Long-Term, Sustained Intraocular Delivery of a VEGF Antagonist Using Encapsulated Cell Technology Implant for the Treatment of Choroidal Neovascular Diseases

Abstract

Purpose: : To develop Encapsulated Cell Technology (ECT) intraocular implants capable of microgram daily intraocular delivery of a VEGF-antagonist over a sustained period. Long-term delivery of a VEGF antagonist will potentially improve the standard-of-care treatment modality of monthly injections by providing a consistent dose, eliminating patient compliance issues and minimizing safety concerns associated with repeated injections in the eye.

Methods: : A human derived cell line with a clinically tested history of safety and long-term implant viability was genetically engineered to produce a VEGF-antagonist in doses ranging from nanogram to microgram daily sustained delivery by ECT intraocular implants. The ability to neutralize VEGF and to block VEGF-induced endothelial cell proliferation was evaluated for the VEGF-antagonist. Studies were conducted to determine the steady state concentrations of VEGF-antagonist in the rabbit eye over a one year period. Maximum vitreous concentrations from several encapsulated cell lines producing escalating doses of VEGF-antagonist were quantified. Sustained intraocular levels of VEGF-antagonist delivered by ECT implants were compared to modeled data of standard-of-care injections for Lucentis^TM, Avastin^TM and Eylea^TM to determine the projected efficacy requirements of steady-state concentration of a VEGF antagonist.

Results: : All doses of VEGF-antagonist produced by ECT implants were determined to be potent and bioactive. Controlled delivery by ECT ranged from nanogram per day to greater than 5 microgram per day sustained delivery in the rabbit eye. While improvements to the production rate of the ECT implant continue, the current steady state concentration of VEGF antagonist exceeds 25 micrograms in the rabbit eye. Potential levels of VEGF-antagonist in the human eye, adjusted for the half-life of the ECT produced protein, conservatively extrapolate to concentrations greater than 50 ug, exceed the modeled levels for steady-state, standard-of-care treatments by monthly injections.

Conclusions: : ECT intraocular implant is capable of sustained delivery of a VEGF antagonist for periods greater than one year in the rabbit. The ability of ECT implant to deliver an efficacious dose over sustained periods, suggest that the ECT implant would have unique advantages compared to traditional standard-of-care treatment for choroidal neovascular diseases, including improved patient compliance and safety.

Keywords: neovascularization • age-related macular degeneration • vascular endothelial growth factor