Long-term Safety and Ocular Hypotensive Efficacy Evaluation of Netarsudil Ophthalmic Solution: Rho Kinase Elevated IOP Treatment Trial (ROCKET-2)

Abstract

PURPOSE: To evaluate netarsudil 0.02% ophthalmic solution in patients with open-angle glaucoma (OAG) and ocular hypertension (OHT). DESIGN: Double-masked, randomized, multicenter, parallel-group, noninferiority clinical study. METHODS: After a washout of all prestudy ocular hypotensive medications, 756 eligible patients with elevated IOP were randomized to receive netarsudil 0.02% once a day (q.d.) (251); netarsudil 0.02% twice a day (b.i.d.) (254); or timolol 0.5% b.i.d. (251) for 12 months, as well as a noninterventional Corneal Observation Study (COS) for patients manifesting cornea verticillata. RESULTS: On treatment, mean IOP at 8:00 AM decreased from a baseline IOP of 22.5-22.6 mm Hg to 17.9-18.8 mm Hg, 17.2-18.0 mm Hg, and 17.5-17.9 mm Hg for netarsudil q.d., netarsudil b.i.d., and timolol, respectively, over 12 months. The most frequently reported adverse events (AEs) were ocular, with the most frequent ocular AE being conjunctival hyperemia, with an incidence of 61%, 66%, and 14%, respectively. The next most frequent AEs were corneal deposits (corneal verticillata), with an incidence of 26%, 25%, and 1%, respectively, and conjunctival hemorrhage (typically petechial), with an incidence of 20%, 19%, and 1%, respectively. All 3 AEs were generally scored as mild, with conjunctival hyperemia and/or hemorrhage appearing sporadically during the study. In the observational follow-up component of this study, there was no clinically meaningful impact of corneal verticillata on visual function in affected patients. CONCLUSIONS: In this randomized, double-masked trial, once-daily dosing of netarsudil 0.02% was effective, consistently lowering IOP through 12 months, and was tolerated by the majority of patients.

Macrophage Plasticity and Function in the Eye and Heart

“…Evidently, further testing will be necessary to elucidate these ambiguous roles. Nevertheless, despite limitations in our mechanistic understanding of the roles of macrophages in the pathogenesis or protection in the eye, modulation of macrophage activation by ROCK inhibition is already being explored clinically with potential promise for macrophage-and age-mediated diseases such as AMD (Box 4) [88][89][90][91][92][93][94].…”

“…The ROCK inhibitor fasudil has already been approved in some countries for cerebral vasospasm [88,89]. Ripasudil and netarsudil, ROCK inhibitors delivered as ophthalmic solutions, are approved for lowering intraocular pressure in glaucoma and ocular hypertension [90,91]. Other compounds such as Y-27632 are undergoing multiple clinical trials for diseases of corneal endothelial cells, and are thought to mediate their therapeutic effects via modulation of the cytoskeleton, cell junctions, or cell proliferation [88,92].…”

Open-Angle Glaucoma: Burden of Illness, Current Therapies, and the Management of Nocturnal IOP Variation

“…As a first-line therapy, physicians most frequently prescribe topical ophthalmic drops. Currently prescribed classes of topical medications include alpha-adrenergic agonists (e.g., brimonidine tartrate), beta-blockers (e.g., timolol and betaxolol), carbonic anhydrase inhibitors (e.g., brinzolamide and dorzolamide), prostaglandins (e.g., latanoprost, bimatoprost, and travoprost), and first-in-class therapies (e.g., lanoprostene bunod and netarsudil) [24][25][26]. Comparatively, pharmacotherapies are favored as the initial intervention because of their Approved pharmacotherapies target IOP reduction by reducing aqueous humor production, increasing aqueous humor outflow, or a combination of these two mechanisms.…”

Effects of Netarsudil and Latanoprost Alone and in Fixed Combination on Corneal Endothelium and Corneal Thickness: Post-Hoc Analysis of MERCURY-2

“…In Phase 3 clinical trials, netarsudil provided 3.3-5.0 mmHg IOP reduction. Common adverse events included conjunctival hyperemia, corneal verticillata, and conjunctival hemorrhages [6,7]. The latter two adverse events occurred more often than typically seen with other IOP-lowering medications, underscoring the importance of robust characterization of the safety profiles of novel therapies.…”