Additive Intraocular Pressure–Lowering Effects of the Rho Kinase Inhibitor Ripasudil (K-115) Combined With Timolol or Latanoprost

Abstract

for the K-115 Clinical Study Group IMPORTANCE Ripasudil hydrochloride hydrate (K-115), a novel rho kinase inhibitor, provides statistically significant intraocular pressure (IOP)-lowering effects and has a tolerable safety profile. However, no studies have evaluated ripasudil combined with β-blockers and prostaglandin analogues.OBJECTIVE To evaluate the additive IOP-lowering effects and the safety of ripasudil, 0.4%, combined with timolol, 0.5%, or latanoprost, 0.005%, in patients with primary open-angle glaucoma or ocular hypertension. DESIGN, SETTING, AND PARTICIPANTSWe conducted 2, multicenter, randomized, double-masked, parallel group comparison studies of ripasudil-timolol and ripasudillatanoprost in 29 and 36 Japanese clinical centers, respectively. Analyses were performed on an intention-treat-treat basis. After appropriate run-in periods with timolol or latanoprost, 208 and 205 patients whose IOP levels were 18 mm Hg or higher were enrolled in the ripasudil-timolol and ripasudil-latanoprost groups, respectively. Enrollment began December 1, 2011, and follow-up was completed on September 7, 2012, in the ripasudil-timolol study. Enrollment began December 1, 2011, and follow-up was completed on September 27, 2012, in the ripasudil-latanoprost study.INTERVENTIONS Patients were subdivided into 2 groups in each study and were treated with ripasudil or placebo twice daily for 8 weeks. MAIN OUTCOMES AND MEASURESThe IOP reductions in the ripasudil and placebo groups were analyzed with a repeated-measures analysis of variance model at weeks 4, 6, and 8, at trough (before instillation [9 AM]) and peak (2 hours after instillation [11 AM]) levels. RESULTSIn the ripasudil-timolol study, the mean IOP reductions from baseline in the ripasudil and placebo groups were −2.4 and −1.5 mm Hg at 9 AM for a difference of 0.9 mm Hg (95% CI, 0.4-1.3 mm Hg; P < .001) and −2.9 and −1.3 mm Hg at 11 AM for a difference of 1.6 mm Hg (95% CI, 1.1-2.1 mm Hg; P < .001), respectively. In the ripasudil-latanoprost study, those IOP reductions were −2.2 and −1.8 mm Hg at 9 AM for a difference of 0.4 mm Hg (95% CI, −0.0 to 0.9 mm Hg; P = .06) and −3.2 and −1.8 mm Hg at 11 AM for a difference of 1.4 mm Hg (95% CI, 0.9-1.9 mm Hg; P < .001), respectively. The most frequently reported adverse event was conjunctival hyperemia, which was mild and in most cases resolved without treatment before the next instillation.CONCLUSIONS AND RELEVANCE These clinical trials found additive IOP-lowering effects of ripasudil from placebo at trough and peak levels in combination with timolol and at peak level in combination with latanoprost. However, a definitive difference in the addition of placebo to latanoprost was not identified in the trough level.

Vascular Normalization by ROCK Inhibitor: Therapeutic Potential of Ripasudil (K-115) Eye Drop in Retinal Angiogenesis and Hypoxia

“…36,37 The steric affinity of the enzyme for ROCK is enhanced by the structural change in the molecule. 21 Ripasudil increases its enzyme affinity by methylation and halogenation.…”

Ocular Hypotension, Actin Stress Fiber Disruption and Phagocytosis Increase by RKI-1447, a Rho-Kinase Inhibitor

“…Two randomized trials involving 413 Japanese primary open-angle glaucoma patients found that Ripasudil achieved an average of 0.4-1.6 mmHg higher IOP reduction than the administration of timolol or latanoprost alone 15 . Phase II/III trials that aim to investigate the IOP-lowering effect of four different ROCK inhibitors (AMA0076 16 , AR-13324…”

The Anti-Inflammatory Effect of Ripasudil (K-115), a Rho Kinase (ROCK) Inhibitor, on Endotoxin-Induced Uveitis in Rats

“…15 In 2014, the first ROCK inhibitor was approved in Japan for the treatment of glaucoma. 16,17 Ripasudil shows high selectivity for ROCK inhibition, especially ROCK 2. The 50% inhibitory concentrations (IC 50 s) of K-115 for ROCK 1, ROCK 2, PKACa, PKC, and CaMKIIa were 0.051, 0.019, 2.1, 27, and 0.37 lM, respectively, while the IC 50 s of other ROCK inhibitors such as Y-27632 and fasudil were 2 to18 times higher than that of ripasudil.…”