ABSTRACT
PURPOSE: Intraocular pressure (IOP) reduction is key to controlling primary open angle glaucoma (POAG). Pharmacotherapies for POAG or ocular hypertension (OHT) commonly lower IOP by increasing uveoscleral outflow or decreasing aqueous humor production. Netarsudil (Rhopressa), a Rho kinase inhibitor, reduces IOP by improving trabecular outflow facility, which is reduced in POAG. We investigated the effects of netarsudil on aqueous humor dynamics in patients with POAG or OHT. DESIGN: Double-masked, randomized, vehicle-controlled, Phase 2 trial. METHODS: Netarsudil 0.02% was instilled in 1 eye and vehicle into the contralateral eye of 20 patients once daily in the morning for 7 days. The primary endpoint was change in mean diurnal outflow facility on day 8 versus that on day 1 (baseline). Outflow facility was measured by using Schiøtz tonography, IOP by pneumotonometry, and episcleral venous pressure (EVP) by automated venomanometry. RESULTS: Eighteen patients (90%) completed the study. Mean diurnal outflow facility increased 0.039 versus 0.007 µL/min/mm Hg from baseline in the netarsudil- and the vehicle-treated groups, respectively (P < .001 vs. baseline for netarsudil), a treatment difference of 0.03 µL/min/mm Hg (P ≤ .001). Mean diurnal IOP change from baseline at day 8 was -4.52 mm Hg for netarsudil versus -0.98 mm Hg for vehicle, a treatment difference of -3.54 mm Hg (P < .0001). Mean diurnal EVP change from baseline was -0.79 mm Hg in the netarsudil-treated group versus 0.10 mm Hg for vehicle, a treatment difference of -0.89 mm Hg (P < .001). All patients reporting an adverse event reported conjunctival hyperemia of mild or moderate severity. CONCLUSIONS: Netarsudil acts on the conventional outflow pathway, both proximal and distal, to significantly reduce IOP in POAG and OHT by improving trabecular outflow facility and decreasing EVP.
Subject(s)
Aqueous Humor/metabolism , Benzoates/therapeutic use , Glaucoma, Open-Angle/drug therapy , Protein Kinase Inhibitors/therapeutic use , Trabecular Meshwork/drug effects , beta-Alanine/analogs & derivatives , Administration, Ophthalmic , Adult , Aged , Double-Blind Method , Female , Glaucoma, Open-Angle/metabolism , Humans , Intraocular Pressure/drug effects , Male , Middle Aged , Ocular Hypertension/drug therapy , Ocular Hypertension/metabolism , Ophthalmic Solutions , Tonometry, Ocular , Trabecular Meshwork/metabolism , beta-Alanine/therapeutic use , rho-Associated Kinases/antagonists & inhibitorsABSTRACT
PURPOSE: To compare the ocular hypotensive efficacy and safety of a once-daily (pm) fixed-dose combination (FDC) product containing netarsudil 0.02% and latanoprost 0.005% with monotherapy with netarsudil or latanoprost. Netarsudil is a Rho kinase inhibitor that lowers intraocular pressure (IOP) primarily by increasing trabecular (conventional) outflow. Latanoprost is the most frequently prescribed of the prostaglandin analogs, which lower IOP primarily by increasing uveoscleral outflow. DESIGN: Three-month, double-masked, randomized (1:1:1), phase 3, superiority study. PARTICIPANTS: Patients had unmedicated IOP > 20 to <36 mmHg at 8:00 am and met other standard criteria for open-angle glaucoma and ocular hypertension. METHODS: Randomization to once-daily (pm) netarsudil/latanoprost FDC, netarsudil, or latanoprost for 3 months. MAIN OUTCOME MEASURES: Mean IOP at 8:00 am, 10:00 am, and 4:00 pm at week 2, week 6, and month 3 (intent-to-treat). Statistical superiority was concluded if the P value for the comparison of netarsudil/latanoprost FDC with each component was <0.05 and the difference in mean IOP (netarsudil/latanoprost FDC minus comparator) was <0 for all time points at all visits. Safety was recorded throughout the treatment period. RESULTS: A total of 750 patients were enrolled, with 90.2%, 89.4%, and 94.4% completing 3 months of treatment with netarsudil/latanoprost FDC, netarsudil, and latanoprost, respectively. Least-squares mean treated IOP ranged from 15.3 to 16.5 mmHg for netarsudil/latanoprost FDC, 17.4 to 19.8 mmHg for netarsudil, and 17.1 to 18.1 mmHg for latanoprost. Netarsudil/latanoprost FDC met the criteria for superiority to each active component at all 9 time points (all P < 0.0001), lowering IOP by an additional 2.2 to 3.3 mmHg versus netarsudil and an additional 1.5 to 2.4 mmHg versus latanoprost. At month 3, the proportion of patients achieving mean diurnal IOP ≤ 15 mmHg was 42.1% for netarsudil/latanoprost FDC, 15.8% for netarsudil, and 18.3% for latanoprost. No treatment-related serious adverse event (AE) was observed. Treatment-related systemic AEs were minimal. The most frequent ocular AE was conjunctival hyperemia (netarsudil/latanoprost FDC, 54.5%; netarsudil, 42.7%; latanoprost, 22.3%), which was generally mild. CONCLUSIONS: Once-daily netarsudil/latanoprost FDC demonstrated IOP reductions that were statistically and clinically superior to its individual components at all 9 time points over 3 months, with tolerable ocular safety. This FDC offers a reduced treatment burden that may improve adherence and clinical outcomes.
