Purpose

To evaluate the safety and tolerability of a microsphere thermo-responsive hydrogel drug delivery system (DDS) loaded with aflibercept in a nonhuman primate model.

Methods

A sterile 50 µL of aflibercept-loaded microsphere thermo-responsive hydrogel-DDS (aflibercept-DDS) was injected intravitreally into the right eye of 10 healthy rhesus macaques. A complete ophthalmic examination, intraocular pressure (IOP) measurement, fundus photography, spectral-domain optical coherence tomography (SD-OCT), and electroretinogram were performed monthly for 6 months. One macaque was euthanized monthly, and the enucleated eyes were submitted for measurement of bioactive aflibercept concentrations. Four eyes were submitted for histopathology.

Results

Injected aflibercept-DDS was visualized in the vitreous until 6 months postinjection. No abnormalities were observed in the anterior segment, and IOP remained within normal range during the study period. A small number of cells were observed in the vitreous of some macaques, but otherwise the remainder of the posterior segment examination was normal. No significant changes in retinal architecture or function as assessed by SD-OCT and histology or full-field electroretinography, respectively, were observed. A mild, focal foreign body reaction around the injectate was observed with histology at 6 months postinjection. A mean of 2.1 ng/µL of aflibercept was measured in the vitreous.

Conclusions

Intravitreally injected aflibercept-DDS achieved controlled, sustained release of aflibercept with no adverse effects for up to 6 months in the eyes of healthy rhesus macaques.

Translational relevance

Aflibercept-DDS may be a more effective method to deliver bioactive antivascular endothelial growth factor agents than current practice by reducing the frequency of intravitreal injections and providing controlled drug release.

A clinical need exists for more effective intravitreal (IVT) drug delivery systems (DDS). This study tested the hypothesis that a novel biodegradable, injectable microsphere-hydrogel drug delivery system loaded with aflibercept (aflibercept-DDS) would exhibit long-term safety and biocompatibility in a non-human primate (NHP) model. We generated aflibercept-loaded poly (lactic-co-glycolic acid) microparticles with a modified double emulsion technique then embedded them into a biodegradable, thermo-responsive poly (ethylene glycol)-co-(L-lactic-acid) diacrylate/N-isopropylacrylamide hydrogel. Aflibercept-DDS (50 µL, 15 µg) was injected into the right eye of 23 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 monthly. Globes from 7 NHPs were histologically examined. Aflibercept-DDS was visualized in the vitreous up to 9 months post-IVT injection, slightly impeding fundoscopy in 4 of 23 eyes; no other consistent abnormalities were appreciated during ophthalmic examination. The IOP and total retinal thickness remained normal in all animals over all timepoints. Central corneal thickness, endothelial cell density, axial globe length, and refractive error did not significantly differ from baseline. Scotopic mixed rod-cone implicit times and amplitudes along with photopic cone response implicit times and amplitudes did not significantly differ from control values. No retinal or choroidal vascular abnormalities were detected with FA and normal retinal architecture was preserved using SD-OCT. Intravitreal injection of a biodegradable aflibercept-DDS was safe and well tolerated in NHPs up to 24 months.