Aflibercept (VEGF-TRAP): The Next Anti-VEGF Drug

Abstract

The inflammatory cytokine, vascular endothelial growth factor (VEGF), plays a central role in human growth and development, and vascular maintenance. VEGF mediated angiogenesis is essential for tumor growth, as well as exudative age-related macular degeneration, proliferative diabetic retinopathy and retinopathy of prematurity, all of which are characterized by abnormal neovascularization. Ischemia and inflammation also lead to VEGF-mediated breakdown of the blood-retinal barrier, which causes vision diminishing macular edema. To combat these effects, anti-VEGF drugs (antibodies, aptamers, and tyrosine kinase inhibitors) have been developed for both systemic and local (intraocular) use. The next drug to receive regulatory approval will probably be aflibercept (VEGF-Trap), a fusion protein with high VEGF affinity attributed to binding sequences from the native receptors VEGFR1 and VEGFR2. Aflibercept monotherapy significantly reduces tumor growth and extends survival in several orthotropic animal models, and has both prevented and reduced the growth of experimental choroidal neovascularization. Ongoing phase III trials are evaluating the effectiveness of aflibercept combined with chemotherapy in patients with advanced carcinomas. The phase III VELOUR trial determined that patients receiving aflibercept with irinotecan/5-FU as second line chemotherapy for metastatic colorectal cancer experienced extended progression free survival and overall survival. Intravitreal aflibercept improved visual acuity in patients with exudative age-related macular degeneration and was non-inferior to standard therapy (ranibizumab). Ongoing phase III trials are investigating the use of aflibercept for retinal vein occlusions and diabetic macular edema. A regulatory approval application for use in exudative macular degeneration has been filed, with a decision expected by late 2011.