Rho-kinase shows potential

If approved, this drug class will be the first to target the trabecular meshwork

Current glaucoma drug classes—beta blockers, carbonic anhydrase inhibitors, and prostaglandins—lower IOP by either suppressing the formation of aqueous humor or enhancing uveoscleral outflow through the ciliary muscle, but they do not target the trabecular meshwork.
A novel drug class, Rho-kinase and Rho-GTPase inhibitors, may offer clinicians a way to target the diseased tissue directly.
“Trabecular meshwork relaxation may lead to increased aqueous outflow,” said P. Vasanth Rao, Ph.D., associate professor, Department of Ophthalmology, Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, N.C. “Biochemically, that’s what happens.” Dr. Rao’s lab is the primary U.S. research center for Rho-kinase use in the eye.
Rho-kinase (ROCK) is a downstream effector of a small-G protein Rho. In preliminary animal studies, it appeared to increase aqueous outflow by widening the extracellular spaces, Dr. Rao said.
Several pharmaceutical companies are pursuing development of this drug class, although the majority are in early phase trials. Among them are Santen (Osaka, Japan), Kowa (Research Triangle Park, N.C.) and Novartis/Senju (Basel, Switzerland and Osaka, Japan).
The furthest along, Kowa’s K-115, was found to have a maximum IOP-decreasing rate higher than latanoprost in monkeys, and an intravitreal formulation exhibited significant reduction of retinal ganglion cell loss in rats. To date, safety has not been an issue in the ophthalmic formulation.
At the time of the Novartis/Senju collaboration, Novartis said the compound (Y39983) “could become the leading treatment for patients with glaucoma.”
“The big pharmaceutical companies are working on ROCK, but not for ophthalmic reasons,” Dr. Rao said. Most are developing the drug class for systemic hypertension, he said. In fact, several blockbuster statin drugs are ROCK inhibitors (see sidebar).

Mechanism of action

The inhibition of Rho-kinase increases aqueous humor outflow through the trabecular meshwork outflow pathway, studies have shown. Further, early clinical work has indicated ROCK and Rho-GTPase inhibitors have been shown to enhance ocular blood flow, retinal ganglion cell survival, and axon regeneration, Dr. Rao said.
According to Dr. Rao, “Another interesting aspect of the ROCK inhibitors is that they may be able to protect ganglion cells. If a drug is approved, not only would it lower IOP, but it could protect the ganglion cells. Human data has shown us that people on statins have a lower incidence of glaucoma.”
Dr. Rao cited Japanese studies that found patients prescribed statins would have systemically lower levels of IOP, and his lab studies have replicated those experiments.
“David L. Epstein, M.D., and I started to ask what the connection between the statins and the lowered incidence of glaucoma was,” Dr. Rao said. That led to the current work on ROCK inhibitors.
Dr. Rao’s hypothesis was “quite opposite” from Dr. Epstein’s, he said. “I was theorizing about agents that can relax instead of contract tissue. The current thought at the time from Dr. Epstein and others was that contraction would lower IOP. So when we both thought about relaxation and the downstream protein of Rho-kinase, it started to make sense. ROCK has been demonstrated to relax tissue by working on myosin and myosin II.”
Drs. Epstein and Rao then hypothesized about de-activating Rho on a molecular level to improve aqueous outflow. “It results in changing the cell shape,” Dr. Rao said. “We’re still working very actively on that area. Our funding is more in cell biology.”
Dr. Rao cited more than seven studies where primary cultures of trabecular meshwork and ciliary muscle cells treated with various ROCK inhibitors revealed dose-dependent and reversible changes in cell morphology. He added topical, intracameral, and intravitreal injection of different ROCK inhibitors in animal models have demonstrated to induce “very rapid and long-lasting decreases in IOP, starting within 30 minutes of administration and lasting for more than six hours.”

Clinical relevance

“The bottom line is ROCK looks like a main target, and when it’s de-activated, it relaxes the cell so the trabecular output increases,” Dr. Rao said. “We still don’t know how drainage is enhanced through these properties.”
He noted that Japanese researchers, working independently from Dr. Rao’s lab, found the same conclusions about ROCK inhibitors. The separate studies have fueled interest in developing the compound for ophthalmic purposes, Dr. Rao believes.
“We may not know how prostaglandins work, but what’s interesting here is that we do know how ROCK inhibitors work and we can explain the reaction. It’s truly targeted therapy on a molecular level. It’s very attractive for clinicians and researchers because we’re able to target one single molecule, and that may lead us to design more potent inhibitors,” Dr. Rao said.
And for the statins currently approved by the U.S. Food and Drug Administration? “There could be a role for them as an ocular drug,” Dr. Rao said.

Editor’s note: Dr. Rao does not have direct financial interest in the products mentioned, but does cite a patent on Rho-kinase through the university.

Contact Information
Rao: 919-681-5883; rao00011@mc.duke.edu