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Mark Weiss, Brian Levy, Casey Kopczynski, Thomas Van Haarlem, Gary Novack, AR-13324-CS201 Study Group; Evaluation of AR-13324, a novel dual mechanism agent, in lowering of IOP in glaucoma and ocular hypertension. Invest. Ophthalmol. Vis. Sci. 2013;54(15):754.
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In this first-in-human study, we sought to evaluate the ocular hypotensive efficacy and safety of AR-13324 ophthalmic solution dosed once-daily in the morning. AR-13324 is both a Rho kinase (ROCK) inhibitor and norepinephrine transporter inhibitor thatthat lowers IOP in animal models through a dual mechanism of action, increasing trabecular outflow and decreasing aqueous production.
Entry criteria for the study included a diagnosis of open angle glaucoma (OAG) or ocular hypertension (OHT), unmedicated or post-washout IOP ≥ 24 mm Hg in one or both eyes at 08:00 hours and ≥ 21 mm Hg at 10:00, 12:00 and 16:00 hours. Enrolled were 85 patients with elevated intraocular pressure in this 7-day, double-masked, randomized, vehicle-controlled, monocular study of 3 doses of AR-13324 or its vehicle.
Mean diurnal IOP at baseline in the 85 enrolled patients was 24.3 to 25.6 mm Hg. After a week of dosing, all active groups experienced IOP reductions that were significantly different from vehicle at all time points (p = 0.018 to <0.001). Peak reduction occurred at 8 hours after the final morning dose, ranged from 6.1 to 7.2 mm Hg relative to baseline, and appeared to be continuing downward. IOP reduction at trough (24 hours after dosing) was 5.6 to 6.3 mm Hg relative to baseline. Mild (+1) to moderate (+2) conjunctival hyperemia was the most prevalent biomicroscopic finding.
AR-13324 0.01% to 0.04% q.d. (AM) produced large reductions in IOP that were statistically and clinically significant and lasted at least 24 hours after dosing, with 0.02% AR 13324 appearing to reach the top of the dose response curve. IOP decreased steadily for 8 hours following dosing, suggesting that peak efficacy may occur beyond 8 hours. The only safety finding of note was dose-related ocular hyperemia that declined in incidence and severity with repeated dosing. AR-13324, with its dual mechanism of action, shows promise as a novel ocular hypotensive agent for the treatment of glaucoma.
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