Netarsudil for the Treatment of Open-Angle Glaucoma and Ocular Hypertension: A Literature Review

Abstract

Objective: To evaluate netarsudil’s role as first-line therapy for the treatment of open-angle glaucoma (OAG) and ocular hypertension (OHT). Data Sources: A literature search utilizing MEDLINE and CINAHL was performed using netarsudil and AR-13324 as keywords. Studies published from January 1970 to September 2020 were eligible. Study Selection and Data Extraction: For inclusion, articles were required to be published in English and participants enrolled in phase I, II, or III clinical trials. Articles were excluded if netarsudil was coformulated with another medication. Preclinical research, case reports, case series, review articles, citations without an abstract, and newsletters were excluded. Literature Review: The search retrieved 97 unique citations; 90 results were excluded, and 7 studies were included for analysis. Relevance to Patient Care and Clinical Practice: In all, 20 years elapsed between the Food and Drug Administration’s approvals of distinct medications to treat OAG. Existing first-line therapies target the uveoscleral pathway, which is responsible for a small amount of aqueous humor outflow. Rho kinase inhibitors target the trabecular pathway, which is responsible for 90% of aqueous humor outflow; thus, Rho kinase inhibitors may significantly reduce intraocular pressure and improve clinical outcomes for patients with OAG or OHT. Conclusions: Evidence demonstrates that netarsudil is inferior to prostaglandin analogues and noninferior to topical -blockers in the treatment of OAG and OHT. Hyperemia is a common adverse drug reaction, which often resolves after medication discontinuation. Additional phase III clinical trials and evidence-based guidelines are necessary to determine netarsudil’s position in OAG and OHT management.

Keywords: netarsudil, Rho kinase inhibitor, open-angle glaucoma, ocular hypertension, hyperemia, pharmacy

Objective

The objective of this review is to evaluate netarsudil’s role as first-line therapy for the treatment of open-angle glau- coma (OAG) and ocular hypertension (OHT).

Data Sources

An electronic literature search utilizing MEDLINE and CINAHL was performed. Netarsudil and AR-13324 were used as keyword terms. Studies written in English and pub- lished from January 1970 to September 2020 were consid- ered for this review. To be included, articles were required to be a phase I, II, or III clinical trial published as either an abstract or full-text article. Articles were excluded if netar- sudil was coformulated with another medication. Preclinical research conducted in animals, case reports, case series, review articles, citations without an abstract, and newslet- ters were excluded.

Study Selection and Extraction, and Literature Review
Epidemiology

Glaucoma is a condition of the eye that is characterized by elevated intraocular pressure (IOP) that, if left untreated, leads to permanent damage of the optic nerve. Serious sequelae include visual field loss and blindness. Glaucoma may be referred to as the “silent thief of sight” because,outside of insidious visual field loss, many patients are asymptomatic and present for care only after their disease has significantly progressed to the point of permanent vision loss. Conservative estimates suggest that almost 80 million patients across the globe may be diagnosed with glaucoma, and 11 million patients will suffer from bilateral blindness. Glaucoma may be further classified as either OAG or angle-closure glaucoma (ACG). OHT is a condition separate from glaucoma and is defined as the elevation of IOP above the normal range but where the optic nerve and vision are preserved. Chronic uncontrolled OHT may be an independent risk factor for glaucoma. Under normal physiological conditions, IOP ranges between 10 and 21 mm Hg.1-4
There has been more than a 20-year lapse between the approvals of novel medications to treat OAG. Latanoprost, a prostaglandin analogue, was approved by the Food and Drug Administration (FDA) in 1996. It was the first in its class to be commercially available in the US market and the first contemporary OAG treatment since topical timolol 18 years prior.5 Within the past 2 decades, the American Optometric Association (AOA), International Council of Ophthalmology, and European Glaucoma Society have published clinical practice guidelines on the appropriate and evidence-based management of OAG.3,6,7 First-line topical therapies to reduce the IOP associated with OAG include prostaglandin analogues and topical -blockers. These classes of medications have been shown to reduce IOP between 15% and 30%. Second-line therapies include carbonic anhydrase inhibitors, -adrenergic agonists, and cholinergic agonists; the IOP-lowering potential for second- line therapy ranges between 10% and 25%.2,3

