Clinical safety and efficacy of the first-in-class Rho kinase inhibitor for lowering IOP: netarsudil and the fixed-dose combination of netarsudil and latanoprost


Janet B. Serle

Jake Radell


Purpose: Netarsudil is a novel Rho kinase (ROCK) and norepinephrine transport (NET) inhibitor designed to lower intraocular pressure (IOP). Preclinical and clinical trials have confirmed the safety, efficacy, and the IOP-lowering mechanisms of this compound. This review discusses the mechanism of action studies and the results of the clinical trials that have been conducted with netarsudil and with the fixed-dose combination (FDC) of netarsudil/latanoprost.
Summary: Netarsudil lowers IOP primarily by enhancing outflow through the trabecular pathway, secondarily by lowering episcleral venous pressure, and additionally by causing small decreases in aqueous humor flow rates. These mechanisms differentiate this agent from the other classes of compounds used to lower IOP. Several clinical investigations have evaluated the efficacy of netarsudil. Comparable efficacy of netarsudil to latanoprost at IOP < 27 mmHg was demonstrated in a phase 2 clinical trial. The four Rho Kinase Elevated IOP Treatment Trials (ROCKET) phase 3 clinical trials in over 1,300 patients confirmed comparable efficacy of netarsudil administered once daily to timolol 0.5% administered twice daily. The ocular hypotensive efficacy of netarsudil is constant over a range of IOPs, lowering IOP similarly at lower and higher baseline IOPs, which differentiates thisagent from other classes of compounds used to lower IOP. Twenty-four-hour IOP studies have demonstrated similar efficacy of netarsudil during the diurnal and nocturnal periods. Substantial efficacy was observed in Japanese-American patients with low baseline IOP. Additivity of netarsudil to latanoprost has been confirmed in the more than 1,400 patients who participated in the two MERCURY phase 3 FDC studies. In these studies, the FDC combination of netarsudil 0.02% and latanoprost 0.005% was greater in efficacy than the individual components. The side effects that have been reported with netarsudil and with the FDC of netarsudil and latanoprost are typically mild and include conjunctival hyperemia, small subconjunctival hemorrhages which resolve spontaneously, and cornea verticillata which do not affect visual acuity or contrast sensitivity and resolve upon discontinuation of drug. Drug-related systemic side effects have not been observed, and netarsudil does not alter blood pressure or pulse rate.
Conclusions: Netarsudil is an effective, well-tolerated, new class of IOP-lowering medication, with a novel mechanism of IOP reduction. Netarsudil is comparable in efficacy to the other classes of compounds used as first-line treatments for glaucoma, beta-adrenergic antagonists and prostaglandin analogues, and is additive to latanoprost. Netarsudil is an option for first-line treatment, is additive to prostaglandins, and is anticipated to be additive to the other classes of compounds used to treat elevated IOP. The FDC of netarsudil 0.02% and atanoprost 0.005% is an excellent treatment choice for patients requiring greater IOP reduction than can be achieved with a prostaglandin analogue alone.

Glaucoma Research 2018-2000, pp. 173-186 #15
Edited by: Paul A. Knepper and John R. Samples
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