Bridging the Gap Between Preclinical and Clinical Evaluation of Therapeutic Candidates

Session 6

Multi-Targeted Kinase Inhibitors as Topical Therapies for Posterior Segment Ocular Disease

John Doukas, Ph.D.
Senior Director, Pharmacology
TargeGen, Inc.
San Diego, CA

Neovascularization and edema are major issues in several ocular diseases, including age-related macular degeneration (AMD), retinal vein occlusions, and diabetic retinopathy. Vascular endothelial growth factor (VEGF) plays a central role in these diseases as a direct inducer of both angiogenesis and edema, with clinical validation of VEGF as a therapeutic target being recently obtained. However, considerable preclinical data implicate other factors as playing important contributory roles in ocular neovascularization (e.g., platelet-derived growth factor-B, the fibroblast growth factor family, and erythropoietin). In addition, cytokines (such as interleukin 6) have been linked to several posterior segment diseases, helping to drive the inflammation that likely contributes to disease progression.

Current biological-based therapies present two main limitations. First, they target only one factor at a single level of its signaling cascade (in the case of approved AMD drugs, VEGF binding to its receptor). Second, due to their relatively large size, administration must be accomplished by repeated intraocular injections; topical delivery, were it feasible, would lessen safety issues, and in addition is more appealing to patients. To address these issues of target selection and deliverability, we have sought to develop small molecule multi-targeted kinase inhibitors with pharmaceutical properties appropriate for topical application to the eye. We will now describe preclinical data for several of these compounds, one of which (a dual receptor tyrosine kinase/Src family kinase inhibitor) has entered clinical trials for the treatment of neovascular AMD.

Up to Top