Pathophysiology

Aqueous humor is the fluid in the eye that functions to regu- late IOP. Balance of aqueous humor is maintained between its production, inflow, and outflow from the eye. Outflow of aqueous humor is facilitated by 2 pathways: the conven- tional, or trabecular, pathway and the unconventional, or uveoscleral, pathway. Up to 90% of outflow occurs via the trabecular pathway. Anatomical structures within the tra- becular pathway include juxtacanalicular connective tissue, Schlemm’s canal endothelium, and episcleral veins. Impaired aqueous humor outflow through the trabecular pathway is hypothesized to be a result of stiffening of those structures and increased contractility.8 The iris and cornea intersect and form “the angle” of the eye, which is in close proximity to the trabecular meshwork. In OAG, the angle is unobstructed by the iris, whereas in ACG, the iris obstructs aqueous humor outflow and leads to elevations in IOP. Although both OAG and ACG may be chronic conditions, the latter is often characterized by acute visual changes, ocu- lar symptoms, and ophthalmalgia, which are collectively managed as ocular emergencies.4 For the purposes of this review, the focus will be OAG.

Although prostaglandin analogues and -blockers have demonstrated efficacy in the management of OAG, these classes do not specifically target the underlying pathophysi- ology that leads to OHT and OAG. Prostaglandin analogues reduce IOP by improving aqueous humor outflow via the uveoscleral pathway, and -blockers reduce IOP by decreas- ing aqueous humor production.2 Although reducing IOP is the only intervention that has been proven to treat OAG, it is a heterogeneous neuropathy with several plausible patho- geneses, including microcirculation impairment, oxidative damage, neurotoxicity, and genetic anomalies.9

Pharmacology

Several products are currently under investigation as novel therapeutic options to treat OHT and OAG by means of affecting aqueous humor dynamics. New targeted pharma- cological mechanisms include Rho kinase inhibitors and adenosine receptor agonists; both classes aim to facilitate aqueous humor outflow via the trabecular pathway. Clinical trials are currently being conducted on modified prosta- glandin analogues, which incorporate the traditional IOP- lowering mechanism of prostaglandins as well as nitric oxide–mediated relaxation of the trabecular pathway. One such product, latanoprostene bunod, was FDA approved in late 2017.10,11

The Rho kinase inhibitors, also referred to as ROCK inhibitors, target the causative pathophysiology of the trabe- cular pathway as a means of reducing IOP. Rho kinase is an enzyme that increases filament contractions in ocular mus- cle cells. Thus, enzyme inhibition with drug therapy relaxes trabecular smooth muscles, improves aqueous humor out- flow, and reduces IOP.8,10 Netarsudil (RhopressaTM) is a Rho kinase inhibitor that was approved by the FDA in 2017, with indications for the treatment of both OHT and OAG. In addition to inhibiting Rho kinase, preclinical data highlight netarsudil activity against the norepinephrine transporter (NET). The pharmacological benefits of inhibit- ing NET are 2-fold: norepinephrine-mediated vasoconstric- tion of the ciliary body reduces aqueous humor formation and norepinephrine activation of noradrenergic receptors delays and prolongs IOP reduction.12 Netarsudil is com- mercially available as a 0.02% ophthalmic solution, with administration instructions to instill 1 drop into the affected eye(s) once daily in the evening. The manufacturer is Aerie Pharmaceuticals, Inc.13

Clinical Trials

Data Synthesis. Figure 1 depicts the search, screening, and eligibility criteria used to determine studies meeting inclu- sion criteria. Authors followed guidelines endorsed by the EQUATOR Network.14,15 Table 1 describes the studies included in this review; ultimately, 7 studies were eligible for review and critique. Phase 1 trials elucidated netar- sudil’s intraocular hypotensive effects—specifically, its safety profile in normal adult volunteers. Phase 2 trials aimed to determine the most appropriate netarsudil concen- tration, dosing schedule, and surrogate end points in patients with confirmed OHT or OAG. During the phase 3 clinical trials, netarsudil 0.02% was compared against other ocular hypotensive medications with an established safety and efficacy profile in an effort to determine netarsudil’s com- parative efficacy in the treatment of OHT and OAG.

Figure 1. Search and screening strategy utilized.

Phase I. The ability of netarsudil to lower IOP in compari- son to baseline was demonstrated in 2 separate phase 1 studies conducted on healthy adult volunteers.

