Sovesudil (locally acting rho kinase inhibitor) for the treatment of normal‐tension glaucoma: the randomized phase II study

Abstract

Purpose: To evaluate ocular hypotensive efficacy and the safety of sovesudil (formally known as PHP-201), a novel Rho-associated protein kinase (ROCK) inhibitor, in patients with normal-tension glaucoma (NTG). Design: Multicentre, prospective, double-masked, randomized, placebocontrolled, parallel clinical study. Methods: Patients with NTG (unmedicated baseline IOP ≤ 21 mmHg) were randomized in 3 groups and treated with sovesudil in concentrations of 0.25% and 0.5%, or with a placebo three times daily (TID) for 4 weeks. The primary end-point was the mean diurnal IOP change from the baseline at week 4. Safety was recorded over a 4-week treatment period and the following 2-week observation period. Results: A total of 119 patients were included in the primary efficacy analysis. The mean diurnal IOP change from the baseline at week 4 was À1.56 mmHg for the high-dose group, À1.10 mmHg for the low-dose group and À0.65 mmHg for the placebo group. The difference between the high-dose and the placebo groups was À0.91 mmHg (95% confidence intervals: À1.73, À0.09). 0.5% sovesudil TID met the criteria for superiority to the placebo. The most frequent ocular adverse event among sovesudil-treated patients was conjunctival hyperaemia (24.4% for the high-dose and 17.5% for the low-dose group) and predominately classified as mild. Conclusions: Sovesudil 0.25% and 0.5% TID showed statistically significant IOP-lowering effects and 0.5% concentration's IOP-lowering effects met the superiority criteria in comparison with the placebo at week 4. Sovesudil was well tolerated with mild adverse events including relatively low incidence of conjunctival hyperaemia in patients with NTG.

Pharmaceutical Approaches to Normal Tension Glaucoma

“…- Rho-associated protein kinase (ROCK) inhibitors : The ROCK inhibitors, many of which are actually under phase II and phase III studies, reduce IOP by disrupting the cytoskeleton and relaxing the smooth-muscle-like cells of the trabecular meshwork and Schlemm’s canal tissues, thus increasing the aqueous humor trabecular outflow [ 77 , 94 , 95 ]. The mean IOP reduction induced by the ROCK inhibitors is approximately 10–20% [ 94 , 95 ].…”

“…ROCK inhibitors have shown a high incidence of local adverse effects, including conjunctival hyperemia, eye pain, irritation, pruritus and discharge, whereas no systemic side effects are reported [ 77 , 94 , 95 ].…”

Glaucoma: Novel antifibrotic therapeutics for the trabecular meshwork

“…Preclinical studies have implicated the importance of ROCK signaling in the regulation of TM contractility and ECM synthesis ( Buffault et al, 2022 ; Pitha et al, 2018 ). So far, several ROCK inhibitors, such as PHP-201 and AR-12286, have been proven to reduce IOP in animal models of glaucoma and are currently being evaluated in clinical trials ( Ha et al, 2022 ; Ren et al, 2023 ). In addition, the potent Rho kinase/norepinephrine transporter inhibitor, netarsudil, is already commercially available for glaucoma treatment due to its hypotensive effect and favorable safety profile, as demonstrated in clinical trials ( Mehran et al, 2020 ).…”

Novel ROCK Inhibitors, Sovesudil and PHP-0961, Enhance Proliferation, Adhesion and Migration of Corneal Endothelial Cells

“…Rho-associated protein kinase (ROCK) inhibitors were developed as drugs to lower intraocular pressure [ 7 ], but it has been suggested to have an effect in hCEnCs [ 8 , 9 ]. It has been reported to promote the adhesion of cultured hCEnCs to the stroma in bullous keratopathy [ 10 ] and to promote wound healing after transcorneal freezing in FECD [ 11 ].…”

“…Sovesudil, a novel ROCK inhibitor, has been developed to improve ROCK affinity and to degrade rapidly to reduce side effects such as conjunctival hyperemia [ 7 ]. Sovesudil, like other soft drugs and are designed to undergo metabolic inactivation by controlled conversion of the active parent molecule into a predictable, nontoxic metabolite [ 12 , 13 ].…”