Retinal Applications for ROCK Inhibitors Represents Next Step in Research, But Questions Remain

Rho-associated protein kinase (ROCK) inhibitors are highly present across ocular tissues, and ROCK pathway upregulation has been demonstrably related to the pathogenesis of multiple ocular disorders, from glaucoma and corneal neovascularization to diabetic retinopathy and age-related macular degeneration (AMD).¹ However, despite the widespread presence of ROCK isoforms throughout the eye, the current applications of ROCK inhibitor therapy are limited to the treatment of glaucoma. But the barriers preventing these therapeutics from being widely used to manage other diseases may be on the verge of crumbling. New research is pointing to the potential for this class of drugs to find broader utilization across ophthalmology.

Here, Ophthalmology Advisor looks to the future of ROCK inhibitors by reviewing some of the current research and speaking with experts about the potential for these drugs to improve clinical care for patients with retinal, corneal, neuro-ophthalmic, and diabetic eye diseases.

Glaucoma Utilization

ROCK inhibitor research isn’t exactly new: Rho-kinase, a member of the serine/threonine protein kinase family and an effector protein of the Rho pathway, was discovered in the 1990s and has been, according to the literature, one of the “most investigated kinases” to date.¹ But while the research dates back decades, their use in practice has been limited.

Currently, ROCK inhibitors are available to treat glaucoma in the forms of Rhopressa (netarsudil ophthalmic solution 0.02%, Aerie Pharmaceuticals) and Rocklatan (netarsudil and latanoprost ophthalmic solution 0.02%/0.005%, Aerie Pharmaceuticals). Both have been approved by the United States Food and Drug Administration (FDA) to lower intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. 

As a 2018 study explains, when attached to Rho, the Rho/Rho-kinase complex regulates numerous complex physiological functions including cell contraction, proliferation, angiogenesis, chemotaxis, neural protection, and vasodilation — among many others.¹ These functionalities provide a large field of potential therapeutic applications for Rho-kinase inhibitors. 

Tania Tai, MD, a glaucoma specialist at the New York Eye and Ear Infirmary and an associate professor of ophthalmology at the Icahn School of Medicine at Mount Sinai in New York City, agrees. “ROCK inhibitors are kind of a new territory for us,” she explains. “We’re excited that they seem to be working really well in lowering the IOP, and also in lowering episcleral venous pressure. It’s actually targeting the site of the disease, so to speak, because the malfunction of the trabecular meshwork is thought to be what causes the pressure to increase.” 

While most of the research into ROCK inhibitors has focused on these IOP-lowering effects, more recent investigations are considering their potential uses in treating diabetic retinopathy, diabetic macular edema (DME), age-related macular degeneration (AMD), and retinal detachments.²

Room for ROCK in the Retina 

As the Centers for Disease Control and Prevention (CDC) points out, the leading causes for blindness and low vision in the United States include retinal diseases.³ Data from the American Academy of Ophthalmology supports this, listing both AMD and diabetic retinopathy among the top causes of visual impairment and legal blindness across racial and ethnic breakdowns.⁴ The potential, then, that ROCK inhibitors represent for both ophthalmologists and patients living with these conditions, is significant. 

Current treatments for diabetic retinal conditions are limited. Both diabetic retinopathy and DME treatment rely on anti-vascular endothelial growth factor (VEGF) drugs.^5,6 However, clinical response to these therapies is significantly limited, and the burden of frequent, repeated injections is high.⁵ 

A new treatment paradigm may be on the horizon, though, as researchers hypothesize that intravitreal ROCK inhibitor injections can decrease retinal complications associated with diabetes through the reduction of vessel permeability and the improvement of retinal perfusion.¹ 

“The results of some studies suggest that [the] intravitreal injection of a ROCK inhibitor may enhance and prolong the effect of an anti-VEGF agent in the treatment of DME [in particular],” explains Vaidehi Dedania, MD, a retinal surgeon at the NYU Langone Eye Center and an assistant professor in the Department of Ophthalmology at the NYU Grossman School of Medicine. “[W]hile VEGF is a single factor in the process, ROCK inhibitors may target multiple disease processes and thus might prove more useful, either as an additional or additive therapy.” 

Research to elaborate on these hypotheses is underway, albeit slowly. Fasudil (Asahi Kasei Pharmaceuticals), a Rho/ROCK pathway inhibitor, has been approved for use in Japan and China since the mid 90s. Recently, though, investigators have been exploring the therapeutic efficacy of Fasudil in DME. Two case studies evaluated a combined Fasudil and bevacizumab intravitreal injection for DME, with results showing a significantly decreased central macular thickness and improved visual acuity.^7,8  

“To date, not many studies in humans using intravitreal ROCK inhibitors have been conducted,” Dr Dedania says.