Levy et al16 conducted an open-label, noncomparative, single-arm, phase I clinical trial in which 18 participants received netarsudil 0.02% ophthalmic solution in each eye once daily in the morning. Participants were healthy adults with noncontributory medical histories (ie, no sys- temic and ocular disorders) and were not taking medica- tions that could affect IOP. The primary safety end point for this phase I trial was plasma blood concentrations of netarsudil and its metabolite, AR-13503 (International Union of Pure and Applied Chemistry name: (2S)-3- amino-2-[4-(hydroxymethyl)phenyl]-N-isoquinolin-6-yl- propanamide), and the secondary safety end point was IOP. Trial duration was 8 days. Liquid chromatography-tandem mass spectrometry was utilized to determine the minimum measurable systemic concentration of netarsudil and AR-13503 (eg, 0.1 ng/mL). Results demonstrated that there
were no detectable systemic concentrations of netarsudil in any of the participants, and only 1 participant developed 1 measurable concentration of AR-13503 on the eighth day of the trial. With respect to the IOP-lowering capacity of netarsudil, participants’ mean baseline IOP prestudy ranged between 15 and 17 mm Hg. On study day 1, mean IOP ranged between 13 and 15 mm Hg, and by study day 8, the mean IOP ranged between 10 and 13 mm Hg. These values represent an approximate 23% to 41% relative decrease in IOP from baseline, respectively, and these differences were statistically significant beginning on day 1 and continued throughout the trial (P < 0.001). The most commonly reported adverse effects were classified as mild per the study investigators, and reactions included conjunctival hyperemia (n = 16, 89%), corneal staining (n = 7, 39%), and headache (n = 3, 17%).16Kazemi et al17 conducted a phase I, double-masked, vehicle-controlled, paired-eye trial to evaluate the aqueous humor dynamics of netarsudil 0.02% ophthalmic solution. A total of 11 participants were enrolled, and 10 completed the study. Trial duration was 7 days. Participants were healthy adults with bilateral IOP within normal limits. Primary end points for aqueous humor dynamics included IOP, outflow facility, episcleral venous pressure (EVP), and uveoscleral outflow. The results revealed a 27% reduction in mean diurnal IOP from baseline in the netarsudil-treated eye as well as a 20% reduction in mean diurnal IOP in the netarsudil-treated eye compared with the paired eye receiv- ing vehicle on the seventh day (−4.6 and −3.5 mm Hg, respectively; P < 0.001 for both). This decrease in IOP can be explained by a corresponding 22% increase in diurnal trabecular outflow facility from baseline (P = 0.02) in addition to a 10% reduction of diurnal EVP from baseline (P = 0.01). All participants experienced conjunctival hyperemia (n = 10, 100%). There were no clinically sig- nificant severe ophthalmic reactions or systemic adverse effects reported throughout the course of the study.17

Phase 2. Weiss et al18 conducted a double-masked, random- ized, vehicle-controlled, monocular study. They enrolled 85 participants with either OHT or OAG, defined as IOP ≥24 mm Hg on awakening and IOP ≥21 mm Hg diurnally. Participants were randomized into 1 of 4 groups: placebo (n = 23), netarsudil 0.01% (n = 22), netarsudil 0.02% (n = 21), or netarsudil 0.04% (n = 19) ophthalmic solution in the selected eye once daily in the morning for 7 days. Mean baseline IOP was approximately 25 mm Hg. Peak IOP reductions (ie, 6.1 to 7.2 mm Hg decrease) in the netar- sudil arms occurred 8 hours after administration, and 24-hour postdose IOP values remained 5.6 to 6.3 mm Hg decreased from baseline. Investigators noted that IOP con- tinued to decrease 8 hours after the morning netarsudil dose, and thus, they proposed that peak efficacy may occur several hours after medication administration. The results showed that netarsudil 0.02% was the lowest concentration to reach the top of the dose-response curve in order to minimize the dose-related conjunctival hyperemia reported in almost 60% (n = 37) of those patients treated with netarsudil. Additionally, investigators noted that hyperemia incidence and severity were lessened as the study progressed.18

