Long-term safety and biocompatibility of a biodegradable, thermoresponsive aflibercept-loaded microsphere-hydrogel drug delivery system in nonhuman primates

Abstract

Purpose : A clinical need exists for more effective intravitreal (IVT) drug delivery systems (DDS). This study tested the hypothesis that a novel biodegradable, thermoresponsive microsphere-hydrogel drug delivery system loaded with aflibercept (aflibercept-DDS) would exhibit long-term safety and biocompatibility in a non-human primate (NHP) model.

Methods : We generated aflibercept-loaded poly(lactic-co-glycolic acid) microparticles with a modified double emulsion technique then embedded them into a biodegradable, thermoresponsive poly(ethylene glycol)-co-(L-lactic-acid) diacrylate/N-isopropylacrylamide hydrogel. Aflibercept-DDS (50 µL, 15 µg) was injected into the right eye of 22 healthy rhesus macaques. A complete ophthalmic examination, intraocular pressure (IOP), corneal pachymetry, specular microscopy, A-scan biometry, streak retinoscopy, spectral-domain optical coherence tomography (SD-OCT), fluorescein angiography (FA), and electroretinography (ERG) were performed. NHPs were monitored up to 9 months. A subset (n=3) received a second injection (9 months) allowing 18 months of long-term follow-up. Globes from 5 NHPs were histologically examined. Mean valves are presented ± SEM. Statistical significance was tested using a Student t test. Significance was set at P <0.05.

Results : Aflibercept-DDS was visualized in the vitreous up to 9 months post-IVT injection, slightly impeding fundoscopy in 4/22 NHPs; no other consistent abnormalities were appreciated during ophthalmic examination. The IOP (14.4 ± 3.5 mmHg) and total retinal thickness (320.5 ± 15.7 µm) remained normal in all animals over all timepoints. Central corneal thickness (498 ± 40 µm), endothelial cell density (2444 ± 316 cells/mm²), axial globe length (20.3 ± 0.7 mm), and refractive states (0.13 ± 1.0 D) did not significantly differ from baseline (P > 0.05). No retinal or choroidal vascular abnormalities were detected with FA and normal retinal architecture was preserved using SD-OCT. Outer retinal function as determined with scotopic and photopic full-field ERG remained normal throughout the study period. Histopathology of enucleated globes showed no inflammatory reaction, retinal degeneration, or uveitis.

Conclusions : Intravitreal injection of a biodegradable aflibercept-DDS was safe and well tolerated in NHPs up to 18 months.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.