Eyeworld

EW GLAUCOMA 124 March 2015 by Michelle Dalton EyeWorld Contributing Writer If approved, this class of drugs would be the first to target the trabecular meshwork T he mechanism of action of today's glaucoma med- ications either enhance outflow or suppress the formation of aqueous hu- mor. A novel class of drugs, rho-ki- nase inhibitors, or ROCK inhibitors, function by relaxing the trabecular meshwork (TM), which leads to im- proved aqueous outflow and lower IOP. ROCK is a downstream effec- tor of a small-G protein Rho. The ROCK inhibitor furthest along in U.S. studies is Rhopressa, a "novel triple-action eye drop" that inhibits both ROCK and the norepineph- rine transporter (NET), according to developer Aerie Pharmaceuticals (Bedminster, N.J.). Phase 3 studies started in July 2014, and a phase 2b study of Roclatan, a combination of Rhopressa and latanoprost, started in June 2014. Preclinical studies have indicated Rhopressa lowers episcleral venous pressure and through NET inhibition can reduce the production of eye fluid. "It is exciting to have a new potential agent for managing glau- coma," said Jason Bacharach, MD, in private practice at North Bay Eye Associates, Petaluma, Calif. "About half the people we treat in the office are unable to be controlled, even with prostaglandins for whatever reason. It might be that people are living longer and the disease is progressing—we don't have any evidence that prostaglandins lose efficacy over time." Some theorize the TM relies on the aqueous "percolating" to supply nutrients and antioxidants, so by di- verting fluid away from the TM, "we may not be helping its long-term health," Dr. Bacharach said. Today's topical medications reduce pressure by shunting fluid primarily through the uveoscleral pathway; by working on the extracellular matrix, ROCK inhibitors may have an effect on the pathology of the disease as well. Outside the U.S., ripasudil (formerly K-115, Kowa Pharmaceu- ticals, Nagoya, Japan) has been filed with Japanese regulators for the treatment of glaucoma and ocular hypertension. Senju Pharmaceuticals (Osaka, Japan) is investigating SNJ- 1656 (previously known as Y-39983) for the treatment of glaucoma and ocular hypertension. Of note, another ROCK inhibitor, Y-27632, is being evaluated for the treatment of corneal epithelial wound healing; published results in primate animal models show promise. Earlier issues and current iterations Pilocarpine was the only other drug developed to work in the trabecular meshwork, but the multitude of issues with the compound included 4 times daily dosing. It was also not well tolerated, was cataractogenic, and irritated the eye. "Pilocarpine fell by the wayside in use because of all its problems," Dr. Bacharach said. Most of the early reports on ROCK inhibitors coupled good results with some issues, including tolerability and hyperemia. Initial reports indicated the ROCK inhib- itors could decrease IOP by about 4 mm Hg, which may make them more of an adjunctive treatment than a first-line therapy. "In the current studies, the hy- peremia lasts about 3–4 hours, and that tends to be when the patient is sleeping," Dr. Bacharach said, since the drug is dosed once daily. Over the course of developing Rhopressa, it averages a 6 mm Hg drop, he said. "It's an important standalone product, but the Roclatan results were more impressive," he said. In the phase 2b studies, Roclatan lowered mean diurnal IOP from 25.1 mm Hg at baseline to 16.5 mm Hg on day 29, which is about 2 mm Hg greater than what latanoprost can accomplish on its own. "You would expect those prod- ucts to be complimentary—one works in the uveoscleral pathway and one in the trabecular mesh- work, so they're not overlapping mechanisms of action. Traditionally, when we've added a second or third medication the MOA is different, but they do not address trabecular outflow," Dr. Bacharach said. When Roclatan was compared to latanoprost alone, 50% of the subjects in the Roclatan arm and 28% of the subjects in the lata- noprost arm had at least a 35% decrease in mean diurnal IOP from baseline, and 46% of those in the Roclatan group had a mean diurnal IOP of 16 mm Hg or less (compared to only 18% of the latanoprost group), a press release noted. Further, there were no abnormal responses in heart rate or blood pres- sure with either drug, Dr. Bacharach said. Richard L. Lewis, MD, in pri- vate practice in Sacramento, Calif., and ASCRS outgoing president, said the data suggested specialists are "on the verge of a true breakthrough in IOP-lowering agents for the treat- ment of glaucoma." Beyond just open-angle glau- coma, Dr. Bacharach thinks ROCK/ NET inhibitors may have a role to play in treating low pressure or even angle closure glaucoma. "If you could effectively reduce episcleral venous pressure, then you might be able to really help people to have low tension glaucoma," he said. In the phase 2b studies, latano- prost worked better in a subgroup of patients with higher baseline IOPs, but for those with lower baseline levels (between 22 mm Hg and 36 mm Hg), Rhopressa worked just as well "clinically and statistically," he said. "What's great and promising about this particular ROCK inhibitor is that it reduced IOP by 39% and episcleral venous pressure by 35% in a rabbit eye study," he added. 1 "The reduction in episcleral venous pressure accounted for 42% of the measured reduction in IOP." EW Reference 1. Kiel JW, Kopczynski C. Effect of AR-13324 on episcleral venous pressure (EVP) in Dutch belted rabbits. Poster presented at: Associa- tion for Research in Vision and Ophthalmology. May 4–8, 2014; Orlando, Fla. Editors' note: Dr. Bacharach has financial interests with Aerie Pharma- ceuticals and Amakem (Diepenbeek, Belgium). Dr. Lewis has financial interests with Aerie Pharmaceuticals. Contact information Bacharach: jb@northbayeye.com Lewis: rlewiseyemd@yahoo.com Rho-kinase inhibitors offer promise in glaucoma treatment In the news: Rhopressa may have second disease-modifying MOA R hopressa may block the effect of fibrosis-promoting proteins on cells of the trabecular meshwork, a tissue that helps maintain normal pressure in the eye, developer Aerie Pharmaceuticals (Irvine, Calif.) said in a press release about data presented at a recent conference. Specifically, the research found that Rhopressa (a Rho- kinase and norepinephrine transporter inhibitor) suppressed the activity of profibrotic proteins, TGF-beta 2 and CTGF, on human trabecular meshwork cells in an in vitro model. This is "the first study to show that Rhopressa, a novel once-daily, triple-action eye drop that lowers IOP in glaucoma patients, has the potential to modify the course of the disease by arresting fibrosis," Aerie said. EW

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