Rho kinase inhibitors: The next new drug class for glaucoma therapy?


by Tony Realini, M.D., M.P.H.


Rho kinase inhibitors lower IOP by enhancing conventional outflow through the trabecular meshwork Source: National Eye Institute, National Institutes of Health


The 1990s were an unprecedented decade for glaucoma therapy. More than 15 years had passed since the advent of topical beta-blockers when suddenly the glaucoma marketplace was inundated by innovation. In the span of just a few years, topical carbonic anhydrase inhibitors, selective alpha adrenergic agonists, and prostaglandin analogues burst onto the scene, forever changing the therapeutic landscape for IOP reduction.

Aside from a few formulation changes and a fixed combination of existing drugs, the last 15 years has been another innovation drought for glaucoma drug development.

That may be about to change. Several companies are developing molecules in a new class called rho kinase inhibitors. These drugs offer efficacy, safety, and a mechanism of action that could expand our current clinical drug armamentarium.



Mechanism of action
Rho kinase inhibitors lower IOP by enhancing conventional outflow through the trabecular meshwork, according to Janet Serle, M.D., Mt. Sinai School of Medicine, New York. This would be the first class of drugs to work at the level of the trabecular meshwork since the introduction of pilocarpine in 1877.

"They reduce cellular contraction by reducing the phosphorylation of non-muscle myosin," she explained. "This activity reduces resistance to aqueous outflow in the trabecular meshwork and lowers IOP."

In a rabbit study presented at the 2011 Association for Research in Vision and Ophthalmology meeting conducted on K-115, the candidate molecule being developed by Japanese company Kowa, "K-115 significantly increased outflow facility with no effect on aqueous humor production or uveoscleral outflow," said Ken Mizuno, Ph.D., Kowa.

Efficacy
K-115 has been evaluated in several early-phase trials to determine its safety, preliminary efficacy, and optimal concentration and dosing.

In a small (n=28) crossover study evaluating 24-hour IOP reduction using several concentrations of K-115 dosed twice daily, peak IOP reductions of 5-6 mm Hg were observed with the 0.4% concentration, said Tetsuya Yamamoto, M.D., Gifu University, Japan. "There was a statistically significant reduction in IOP between K-115 0.4% and placebo until 7 hours after dosing." These data may suggest the need for more than twice daily dosing or a different formulation.

In a larger (n=210) parallel group study, following 8 weeks of twice daily dosing with K-115 0.4%, mean IOP was reduced by 3-4.5 mm Hg compared to placebo, said Hidenobu Tanihara, M.D., Kumamoto University, Japan. "The IOP-lowering of 0.4% K-115 at the 8-week visit was statistically significant at all time points compared to placebo," he said.

To evaluate the potential for rho kinase inhibitors to be dosed once daily, Dr. Serle and coworkers studied the efficacy and safety of compound AR12286 from Aerie Pharmaceuticals (Bridgewater, N.J.).

In a moderately sized (n=217) parallel group trial, two regimens of AR12286 (0.25% twice daily and 0.5% once daily at night) were compared to evening dosing of latanoprost for 28 days.

Diurnal IOP reductions ranging from 2.9 to 6.1 mm Hg across daytime time points were observed for once-daily dosing of AR12286, compared to reductions ranging from 4.4 to 7.7 mm Hg for latanoprost, Dr. Serle said.

"Dosed once daily, mean diurnal IOP for AR12286 0.5% was within 1 mm Hg of latanoprost," she said, adding that this small difference was statistically significant in favor of latanoprost.

Safety
The safety profile of rho kinase inhibitors appears to be quite favorable. The most common drug- related adverse event observed in all studies was conjunctival hyperemia. In the study by Dr. Yamamoto and colleagues, nearly all (96.4%) patients receiving K-115 0.4% twice daily exhibited hyperemia, although all cases were graded as mild to moderate and none were severe.

Similarly, in the study by Dr. Tanihara and coworkers, two-thirds of patients receiving K-115 0.4% twice daily had hyperemia; again, all cases were mild to moderate in severity.

Hyperemia appears to be a class effect of rho kinase inhibitors. Dr. Serle's evaluation of AR12286 also revealed significant hyperemia that was apparently dose-related. In the twice-daily dosing arm, 30% of patients experienced hyperemia, while in the once-daily arm and the latanoprost arm, the rate was closer to 10%.

"These results confirm that dosing at a higher concentration of AR12286 once daily in the evening can produce effective control of IOP the following day while allowing ocular hyperemia to resolve during sleep," she said.

Potential therapeutic impact
Assuming one or more rho kinase inhibitors gains FDA approval, where will this class of drugs fit into our current treatment algorithm? "The initial data from the rho kinase trials do not suggest that this class of drugs will surpass the prostaglandin analogues in efficacy," said Robert Fechtner, M.D., New Jersey Institute for Ophthalmology and Visual Science, Newark, "but they may provide a safe alternative for monotherapy. Local hyperemia appears to be the limiting adverse effect."

He added, "It is intriguing to have the possibility of a modern trabecular meshwork outflow drug."

Dr. Fechtner also speculated on the additivity of these drugs to prostaglandin therapy, as to date there has been little consensus on the optimal adjunctive therapy for patients needing more than a prostaglandin. "The mechanism of action for the prostaglandins is uveoscleral outflow. Will two outflow drugs with different mechanisms show additivity?"

Editors' note: The physicians mentioned have no financial intersts related to their comments.


Contact information
Fechtner: fechtner@umdnj.edu
Mizuno: kmizuno@kowa.co.jp
Realini: realinia@wvuh.com
Serle: jserle@optonline.net
Tanihara: tanihara@pearl.ocn.ne.jp



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