeutic concentrations in the back of the eye of rabbits.

Abstract

Purpose : Topical drug delivery to the back of the eye is a challenging task, with drugs often failing to reach the retina at therapeutic concentrations. VIAN-c4551, a small cyclic peptide vasoinhibin analog that inhibits VEGF signaling with high potency (IC₅₀=110 pM), has emerged as a potential antiangiogenic therapy dampening blood vessel growth and permeability in vascular retinopathies. Here, we evaluate the penetration of VIAN-c4551 across an epithelium monolayer and its ocular pharmacokinetic profile after eye drop delivery in rabbits.

Methods : VIAN-c4551 is a seven amino acid peptide (768.87 Da), positively charged and highly soluble (5-10 mg/ml in water). Permeability was evaluated using the MDCK epithelial cells in transwell inserts. Pharmacokinetic profile was analyzed in New Zealand White rabbits treated with eye drops containing VIAN-c4551 (0.5 % w/v) in a trehalose solution. Blood, vitreous, and retinas were collected at different times post-treatment. VIAN-c4551 in vitreous and retina was determined by its effect blocking VEGF-induced proliferation of human umbilical vein endothelial cells in culture. Penetration was confirmed using VIAN-c4551 coupled to fluorescein.

Results : VIAN-c4551 demonstrated high permeability efficacy across epithelium with a permeability coefficient (P_app = 2.3x10^-5 ± 7.1x10^-6 cm/s) exceeding that of other ophthalmic drugs under development for topic delivery (e.g., dexamethasone P_app= 0.9x10^-5 cm/s). After eye drop administration, VIAN-c4551 steadily increased in the vitreous and retina reaching a maximal concentration of 275±17.7 nM (2,500 times its IC₅₀) at 6 hours, 90% of which was eliminated at 12 hours. Despite this, the in vivo anti-VEGF effect persists for up to 24 hours, implying the efficacy of a daily eye drop treatment. VIAN-c4551-FITC in eye drops achieved a 500 pM level in the circulation after 45 minutes that was reduced by 50% at 6 hours, and eliminated at 12 hours, reflecting minimal systemic exposure.

Conclusions : Consistent with its ability to penetrate across epithelium, VIAN-c4551 in eye drop successfully penetrated ocular barriers and reached the back of the eye at therapeutic concentrations that lasted up to 24 hours. VIAN-c4551 is a potent, non-invasive, and safe alternative to anti-VEGF intravitreal injections for the treatment of diabetic retinopathy, age related macular degeneration, and other vasoproliferative retinopathies.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.