ROCK inhibitors show promise in glaucoma treatment

A novel class of drugs ‒ rho-kinase, or ROCK inhibitors ‒ appears to lower IOP by relaxing the trabecular meshwork.

Take-home message: A novel class of drugs ‒ rho-kinase, or ROCK inhibitors ‒ appears to lower IOP by relaxing the trabecular meshwork.


By Michelle Dalton, ELS; Reviewed by Richard A. Lewis, MD

Sacramento, CA-Topical therapy remains the first-line treatment for patients with primary open-angle glaucoma, but these treatment options are not perfect, nor are they “one size fits all,” and most patients require multiple medications to control their IOP. Further, some patients require IOP to be lowered to “low normal (e.g. below 15mm Hg)” to prevent visual field loss.

To date, there are no commercially available treatments that are able to target the diseased trabecular meshwork (TM) and lower episcleral venous pressure (EVP) to show consistent efficacy across all pressure ranges, and maintain minimal daily dosing. However, a novel class of drugs (rho-kinase, or ROCK inhibitors) appears to lower IOP by relaxing the TM. Several published studies in the U.S., Europe, and Japan have shown that ROCK inhibitors relax pre-contracted TM tissue ex vivo and increase outflow of aqueous humor in animal and human eyes.

The ROCK inhibitor furthest along in clinical development is Rhopressa (Aerie Pharmaceuticals, Bedminster, NJ), a novel triple-action eye drop that inhibits both ROCK and the norepinephrine transporter (NET). Preclinical studies have indicated that Rhopressa lowers IOP by improving outflow via the TM, lowering EVP, and reducing the production of aqueous humor through NET inhibition.

“Doctors want to get the IOP as low as possible quickly with the least amount of medications,” said Richard A. Lewis, MD, (Sacramento, Calif.) a world-renowned leader in ophthalmology, particularly in glaucoma, and the newly appointed Chief Medical Officer for Aerie Pharmaceuticals. “We used to start off with a single drug and then kept adding. Now when a patient presents with moderately advanced glaucoma, we want maximal pressure reduction as soon as we can get it.”

Rhopressa Phase 3 Program

Phase 3 Rhopressa studies commenced in July 2014, with Rocket 1. That trial enrolled 411 subjects at 36 sites with untreated baseline IOP > 20 mm Hg and < 27 mm Hg. The primary goal of this trial was to demonstrate non-inferiority of Rhopressa 0.02%, dosed QD, compared to timolol 0.5% dosed BID. Rhopressa did not meet the primary endpoint, however, it did meet the non-inferiority to timolol in subjects with baseline IOPs analyzed below 27 mm Hg. 

The Rocket 2 Phase 3 study enrolled 756 patients with baseline IOPs between 20 mm Hg and 27 mm Hg at 62 sites. Patients were randomly assigned 1:1:1 to receive Rhopressa 0.02% QD, Rhopressa 0.02% BID, or timolol 0.5% BID; the primary endpoint was non-inferiority to timolol with subjects with baseline IOP > 20 mm Hg and < 25 mm Hg. In this trial, Rhopressa demonstrated non-inferiority to timolol in the primary endpoint analysis range at all time points evaluated (8am, 10am, 4pm, at weeks 2 and 6, and at month 3). Ocular and systemic safety measures are being evaluated through 12 months.

Baseline demographics were similar in all three treatment groups, Dr. Lewis said.

“The really interesting question was whether this drug has potential beyond lowering IOP, meaning could this drug perhaps cause some element of disease modification? We haven’t had a new compound in glaucoma since latanoprost was introduced 20 years ago. The opportunity to see what happens with this drug, in terms of what its effect is, how it remodels the trabecular meshwork ‒ that is very exciting,” Dr. Lewis said.

He said the majority of patients who are diagnosed with confirmed glaucoma in his practice tend to be below 25 mm Hg initially.

“Most of the drugs have been studied in patients with higher IOPs, and the prostaglandins are very effective in treating those pressure levels. But as you get down in the low 20s, they are less effective and that creates a gap in efficacy at lower IOPs. There also are patients who achieve low IOPs with medication, but need to get IOP even lower to prevent vision loss. Rhopressa may be able to fill that gap, once all the data is analyzed,” he said.

In Rocket 2, timolol was “slightly more efficacious than Rhopressa, but similarly showed loss of efficacy at lower baseline IOPs, same as it had in Rocket 1,” Dr. Lewis said.

The most common adverse events (AEs) in either Rhopressa arm were conjunctival hyperemia and the majority of AEs in each arm were considered mild. Based on these new Rocket 2 results, Aerie expects to file Rhopressa for U.S. regulatory approval in mid-2016.

“There’s a good likelihood that, if approved, Rhopressa will be additive to other IOP lowering agents. It’s a different mechanism of action, so you are attacking the pressure issues from three sides,” Dr. Lewis said. “ROCK inhibitors also may have benefits above and beyond treating pressure. Some preliminary animal studies are looking at neuroprotection, anti-fibrotic effects, and increased TM perfusion. There are hints from Dr. Kinoshita’s group in Kyoto of a potential supportive role of ROCK inhibitors on corneal endothelium.”


Roclatan is a combination of Rhopressa and latanoprost. Positive results of a phase 2b study of Roclatan were also reported in 2014.

“Combination products have been particularly challenging to get approved in the U.S.,” Dr. Lewis said. “There has never been a combination prostaglandin product approved here, even though 50% of our patients on a prostaglandin are taking a second medication.”

In the Roclatan phase 2b trial of about 300 patients, Roclatan lowered mean diurnal IOP from 25.1 mm Hg at baseline to 16.5 mm Hg on day 29, about 2 mm Hg greater than monotherapy with latanoprost.

Aerie Pharmaceuticals recently commenced Mercury 1, the first phase 3, 12-month, 3-arm study evaluating Roclatan vs. Rhopressa QD and latanoprost monotherapy. If the phase 3 clinical trials prove successful, Roclatan would be the first topical glaucoma medication with four distinct mechanisms of action to lower IOP.

If Mercury 1 bears out the earlier results, “it would be a great opportunity for patients because it would ease the compliance adherence problem inherent in taking more than one medication each day,” Dr. Lewis said.

Topline results from Mercury 1 are expected during the first half of mid-2016.

“We are just scratching the surface of the potential of this drug class. It offers an exciting opportunity for ophthalmology,” Dr. Lewis said.


Richard A. Lewis, MD

P: 916/649-1515


Dr. Lewis is the medical monitor for Aerie Pharmaceuticals, and recently became the company’s part-time chief medical officer.

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