Bacharach et al19 conducted the largest phase 2 study. The study design was that of a double-masked, randomized, dose-response, phase 2b trial that enrolled 224 adult partici- pants diagnosed with either OAG or OHT; 213 participants completed the study. The exclusion criteria were extensive and are listed in Table 1. Notably, participants were eligible for inclusion in this study if they had previously taken other medications to lower IOP, so long as they completed a washout period prior to enrolling in this phase 2b trial. Interventions included netarsudil 0.01% in each eye once daily in the evening, netarsudil 0.02% in each eye once daily in the evening, or latanoprost 0.005% in each eye once daily in the evening for 28 days. The results reflected a sta- tistically significant reduction in mean diurnal IOP in all 3 treatment groups (5.5 vs 5.7 vs 6.8 mm Hg, respectively; P < 0.001). However, neither arm receiving netarsudil demonstrated noninferiority (ie, 1.5 mm Hg limit) to the latanoprost treatment group in the modified intent-to-treat population (2.3 and 2.2 mm Hg, respectively; P > 0.05). Only the arm receiving netarsudil 0.02% met noninferiority criteria to latanoprost in prespecified patients with a base- line IOP <26 mm Hg. The most common adverse effect was mild conjunctival hyperemia, which occurred signifi- cantly more often in netarsudil-treated patients than in those treated with latanoprost (52% vs 57% vs 16%, respectively; P < 0.001).19

The nightly administration regimen (to diminish the prevalence of daytime conjunctival hyperemia) of netar- sudil 0.02% was determined in a pilot, double-masked, ran- domized, single-center, placebo-controlled phase 2 study. In this trial, 12 patients with OAG or OHT received netar- sudil 0.02% ophthalmic solution (n = 8) or vehicle (n = 4) in each eye once daily in the evening. The results confirmed an equivalent diurnal and nocturnal IOP-lowering effect, which equates to a 24-hour hypotensive activity indepen- dent of dosing schedule.20

Clinical data from the aforementioned phase 2 trials cemented the selection of netarsudil 0.02% as the most efficacious and safest dose to be evaluated in phase 3 clini- cal trials.Phase 3. The safety and efficacy of netarsudil 0.02% oph- thalmic solution was established by 3 signature clinical trials: ROCKET-1, ROCKET-2, and ROCKET-4.

The first double-masked, randomized, noninferiority study (ROCKET-1) compared netarsudil 0.02% ophthalmic solution in the selected eye once daily in the evening in 202 patients versus timolol 0.5% ophthalmic solution in the selected eye twice daily in 209 patients. In this 3-month study, netarsudil did not meet noninferiority criteria compared with timolol in 3 of the 9 time points in the per- protocol patient population with a baseline IOP <27 mm Hg but did achieve noninferiority status in a post hoc patient population with a baseline IOP <25 mm Hg across all 9 time points (P < 0.0001). The most commonly reported adverse effects included conjunctival hyperemia (netarsudil 53.2% vs timolol 8.2%; P < 0.0001), corneal verticillata (netarsudil 5.4% vs timolol 0%; P = 0.0004), and con- junctival hemorrhage (netarsudil 13.3% vs timolol 0.5%; P < 0.0001).21

The double-masked, randomized, noninferiority design of the second 12-month study (ROCKET-2) consisted of 3 treatment arms: netarsudil 0.02% ophthalmic solution in the selected eye once daily in the evening (n = 251), netarsudil 0.02% ophthalmic solution in the selected eye twice daily (n = 254), and timolol 0.5% ophthalmic solution in the selected eye twice daily (n = 251). The results demon- strated that netarsudil 0.02% once daily was noninferior to timolol 0.5% twice daily in a patient population with base- line IOP <25 mm Hg across all 9 time points (P < 0.0001). Twice-daily netarsudil 0.02% was disregarded as a potential alternative because of a similar therapeutic efficacy com- pared with the daily dosing regimen as well as a greater incidence of patient intolerability in the twice-daily cohort. The side effect profile of netarsudil led to more patient dis- continuations compared with timolol (netarsudil 0.02% once daily, 28%; netarsudil 0.02% twice daily, 52%; timolol 0.5% twice daily, 6%; P values were unreported). The main adverse events reported included conjunctival hyperemia (netarsudil 0.02% once daily, 60.6%; netarsudil 0.02% twice daily, 66.4%; timolol 0.5% twice daily, 13.9%), corneal verticillata (netarsudil 0.02% once daily, 25.5%; netarsudil 0.02% twice daily, 25.3%; timolol 0.5% twice daily, 0.8%), and conjunctival hemorrhage (netarsudil 0.02% once daily, 19.5%; netarsudil 0.02% twice daily, 19.4%; timolol 0.5% twice daily, 0.8%).22

