EyeWorld India December 2014 Issue

December 2014 44 EWAP GLAUCOMA by Tony Realini, MD, MPH Glaucoma drug innovation Prostaglandins have set the bar high for new innovations in glaucoma therapy because of excellent efficacy I n 1978, timolol maleate was first approved by the U.S. Food and Drug Administration (FDA) and forever altered the glaucoma therapeutic landscape. Timolol shifted the paradigm from pilocarpine, epinephrine and oral acetazolamide, bringing glaucoma treatment from the dark ages into the light. Nearly two decades would pass before the next series of glaucoma drug innovations, starting with the approval of the first topical carbonic anhydrase inhibitor (dorzolamide) in 1994 and both the first prostaglandin (latanoprost) and the first alpha-2 adrenergic agonist for chronic use (brimonidine) in 1996. The paradigm shifted again, and timolol—once the shining star— became old news. Since then? Not so much—a few me-too drugs that offered little over the first-in-class prototypes and a handful of fixed combinations combining existing drugs with predictable efficacy and safety profiles. But no innovation, and certainly no new paradigm shifts. Nearly two decades later, we are overdue for the next round of innovation in IOP-lowering therapy. There are a few interesting compounds in development, but none are likely to materially change the therapeutic landscape. Why? Because prostaglandins work too well, are too safe, and are too convenient with once- daily dosing. The bar has been set extraordinarily high—and there may never come another drug that can beat the prostaglandin performance profile. Thus, it is perhaps not surprising that the best hopes for novel drug development in the near future are either augmentations of the prostaglandin platform or intended to serve as adjunctive therapy to prostaglandins. New possibilities Bausch + Lomb (Bridgewater, NJ, U.S.) is developing a compound called latanoprostene bunod, which—as the name implies—is a modified version of latanoprost that also features a nitric oxide- donating moiety. It is currently in 2 separate clinical trials, named APOLLO and LUNAR. Rho kinase inhibitors In the trabecular meshwork, activation of the rho kinase pathway leads to contraction of the actin and myosin structural skeleton of the extracellular matrix, decreasing aqueous outflow, said Paul Kaufman, MD , University of Wisconsin, Madison, Wisc., U.S. Conversely, inhibition of the rho kinase pathway leads to relaxation of the actin-myosin system and increases aqueous outflow through the meshwork. “This is the first class of drugs that has its primary mechanism of action in the trabecular meshwork,” he said, “and there are currently five rho kinase inhibitors in clinical trials.” Average IOP reductions in phase 2 studies of rho kinase inhibitors demonstrate that they lower IOP on average between 4 and 6 mmHg when used as monotherapy, Dr. Kaufman said. This modest performance is not likely to significantly alter the first line IOP-lowering landscape. Recognizing this, at least one drug company has begun exploring fixed combination products containing a rho kinase inhibitor. One of these combines a rho kinase inhibitor with latanoprost and, if approved, would be the first latanoprost-containing fixed combination product in the U.S. marketplace. Marijuana “There are cannabinoid receptors in the eye,” said Henry Jampel, MD , Johns Hopkins University, Baltimore, Md., U.S., “and marijuana has been of interest for IOP reduction in glaucoma for decades.” The problem is one of drug delivery. “Topical formulations have been unable to penetrate into the eye,” he said. Likewise, trans- alveolar delivery (via smoking) produces only modest IOP reductions of impractically short duration. The issue of medical marijuana for glaucoma therapy has been made relevant recently by the legalization of recreational marijuana use in Washington and Colorado, as well as the approval of medical marijuana use in 22 states and the District of Columbia. A recent study evaluated attitudes toward marijuana use by glaucoma patients conducted by David Belyea, MD , and colleagues at George Washington University in D.C. In this study, 204 glaucoma patients completed a survey that included items related to their perceptions toward marijuana and their intentions to use marijuana for glaucoma. The results showed that prior use of marijuana, false beliefs about marijuana, perceptions that marijuana should be legal, and lower satisfaction with glaucoma management are significant predictors to use marijuana. Surprisingly, neither glaucoma diagnosis nor the severity of glaucoma disease were found to be correlated with intentions to