Preclinical Evaluation of the Novel Small-Molecule Integrin α5β1 Inhibitor JSM6427 in Monkey and Rabbit Models of Choroidal Neovascularization

Objective: To evaluate the pharmacologic activity and tolerability of JSM6427, a potent and first selective small-molecule inhibitor of integrin alpha 5 beta 1, in monkey and rabbit models of choroidal neovascularization (CNV). Methods: JSM6427 selectivity for alpha 5 beta 1 was evaluated by in vitro binding assays while the ability of JSM6427 to inhibit CNV was investigated in a laser-induced monkey model and a growth factor-induced rabbit model. Intravitreal injections of JSM6427 (100, 300, or 1000 mu g) or vehicle were administered immediately after the CNV induction procedure and at weekly intervals for 4 weeks. Fluorescein angiography was performed weekly. Ocular tolerability was evaluated ophthalmoscopically and histologically in both models; additional assessments in monkeys included electroretinography, biomicroscopy, pathological examination, and analysis of JSM6427 pharmacokinetics. Results: JSM6427 was highly selective for the alpha 5 beta 1-fibronectin interaction. Weekly intravitreal injections of JSM6427 resulted. in a statistically significant dose-dependent inhibition of CNV in laser-induced and growth factor-induced models without any ocular JSM6427-related adverse effects. JSM6427 was cleared through the systemic circulation with no evidence of systemic accumulation. Conclusions: Intravitreal JSM6427 provided dose-dependent inhibition of CNV in monkey and rabbit experimental models. Clinical Relevance: JSM6427 may provide a new approach for the treatment of ocular neovascular diseases such as age-related macular degeneration in humans.