Using the Past to Inform the Future: Anti-VEGF Therapy as a Road Map to Develop Novel Therapies for Diabetic Retinopathy

Therapies targeting vascular endothelial growth factor (VEGF) are revolutionizing the treatment of diabetic retinopathy (DR) and diabetic macular edema (DME). In August 2012, ranibizumab, a monoclonal antibody fragment targeting VEGF designed for ocular use, became the first and only U.S. Food and Drug Administration–approved medical therapy for DME and the first approved treatment in over 25 years. This approval was based on strong preclinical data followed by numerous clinical trials that demonstrate an essential role of VEGF in vascular permeability and angiogenesis in both normal physiology and disease pathology. In this Perspective, we will examine the experimental studies and scientific data that aided in the success of the development of therapies targeting VEGF and consider how these approaches may inform the development of future therapeutics for diabetic eye disease. A multipoint model is proposed, based on well-established drug development principles, with the goal of improving the success of clinical drug development. This model suggests that to provide a validated preclinical target, investigators should demonstrate the following: the role of the target in normal physiology, a causal link to disease pathogenesis, correlation to human disease, and the ability to elicit clinically relevant improvements of disease phenotypes in animal models with multiple, chemically diverse interventions. This model will provide a framework to validate the current preclinical targets and identify novel targets to improve drug development success for DR.