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Preclinical Evaluation of the Novel Small-Molecule Integrin 5β1 Inhibitor JSM6427 in Monkey and Rabbit Models of Choroidal Neovascularization

Grit Zahn, PhD; Dörte Vossmeyer, PhD; Roland Stragies, PhD; Margaret Wills, MS; Corinne G. Wong, PhD; Karin U. Löffler, MD; Anthony P. Adamis, MD; Jochen Knolle, PhD

Arch Ophthalmol. 2009;127(10):1329-1335.

Objective  To evaluate the pharmacologic activity and tolerability of JSM6427, a potent and first selective small-molecule inhibitor of integrin 5β1, in monkey and rabbit models of choroidal neovascularization (CNV).

Methods  JSM6427 selectivity for 5β1 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 µg) 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 5β1-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.

Author Affiliations: Jerini AG, Berlin, Germany (Drs Zahn, Vossmeyer, Stragies, and Knolle); Jerini Ophthalmic, New York, New York (Drs Zahn and Adamis); Charles River Laboratories, Preclinical Services, Sparks, Nevada (Ms Wills); Sclera LLC, Carlsbad, California (Dr Wong); and Department of Ophthalmology, University of Bonn, Bonn, Germany (Dr Löffler). Dr Knolle is now in private practice in Frankfurt, Germany.

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