A phase I trial of an IV-administered vascular endothelial growth factor trap for treatment in patients with choroidal neovascularization due to age-related macular degeneration

Objectives: To assess the safety, pharmacokinetics, and biological activity of IV administration of vascular endothelial growth factor trap (VEGF Trap), a recombinant protein containing the binding domains of VEGF receptors 1 and 2, in patients with neovascular age-related macular degeneration (AMD). Design: Randomized, multicenter, placebo-controlled clinical trial. Participants: Twenty-five patients were enrolled (11 male, 14 female); 19 received VEGF Trap (0.3 [n = 7], 1.0 [n = 7], or 3.0 mg/kg [n = 5]), and 6 received a placebo. Methods. Patients were randomized to receive a placebo or 0.3-, 1.0-, or 3.0-mg/kg VEGF Trap-a single IV dose followed by a 4-week observation period and then 3 doses 2 weeks apart. Main Outcome Measures: Safety and biological activity, including change in excess retinal thickness and volume assessed by optical coherence tomography and visual acuity (VA) measured by the Early Treatment Diabetic Retinopathy Study protocol. Results: The majority of adverse events attributable to VEGF Trap were mild to moderate in severity, but 2 of 5 patients treated with 3.0 mg/kg experienced dose-limiting toxicity (1 with grade 4 hypertension and 1 with grade 2 proteinuria); therefore, all patients in the 3.0 mg/kg-dose group were withdrawn from the study. The mean percent changes in excess retinal thickness were -12%, -10%, -66%, and -60%, respectively, for the placebo and 0.3-, 1.0-, and 3.0-mg/kg groups at day 15 (P < 0.02 by analysis of covariance [ANCOVA]) and -5.6%, +47.1%, and -63.3% for the placebo and 0.3- and 1.0-mg/kg groups at day 71 (P < 0.02, ANCOVA). A significant change in VA was not noted in this small study. Conclusions: The maximum tolerated dose of IV VEGF Trap in this study population was 1.0 mg/kg. This dose resulted in elimination of about 60% of excess retinal thickness after either single or multiple administrations. Alternative routes of delivery to increase the therapeutic window are being explored.