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  • Written By: Steven Vold

    Previous animal studies have shown AR-12286, a Rho kinase inhibitor, can lower IOP by increasing aqueous humor drainage through the trabecular meshwork. This prospective, double-masked study randomized 89 glaucoma patients to three different concentrations of AR-12286 or vehicle to test safety and efficacy in humans. Results were promising as the new treatment produced statistically and clinically significant reductions in mean IOP and no significant adverse events.

    Rho kinase inhibitors have been shown to reduce IOP in rabbits and monkeys by increasing aqueous humor drainage through the primary outflow pathway in the eye, the trabecular meshwork. Several lines of experimental evidence indicate that modulating the activity of Rho kinase within the primary aqueous humor outflow pathway may offer substantial advantages for the treatment of patients with glaucoma. In addition to improving the outflow function of the trabecular meshwork, Rho kinase inhibitors have been shown to increase ocular blood flow, and to enhance retinal ganglion cell survival after ischemic injury.

    In this first human trial, all three concentrations of AR-12286 produced statistically and clinically significant reductions in mean IOP relative to diurnally adjusted baseline, with peak effects occurring two to four hours after acute or chronic dosing. Mean IOP at peak effect ranged from 17.6 to 18.7 mm Hg. The largest IOP reductions were produced by 0.25% AR-12286 after twice daily dosing (up to -6.8 mm Hg). The 0.25% concentration dosed once-daily in the evening produced highly significant IOP reductions throughout the following day (-5.4 to -4.2 mm Hg). Given that the highest concentration tested, 0.25%, was more effective than the two lower concentrations after both once-daily evening and twice-daily dosing, this study was unable to define the top of the dose-response curve for AR-12286.

    The only adverse event of note was trace (+0.5) to moderate (+2) conjunctival hyperemia that was transient, typically lasting four hours or less. After once-daily evening dosing, hyperemia was seen in less than 10 percent of patients. Since the hyperemia itself was not associated with any other ocular safety finding, nor was it associated with any patient discomfort, it is possible that once-daily evening dosing may offer a simple method to provide the therapeutic benefits of AR-12286 without producing a notable hyperemia effect.

    For many patients, current glaucoma medications are insufficiently effective as monotherapy to achieve low target IOPs, and about half of patients with elevated IOP are treated by co-administration of two or more glaucoma medications. As a result, there remains a need for novel pharmacotherapies that can produce greater IOP-lowering efficacy with improved dosing convenience for patients. This early clinical data shows Rho kinase inhibitors have promise.