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Rho kinase inhibitors getting to the heart of the matter


Glaucoma drug therapy continues to evolve with Rho kinase inhibitors that specifically target glaucomatous abnormalities such as trabecular meshwork outflow.

Rho kinase inhibitors-the newest drugs introduced for treating glaucoma-"get to the heart of the matter” by targeting specific glaucomatous abnormalities, such as trabecular meshwork outflow, said Yvonne Ou, MD.

Previously released glaucoma drugs have instead lowered IOP by increasing uveoscleral outflow or decreasing the production of aqueous humor.

Rho kinases, ROCK 1 and 2, are present throughout the body as well as in the trabecular meshwork, and they are instrumental in actomyosin contractility.

Overall, they increase cellular stiffness by modulating microtubules, actin filament disassembly, and forming focal adhesion complexes, said Dr. Ou, associate professor of ophthalmology, and co-director of the glaucoma service, University of California, San Francisco.

Dr. Ou’s mentor-David Epstein, MD, whom she credits with ground-breaking insights into treatments for glaucoma-challenged ophthalmic researchers to remain focused on the main goal in glaucoma research, i.e., new treatments must focus on the diseased trabecular meshwork and be specific to the optic nerve in order to address the basic abnormalities in primary open-angle glaucoma.

He emphasized that none of the treatments available at the time of his comments addressed glaucomatous abnormalities.

Dr. Epstein’s subsequent research and his collaboration with cell biologists and with Paul Kaufman, MD, and Vasantha Rao, PhD, made discoveries that led to the development of Rho kinase inhibitors as an outflow drug, which acts directly on the trabecular meshwork.

Rho kinase inhibitors answered Dr. Epstein’s challenge in that they focus on a glaucomatous abnormality.

Aerie Pharmaceuticals announced in March 2019 that the FDA approved Rocklatan (netarsudil and latanoprost ophthalmic solution) 0.02%/0.005% to reduce elevated IOP in patients with open-angle glaucoma or ocular hypertension. The once-daily eye drop is a fixed-dose combination of latanoprost and netarsudil.

Netarsudil 0.02% ophthalmic solution (Rhopressa, Aerie Pharmaceuticals), a ROCK inhibitor and norephinephrine transport (NET) inhibitor, lowers IOP by relaxing the trabecular meshwork and thus increasing the trabecular outflow. In addition to acting on the trabecular meshwork, the ROCK/NET inhibitor has multiple mechanisms of action in that it also decreases both the episcleral venous pressure and aqueous production.

“Most of our glaucoma drugs either increase uveoscleral outflow or decrease production of aqueous humor,” Dr. Ou said. “Until recently, no drug has been available that works directly on trabecular meshwork outflow.”

In addition, a recent addition to the armamentarium that targets the trabecular meshwork is latanoprostene bunod 0.024% ophthalmic solution (Vyzulta, Bausch + Lomb). This drug is a novel nitric oxide (NO)-donating prostaglandin prostaglandin F2-alpha analog. NO is thought to relax the trabecular meshwork and increase trabecular outflow, while the latanoprost component increases uveoscleral outflow.

Clinical studies

Dr. Ou recounted a clinical trial in which various doses of netarsudil (0.01% and 0.02%) were compared with latanoprost 0.005% (Xalatan, Pfizer). The study found that netarsudil was about 1 mm Hg less effective than latanoprost. In a subgroup of patients in whom the IOP was 26 mm Hg or less, netarsudil 0.02% was noninferior to latanoprost. This study was published in the British Journal of Ophthalmology (2016;100:339-344).

The ROCKET phase III clinical studies compared netarsudil 0.02% dosed at nighttime or twice daily with timolol twice daily. In the four studies, the investigators reported in the American Journal of Ophthalmology (2018;186:116-22) that netarsudil was noninferior to timolol in three groups of patients with IOPs less than 25, 27, and 30 mm Hg.

The mean IOP decreases ranged from 3 to 4.5 mm Hg; greater decreases were seen with netarsudil dosed twice daily but there were side effects such as hyperemia (about 50% of patients), petechial hemorrhages (13% to 15%), and corneal verticillata (5.4% to 9%), which resulted in patient discontinuation of netarsudil up to 30% in the twice daily group and 10% to 12% in the once daily group. Most cases of hyperemia were mild; all adverse effects resolve with drug discontinuation and vision was not adversely affected.

Moving forward

“Rho kinase inhibitors are specific for targeting glaucomatous abnormalities by targeting the trabecular outflow pathway, relaxing the trabecular meshwork, and increasing conventional outflow,” Dr. Ou said.

“They have novel mechanisms of action. The fixed-combination of netarsudil and latanoprost lowers IOP approximately by an additional 2 to 3 mm Hg compared with netarsudil alone.  The side effects include conjunctival hyperemia, petechial hemorrhages, and corneal verticillata. There are no systemic side effects,” Dr. Ou concluded.

Editor’s Note: This article was written prior to the March 2019 approval of netarsudil and latanoprost ophthalmic solution 0.02%/0.005% (Rocklatan, Aerie Pharmaceuticals) and has since been updated to reflect the announcement.


Yvonne Ou, MD
E: yvonne.ou@ucsf.edu
Dr. Ou is a consultant and advisor to Merck & Co. Inc.

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