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EW GLAUCOMA 66 October 2017 by Tony Realini, MD, MPH baseline IOP <25 mm Hg," he said. In fact, netarsudil was non-inferior to timolol in eyes with baseline IOP ranging from 23 to 30 mm Hg. "The most common ocular adverse event was conjunctival hyperemia, seen in 42.2% of ne- tarsudil-treated eyes and 6.7% of timolol-treated eyes, and was graded as mild in 85% of cases," Dr. Khouri said. Other adverse events occurring in 5–12% of subjects included con- junctival petechial hemorrhages and corneal verticillata. "The latter—sim- ilar to those seen with diuretics such as spironolactone—are thought to arise due to phospholipidosis, were asymptomatic in these subjects, and did not affect visual acuity," Dr. Khouri said. Circadian IOP control In recent years, the role of 24-hour IOP control has become a hot topic in glaucoma management, par- ticularly since most patients with glaucoma experience their peak IOP at night while asleep. "Large diurnal fluctuations in IOP are an independent risk factor for progression in patients with glaucoma," said James Peace, MD, Inglewood, California. "Peak IOP usually occurs at night, and many IOP-lowering medications have little or no efficacy during the nocturnal period." He conducted a small trial of 12 subjects with open angle glaucoma or ocular hypertension, randomized in a 2:1 ratio to netarsudil or place- bo. Subjects underwent 24-hour IOP measurement at baseline and after 1 week of treatment with assigned therapy. IOP was measured using the Perkins handheld applanation tonometer and was performed with patients in the habitual position— sitting during waking hours and supine during sleeping hours. Baseline mean 24-hour IOP was 22.6 mm Hg and was slightly higher in the nocturnal than diurnal period (23.1 versus 22.1 mm Hg, respective- ly). After 1 week of therapy, mean 24-hour IOP in netarsudil-treated eyes was reduced by 3.5 mm Hg in both the diurnal and nocturnal Experts discuss the rho kinase inhibitor netarsudil M ore than 20 years have passed since the last major innovation in glaucoma medical therapy. We are now poised for a series of new drugs to potentially achieve FDA clearance in 2017. Among these is netarsudil, a novel compound in the first new class of IOP-lowering drugs since latanoprost debuted in 1996. Two products containing netarsudil—one a single agent and the other a fixed combination with latanoprost— are completing clinical trials and awaiting FDA evaluation. This was a subject of discussion at the 2017 As- sociation for Research in Vision and Ophthalmology annual meeting. Netarsudil monotherapy According to Albert S. Khouri, MD, Rutgers University, Newark, New Jersey, "Netarsudil is in late-stage clinical development for the reduc- tion of IOP in eyes with open angle glaucoma or ocular hypertension." Netarsudil is thought to have three distinct mechanisms of action. "Through its inhibition of the enzyme rho kinase, netar- sudil relaxes smooth muscle in the trabecular meshwork and reduces episcleral venous pressure, both of which effectively increase trabecular outflow," Dr. Khouri said. "Addition- ally, through inhibition of norepi- nephrine transporter, netarsudil is thought to reduce aqueous produc- tion by the ciliary body." In Rocket 4, a Phase 3 clinical trial, subjects with open angle glau- coma or ocular hypertension and untreated IOP between 21 and 29 mm Hg were randomized to treat- ment with either netarsudil dosed once daily or timolol 0.5% dosed twice daily. The primary outcome was IOP reduction assessed at nine time points: 8:00 a.m., 10:00 a.m., and 4:00 p.m. at weeks 2, 6, and 12. "Netarsudil demonstrated non-inferiority to timolol in the primary efficacy analysis through 3 months of follow-up in eyes with Shaking up the glaucoma drug market Presentation spotlight periods. The placebo group, in con- trast, had diurnal and nocturnal IOP reductions of 0.4 mm Hg and 0.9 mm Hg, respectively. "Netarsudil maintained consis- tent 24-hour IOP reduction through- out the 24-hour period," Dr. Peace said. Netarsudil/latanoprost fixed combination In addition to a single agent formu- lation, a fixed combination of netar- sudil and latanoprost is in late-stage clinical development. "Mercury 1 is a Phase 3 clinical trial of the netarsudil/latanoprost fixed combination," said Janet Serle, MD, Icahn School of Medi- cine, Mt. Sinai, New York. "In this trial, patients with open angle glau- coma or ocular hypertension, with IOP after washout >21 mm Hg and <36 mm Hg, were randomized 1:1:1 to receive the fixed combination of netarsudil and latanoprost or each of the components separately." The primary outcome was IOP reduction. "IOP was assessed at each of nine IOP time points, at 8:00 a.m., 10:00 a.m. and 4:00 p.m. at 2, 6, and 12 weeks after initiating therapy," she said. "At each of the nine time points, IOP was significantly lower in the fixed combination group than in either of the component groups (p<0.001)." Also at each time point, the fixed combination lowered IOP by 1.3 to 3.0 mm Hg more than either component dosed individually. "Overall, 61% of patients receiv- ing the fixed combination achieved an IOP of 16 mm Hg or less, and 33% achieved an IOP of 14 mm Hg or less," said Dr. Serle. "In terms of percent IOP reduction, 65% of patients receiving the fixed com- bination achieved IOP reductions of 30% or more, and 35% achieved reductions of 40% or more." There were no serious adverse events, she said, and there was a 15% discontinuation rate in the fixed combination group, due most- ly to non-serious adverse events. Conjunctival hyperemia was seen in 53.4% of subjects receiving the fixed combination, compared to 41% re- ceiving netarsudil monotherapy and 14% receiving latanoprost therapy. The hyperemia was typically graded as mild in severity. Small, petechial conjunctival hemorrhages were seen in 10.5% of subjects receiving the fixed com- bination, compared to 13.9% and 0.4% of subjects receiving netar- sudil and latanoprost, respectively. "The cause of these hemorrhages is unknown, and they appear to be clinically insignificant aside from their cosmetic appearance," Dr. Serle said. Practical impact Dr. Khouri said that while frequency of side effects with netarsudil seems higher than with comparators in clinical trials, these are typically mild in severity and infrequently lead to discontinuation. "Netarsudil will be a significant addition to our current treatment options," he said. "It offers several mechanisms to lower IOP and will benefit many patients with glaucoma." Dr. Serle offered a similar opinion about the fixed combina- tion: "The netarsudil/latanoprost fixed combination demonstrated statistically significantly greater IOP reductions at all nine time points compared to either of its component drugs and will be a beneficial addi- tion for our glaucoma patients." EW Editors' note: Dr. Khouri has financial interests with Aerie Pharmaceuticals (Irvine, California), Allergan (Dublin, Ireland), and New Jersey Health Foun- dation (New Brunswick, New Jersey). Dr. Serle has financial interests with Aerie Pharmaceuticals, Allergan, Baus- ch + Lomb (Bridgewater, New Jersey), Inotek Pharmaceuticals (Lexington, Massachusetts), Ocular Therapeutix (Bedford, Massachusetts), and Pfizer (New York). Contact information Khouri: albert.khouri@rutgers.edu Peace: drjpeace@pacbell.net Serle: jserlemd@gmail.com

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