Evaluation of Retinal Structure and Function of Rabbits Following Continuous VEGF Inhibition by Encapsulated Cell Therapy (ECT)

Abstract

Purpose: ECT delivery of a novel VEGF-receptor (910-VEGFR) has demonstrated clinically meaningful improvements in visual acuity and reductions in macular thickening in patients with neovascular AMD for at least 20 months. Evolving animal (Saint-Geniez, 2008) and human (Martin, 2012) data suggests that VEGF inhibition may negatively influence non-vascular tissues including the retina, although this remains unconfirmed. The following sub-group analysis of a GLP toxicology study evaluating the delivery of 910-VEGFR by ECT over a period of 9 months examined if chronic VEGF inhibition was detrimental to retinal function or structure in normal NZW rabbits.

Methods: Rabbit and human VEGF sequence homology and picomolar binding affinity of 910-VEGFR to rabbit VEGF suggests the rabbit is an appropriate toxicology model. In the current study, ERG function over 9 months was determined during predose, and weeks 4, 12 and 36 of dosing. Serum levels were collected predose, day 1, weeks 2, 4, 8, 12 and 36, and analyzed for free (unbound) VEGFR and toxicokinetic parameters calculated. Implanted and naïve animals were terminated following 1 and 9-months, devices removed, fixed, and histologically processed. Repeated measurements of the INL and ONL for each of four serial regions of the retina were conducted by blinded observers. Student’s t-test comparing treated to untreated animal eyes and single factor ANOVA of all samples were performed.

Results: Serum levels of free VEGFR peaked (C_max) at 4 weeks and then remained constant through 9 months with a half-life of greater than 6 years. These levels are estimated to be below detectable levels in humans. ERG data suggests no changes in retinal function during the study period comparing VEGFR treated to untreated eyes. No differences in INL thickness (P= 0.9882) or ONL thickness (P=0.2656) comparing all VEGFR treated and untreated eyes were observed in an ANOVA analysis of preliminary data.

Conclusions: A single, intraocular ECT implant delivering 910-VEGFR is anticipated to provide equivalent or improved efficacy compared to standard-of-care therapy while eliminating the burden of frequent injections in patients with neovascular AMD. In the current study, no functional or structural changes occurred in the normal rabbit eye following continuous VEGF inhibition over a 9-month period.