Peptide-Bound Aflibercept Eye Drops for Treatment of Neovascular Age-Related Macular Degeneration in Nonhuman Primates.

The advent of biomacromolecules antagonizing vascular endothelial growth factor (VEGF) has revolutionized the treatment of neovascular age-related macular degeneration (nAMD). However, frequent intravitreal injections of these biomacromolecules impose an enormous burden on patients and create a massive workload for healthcare providers. This causes patients to abandon therapy, ultimately leading to progressive and irreversible vision loss. In order to address this unmet clinical need, a noninvasive treatment for nAMD is developed. An optimized cell-penetrating peptide derivative, Penetratin (bxyWP), is used to non-covalently complex with the anti-VEGF protein aflibercept (AFL) via reversible hydrophobic interaction. The interaction is crucial for AFL delivery, neither impairing the affinity of AFL to pathological VEGF, nor being interfered by endogenous proteins in tear fluids. AFL/bxyWP eye drops exhibit prolonged retention on the eye and excellent absorption into the posterior ocular segment following topical administration, with significant drug distribution to the retina and choroid. In a laser-induced choroidal neovascularization model on cynomolgus monkeys, AFL/bxyWP eye drops efficiently reduce lesion size and leakage comparable to conventional intravitreal injection of AFL. These results suggest that AFL/bxyWP eye drops are feasible self-administered treatment for neovascular retinal diseases and potentially become a substitute for intravitreal injections.