Eyeworld

EW GLAUCOMA 78 by Tony Realini, M.D., M.P.H. Rho kinase inhibitors: The next new drug class for glaucoma therapy? T he 1990s were an unprece- dented decade for glau- coma therapy. More than 15 years had passed since the advent of topical beta- blockers when suddenly the glau- coma marketplace was inundated by innovation. In the span of just a few years, topical carbonic anhydrase in- hibitors, selective alpha adrenergic agonists, and prostaglandin ana- logues 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 cur- rent 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 contrac- tion by reducing the phosphoryla- tion of non-muscle myosin," she explained. "This activity reduces re- sistance 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 Japan- ese company Kowa, "K-115 signifi- cantly 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 op- timal concentration and dosing. In a small (n=28) crossover study evaluating 24-hour IOP reduc- tion using several concentrations of K-115 dosed twice daily, peak IOP re- ductions of 5-6 mm Hg were ob- served with the 0.4% concentration, said Tetsuya Yamamoto, M.D., Gifu University, Japan. "There was a sta- tistically 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 differ- ent 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 signifi- cant 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 stud- ied the efficacy and safety of com- pound AR12286 from Aerie Pharma- ceuticals (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 day- time time points were observed for once-daily dosing of AR12286, com- pared 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 differ- ence was statistically significant in favor of latanoprost. Safety The safety profile of rho kinase in- hibitors appears to be quite favor- able. 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%) pa- tients 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 dos- ing at a higher concentration of AR12286 once daily in the evening can produce effective control of IOP the following day while allowing oc- ular 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 February 2011 September 2011 An update continued from page 77 Lewis. "That's probably the most ex- citing part. For so many years, we've only had trabs and tubes, and now we're branching out. We're going to be able to someday treat glaucoma patients with specific treatments, in- stead of lumping everyone into tra- beculectomy. It's a big step in the right direction." EW Editors' note: Dr. Lewis has financial interests with Alcon (Fort Worth, Texas), Glaukos (Laguna Hills, Calif.), iScience (Menlo Park, Calif.), and Sanofi-aventis (Bridgewater, N.J.). Dr. Noecker has financial interests with Alcon, Allergan (Irvine, Calif.), and Endo Optiks (Little Silver, N.J.). Contact information Lewis: rlewiseyemd@yahoo.com Noecker: noeckerrj@gmail.com Rho kinase inhibitors lower IOP by enhancing conventional outflow through the trabecular meshwork Source: National Eye Institute, National Institutes of Health

• Cover