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
Received 4 November 2005; accepted 10 May 2006. published online 27 July 2006.
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).
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(1 with grade 4 hypertension and 1 with grade 2 proteinuria); therefore, all patients in the 3.0 mg/kg–dose group were withdrawn from the study.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.
1Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Correspondence to Peter A. Campochiaro, MD, Maumenee 719, Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287-9277.
Manuscript no. 2005-1071.
Supported by a grant from Regeneron Pharmaceuticals.
2 Dr Nguyen is a recipient of a K23 Career Development Award (grant no.: EY 13552) from the National Eye Institute, Bethesda, Maryland.
3 Dr Campochiaro is the George S. and Dolores Dore Eccles Professor of Ophthalmology and Neuroscience. Dr Campochiaro has acted as a consultant for Regeneron, which has been monitored by the conflict of interest committee of Johns Hopkins University School of Medicine.
4 Ms Chu and Dr Cedarbaum are employees of Regeneron, which has a commercial interest in the VEGF Trap.
ABSTRACT