Phase 2 Randomized Clinical Study of Netarsudil Ophthalmic Solution in Japanese Patients with Primary Open-Angle Glaucoma or Ocular Hypertension

Abstract

Introduction: Netarsudil reduces intraocular pressure (IOP) by increasing aqueous outflow through the trabecular meshwork (TM) pathway and decreasing episcleral venous pressure. The primary objective of this phase 2 study was to evaluate ocular hypotensive efficacy and safety of three netarsudil concentrations (0.01%, 0.02%, and 0.04%) relative to its placebo over 4 weeks in Japanese patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT).

Methods: Patients were randomized to one of four treatment arms, netarsudil ophthalmic solution 0.01%, 0.02%, 0.04%, or placebo, and treated once-daily (QD) in the evening (P.M.) for 4 weeks. The primary efficacy variable was mean diurnal IOP (average of diurnal time points at 9 A.M., 11 A.M., and 4 P.M.) at week 4.

Results: A total of 215 patients were randomized and 207 (96.3%) completed the study. The mean of mean diurnal IOP at baseline ranged from 20.28 to 21.14 mmHg across groups. At week 4, least squares (LS) mean of mean diurnal IOP adjusted for baseline was 16.53, 15.82, 16.06, and 18.94 mmHg in the netarsudil 0.01%, 0.02%, 0.04%, and placebo groups, respectively, demonstrating the superiority of netarsudil (all concentrations) over placebo. At week 4, mean reduction (mean percentage reduction) from baseline in mean diurnal IOP was 4.10 (19.8%), 4.80 (23.5%), 4.81 (23.8%), and 1.73 mmHg (8.2%), respectively, demonstrating statistically significant reductions (p < 0.0001) in all netarsudil concentrations over placebo. Adverse events (AEs) occurred in a concentration-dependent manner, and the incidence of ocular AEs was 34.5%, 42.6%, 68.6%, and 9.1% in the netarsudil 0.01%, 0.02%, 0.04%, and placebo groups, respectively. The most frequently reported AE was conjunctival hyperemia, with an incidence of 23.6%, 37.0%, 56.9%, and 1.8%, respectively. No serious AEs were reported.

Conclusion: Netarsudil ophthalmic solutions 0.01%, 0.02%, and 0.04% dosed QD (P.M.) demonstrated superiority to placebo in terms of hypotensive effectiveness at week 4 and were found to be safe and generally well tolerated. Netarsudil 0.02% QD provided an optimal efficacy and safety profile for the treatment of Japanese patients with POAG or OHT.

Trial registration: NCT03844945.

Keywords: Conjunctival hyperemia; Glaucoma; Intraocular pressure; Netarsudil; Rho-associated protein kinase.

Fig. 1

Study disposition. N total number of patients in the given treatment, n number of patients in a given treatment

Fig. 2

Mean IOP ± SE of study eye at each time point (9 a.m., 11 a.m., and 4 p.m.) at baseline, week 1, week 2, and week 4 (ITT population, observed data). IOP intraocular pressure, ITT intent-to-treat, SE standard error

Fig. 3

Percentage of patients with a mean diurnal IOP ≤ 18 mmHg at week 4, b mean diurnal IOP reduction ≥ 2 mmHg from baseline at week 4, c mean diurnal IOP ≥ 20% reduction from baseline at week 4 in the study eye. IOP intraocular pressure

Fig. 4

Mean conjunctival hyperemia score in the study eye at 9 a.m. at baseline, week 1, week 2, and week 4