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A. Capone, Jr., V. H. Gonzalez, J. S. Heier, J. A. Wells, III, S. S. Patel, D. S. Boyer, A. J. Berman, D. T. Shima, G. Zahn, A. P. Adamis; A Phase I Open-Label Study of Single and Repeated Doses of Intravitreal JSM6427, a Small Molecule Integrin 5β1 Antagonist, in Neovascular Age-Related Macular Degeneration (AMD). Invest. Ophthalmol. Vis. Sci. 2009;50(13):1259.
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To determine the safety, tolerability, pharmacokinetics, and maximum tolerated dose of single and repeat doses of intravitreal JSM6427 in patients with previously treated neovascular AMD.
Integrin 5β1, the fibronectin receptor, is part of a final common downstream pathway for many angiogenic growth factors and is expressed on many cell types involved in ocular neovascularization. JSM6427 is a highly potent and specific small molecule antagonist of 5β1 and in animal models inhibits new choroidal neovascularization (CNV), regresses established CNV, and inhibits ocular and systemic inflammation and fibrosis, making JSM6427 an attractive option for a multi-pronged therapeutic strategy for the treatment and prevention of pathologic angiogenesis. The phase I, open label, first in human, dose escalation study enrolled patients with subfoveal CNV, OCT center point ≥ 250 µm, and ETDRS best-corrected visual acuity (BCVA) of 20/40 - 20/800. Patients received 1 - 4 intravitreal injections of JSM6427 and were followed for safety and efficacy with BCVA, OCT, fundus photography, ERG, fluorescein angiography, and eye exams for 1 year.
All single-dose patients are in extended safety follow up and show no signs of toxicity to date. Despite extensive treatment for wet AMD (mean 8.6 ± 4.8 prior treatments) and long-standing disease (mean 27.8 ± 17.6 months), BCVA increased by a mean of +3.5 to +8.0 letters at day 15 depending on dose group and remained increased through day 43 in the 2 highest dose groups combined (mean +6.8 letters.) Unexpectedly, despite the known short vitreous half life of the current drug formulation and ≥ 60 days washout for other therapy, 60% of the patients in the 2 highest dose groups did not receive other therapy for AMD for at least 12 weeks after JSM6427 administration.
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