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. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01634-9.

Comparison of safety and efficacy of Netarsudil 0.02% and Bimatoprost 0.01% monotherapy and combination therapy in primary open-angle glaucoma and ocular hypertension

“…Zaman et al (2021),[ 9 ] in their study of 260 patients with OAG and ocular hypertension who were prescribed netarsudil 0.02% as monotherapy or added with concomitant therapy, reported a statistically significant reduction in IOP in both subgroups at 6 and 12 weeks. In a randomized study by Araie et al (2021)[ 10 ] on 207 patients, the IOP-lowering effect of three concentrations (0.01%, 0.02%, and 0.03%) of netarsudil ophthalmic solution was compared to placebo over 4 weeks in POAG and ocular hypertension patients. The study showed a superior mean reduction in diurnal IOP from baseline as compared to placebo ( P < 0.001) in all concentrations of netarsudil.…”

Phase 3 Clinical Trial Comparing the Safety and Efficacy of Netarsudil to Ripasudil in Patients with Primary Open-Angle Glaucoma or Ocular Hypertension: Japan Rho Kinase Elevated Intraocular Pressure Treatment Trial (J-ROCKET)

“…Glaucoma is a leading cause of blindness affecting 64 million people in the world and is estimated to rise to 112 million by 2040 [ 1 , 2 ]. It affects about 4.65 million people in Japan alone [ 1 ].…”

“…Glaucoma is a leading cause of blindness affecting 64 million people in the world and is estimated to rise to 112 million by 2040 [ 1 , 2 ]. It affects about 4.65 million people in Japan alone [ 1 ]. A major risk factor for disease progression is elevated intraocular pressure (IOP) [ 3 ], and every millimeter of IOP reduction is reported to significantly delay the disease progression, not only in patients with primary open-angle glaucoma (POAG) with elevated IOP but also in those with normal-tension glaucoma (NTG) [ 3 – 7 ].…”

“…A recently completed Phase 2 study in Japan showed clinically relevant efficacy and safety, and superiority of netarsudil ophthalmic solution 0.01%, 0.02%, and 0.04% QD to placebo in mean diurnal IOP following 4 weeks of treatment in Japanese subjects with POAG or OHT. Based upon the cumulative efficacy and safety results, 0.02% was determined as the concentration with the optimum efficacy and safety profile for the Japanese population [ 1 ]. Indirect, cross-study comparison between this netarsudil Phase 2 study [ 1 ] and a ripasudil Phase 2 study [ 35 ] suggests superior IOP lowering efficacy of netarsudil ophthalmic solution 0.02% QD to ripasudil hydrochloride hydrate ophthalmic solution 0.4% BID.…”

“…Based upon the cumulative efficacy and safety results, 0.02% was determined as the concentration with the optimum efficacy and safety profile for the Japanese population [ 1 ]. Indirect, cross-study comparison between this netarsudil Phase 2 study [ 1 ] and a ripasudil Phase 2 study [ 35 ] suggests superior IOP lowering efficacy of netarsudil ophthalmic solution 0.02% QD to ripasudil hydrochloride hydrate ophthalmic solution 0.4% BID. The current Phase 3 study was therefore designed to directly compare the ocular hypotensive efficacy and safety of netarsudil ophthalmic solution 0.02% QD to the active comparator, ripasudil hydrochloride hydrate ophthalmic solution 0.4% BID, over a 4-week period.…”