The Effects of Netarsudil Ophthalmic Solution on Aqueous Humor Dynamics in a Randomized Study in Humans

Abstract

Purpose: Netarsudil, an inhibitor of Rho kinase and a norepinephrine transporter, has been shown to lower elevated intraocular pressure (IOP) in controlled studies of patients with open-angle glaucoma and ocular hypertension, and in healthy volunteers. The mechanism of this ocular hypotensive effect in humans is unknown.Methods: The objective of this study was to evaluate the effect of netarsudil 0.02% on aqueous humor dynamics (AHD) parameters. In this double-masked, vehicle-controlled, paired-eye comparison study, 11 healthy volunteers received topical netarsudil ophthalmic solution 0.02% or its vehicle once daily for 7 days (morning dosing). The primary endpoints were the change in AHD parameters, compared between active and vehicle-treated eyes.Results: In netarsudil-treated eyes, diurnal outflow facility increased from 0.27 ± 0.10 μL/min/mmHg to 0.33 ± 0.11 μL/min/mmHg (+22%; P = 0.02) after 7 days of treatment. In placebo-treated eyes, diurnal outflow facility did not significantly change (P = 0.94). The difference between netarsudil and placebo eyes in diurnal change of outflow facility was 0.08 μL/min/mmHg (P < 0.001). Diurnal episcleral venous pressure (EVP) in netarsudil-treated eyes decreased from 7.9 ± 1.2 mmHg to 7.2 ± 1.8 (-10%; P = 0.01). Diurnal EVP was not significantly different between netarsudil- and placebo-treated eyes. There was a trend toward decreasing aqueous humor flow rate (-15%; P = 0.08). No treatment changes were seen in uveoscleral outflow rate.Conclusions: Once-daily dosing of netarsudil ophthalmic solution 0.02% lowered IOP through increasing trabecular outflow facility and reducing EVP. This suggests a combination of mechanisms that affect both the proximal and distal outflow pathways.

Fixed-Dose Combination of Netarsudil and Latanoprost in Ocular Hypertension and Open-Angle Glaucoma: Pooled Efficacy/Safety Analysis of Phase 3 MERCURY-1 and -2

“…Percentages are based on the number of patients (n) in a given treatment group for the safety population AE treatment emergent adverse event In the system organ class or preferred term, n is the number of patients with at least one adverse event; % is based on the number of patients (n) in a given treatment group for the safety population When reporting incidence, a patient was only counted once if they ever experienced an event within the system organ class or individual preferred term. System organ class and preferred term are based on Version 19.0 of the MedDRA coding dictionary DISCUSSION Netarsudil, a ROCK inhibitor, reduces IOP by novel mechanisms of action that lead to increased trabecular outflow [12][13][14][15][16]18]. In preclinical and human studies, the distinct mechanism of action of netarsudil has been demonstrated to involve increasing trabecular outflow by decreasing actomyocin-driven cellular contraction and reducing production of extracellular matrix proteins [12,19].…”

“…System organ class and preferred term are based on Version 19.0 of the MedDRA coding dictionary DISCUSSION Netarsudil, a ROCK inhibitor, reduces IOP by novel mechanisms of action that lead to increased trabecular outflow [12][13][14][15][16]18]. In preclinical and human studies, the distinct mechanism of action of netarsudil has been demonstrated to involve increasing trabecular outflow by decreasing actomyocin-driven cellular contraction and reducing production of extracellular matrix proteins [12,19]. Netarsudil was also shown to decrease episcleral venous pressure [12,18,19].…”

“…In preclinical and human studies, the distinct mechanism of action of netarsudil has been demonstrated to involve increasing trabecular outflow by decreasing actomyocin-driven cellular contraction and reducing production of extracellular matrix proteins [12,19]. Netarsudil was also shown to decrease episcleral venous pressure [12,18,19]. Latanoprost has a complementary mechanism of action, lowering IOP by increasing uveoscleral outflow, and is the most commonly prescribed prostaglandin analogue to treat elevated IOP [9].…”

“…Netarsudil, a Rho kinase (ROCK) inhibitor, was approved by the US Food and Drug Administration in December 2017 for reducing IOP in patients with OAG or OHT [10]. Netarsudil targets the underlying pathophysiology of elevated IOP, increased trabecular outflow resistance, and thereby increases trabecular outflow and reduces IOP [11][12][13][14][15][16]. Latanoprost, the most commonly prescribed prostaglandin analogue, has a complementary mechanism of action, lowering IOP by increasing uveoscleral outflow [9,17].…”

Genome-wide Expression Profiling and Pathway Analysis in Cyclic Stretched Human Trabecular Meshwork Cells

“…Even though dysfunction of the trabecular outflow pathway is responsible for elevated IOP, clinically, most of IOP-lowering medications target the unconventional outflow pathway or secretion. New medications targeting the predominant drainage pathway (the TM pathway) are in high demand, including two recently approved medications (8, 12, 13). Thus, rho kinase inhibitors and nitric oxide drugs are the results of research over the last 25 years that identified important regulatory processes in the trabecular outflow pathway (8).…”