VIAN-c4551 is a potent topical inhibitor of VEGF and Ang-2 that reduces macular edema and angiogenesis in vascular retinopathies.

Abstract

Purpose : There is an unmet therapeutic need for more effective and less invasive treatments for diabetic macular edema (DME), diabetic retinopathy (DR), and wet age-related macular degeneration (wAMD). Half of the patients exhibit persistent disease and suboptimal vision recovery when treated with VEGF inhibitors. Moreover, anti-VEGF treatments are highly invasive, costly, and have poor adherence. Here, we introduce VIAN-c4551 as a promising non-invasive treatment for DME, DR, wAMD, and other vascular retinopathies.

Methods : Inhibitory effects of VIAN-c4551, a small cyclic peptidic vasoinhibin analog, and its optimized version (VIAN-opt) were evaluated on VEGF-induced proliferation and angiopoietin 2 (Ang-2)-induced permeability of cultured endothelial cells (EC). Binding partners in EC were identified through a pull-down assay, mass spec, and western blot. Knockdown of integrin α5 in EC was achieved with shRNA lentivirus. Permeability across renal epithelial cells was measured in vitro. Electroretinogram and intraocular pressure after intravitreal injection were monitored for 10 days. Bioactive levels were measured in rat vitreous 3 hours after eyedrop delivery. Efficacy was evaluated by measuring retinal vascular permeability in diabetic mice.

Results : VIAN-c4551 and VIAN-opt effectively inhibit VEGF- and Ang-2-induced proliferation and permeability of EC with high potency (IC₅₀ of 110 pM). VIAN-c4551 binds to integrin α5β1 in EC with high specificity and selectivity without inducing EC apoptosis or inflammation. Additionally, VIAN-c4551 does not alter the electrical activity and thickness of the retina or the intraocular pressure. VIAN-opt is 70 to 80 % more permeable than VIAN-c4551 across epithelia and it reaches 720 nM in the vitreous after its delivery in a single eye drop, ensuring a retinal therapeutic concentration for at least 24 hours. Daily eyedrops of VIAN-c4551 or VIAN-opt effectively reduce diabetes-induced retinal edema in mice.

Conclusions : VIAN-c4551 and VIAN-opt stand as effective and safe therapeutics for the non-invasive early treatment of DME, DR, wAMD, and other vascular retinopathies. By targeting pathways beyond VEGF, they could help solve resistance to anti-VEGFs. Finally, their eye drop delivery ensures safety, adherence, and more favorable outcomes.

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