In the double-masked, randomized, noninferiority, 6-month study (ROCKET-4), netarsudil 0.02% ophthalmic solution in each eye once daily in the evening (n = 351) was compared with timolol 0.5% ophthalmic solution in each eye twice daily (n = 357). The primary efficacy analy- sis confirmed that netarsudil was noninferior to timolol in patients (n = 186) with a baseline IOP <25 mm Hg across all 9 time points. The secondary efficacy analysis showed that netarsudil was also noninferior to timolol in patients (n = 240) with baseline IOP <27 mm Hg as well as patients (n = 306) with baseline IOP <30 mm Hg across all 9 time points. Similar to the previous 2 trials, there were no clinically severe ophthalmic reactions or systemic adverse effects reported, whereas the most predominant adverse effects documented included conjunctival hyperemia (netarsudil 47.9% vs timolol 9.2%), corneal verticillata (netarsudil 24.5% vs timolol 0%), and conjunctival hemor- rhage (netarsudil 16.0% vs timolol 3.1%).23

Discussion

The only evidence-based intervention that ameliorates the prognosis of patients with OHT and OAG has been lower- ing IOP.3,9,24 Therefore, it is important to note that the prin- cipal cause of elevated IOP has been attributed to the increased resistance to aqueous humor outflow in the tra- becular meshwork and that every 1 mm Hg IOP reduction is associated with an estimated 10% to 19% decrease in glau- coma progression.24-27 As a result, netarsudil was expected to be a revolutionary therapeutic modality to treat patients with OHT and OAG based on its pharmacological mecha- nism. Netarsudil is a potent inhibitor of Rho kinase as well as an antagonist of NET. It relaxes the actin cytoskeleton of the trabecular meshwork, which consequently increases tra- becular outflow facility and aqueous humor drainage.28-30 It also blocks the norepinephrine-mediated aqueous humor production and lowers the EVP, a key IOP-determining fac- tor according to the Goldmann equation.24,31,32 Netarsudil’s ability to decrease EVP can be of importance because ele- vated EVP contributes to more than half of the measured IOP in patients with normal-tension glaucoma, and netar- sudil has been proven effective in normotensive adults and patients with baseline IOP less than 25 mm Hg.33

The clinical trials portrayed a less relevant, and perhaps unexpected, efficacy profile. Even though netarsudil pro- duced statistically significant IOP reductions from baseline in normal healthy adults and in patients with OHT and OAG, it was never superior, and sometimes determined to be inferior, to other commercially available agents. When compared with latanoprost 0.005%, the current gold stan- dard within ocular hypotensive medications, netarsudil 0.02% did not meet noninferiority criteria in the modified intent-to-treat population. It was only deemed noninferior to latanoprost 0.005% in a post hoc analysis of a prespeci- fied population with mean diurnal IOP ≤26 mm Hg.19 Based on these findings, investigators compared netarsudil 0.02% against timolol 0.5% in the subsequent phase 3 clini- cal trials. Although the ROCKET-1 trial demonstrated net- arsudil’s noninferiority to timolol in patients with a baseline IOP less than 25 mm Hg, netarsudil failed to meet noninfe- riority criteria versus timolol in the patient population with a baseline IOP less than 27 mm Hg.21 The results from the ROCKET-1 trial influenced subsequent adjustments in acceptable baseline IOP parameters observed in the follow- ing trials. In the ROCKET-2 trial, netarsudil reaffirmed noninferiority compared with timolol in patients with a baseline IOP less than 25 mm Hg.22 Thereafter, netarsudil revendicated its ocular hypotensive effects in patients with baseline IOP greater than 25 mm Hg based on the results from the ROCKET-4 trial. In this study, not only was netarsudil noninferior to timolol in patients with a baseline IOP less than 25 mm Hg, but it also met noninferiority cri- teria in patient populations with a baseline IOP less than 27 mm Hg and less than 30 mm Hg, respectively.23 At a mini- mum, ROCKET-4 opened the door for future investigators to perform additional research evaluating netarsudil in other settings, protocols, and diverse populations. It is worth- while to note that there are no published clinical studies, nor are there any protocols indexed in ClinicalTrials.gov, assessing netarsudil’s safety and efficacy to second-line ocular hypotensive medications such as brinzolamide or brimonidine. Despite the promising results from phase 3 tri- als, head-to-head comparisons of netarsudil versus prosta- glandin analogues are not only lacking in the published literature, but also necessary to either confirm or refute net- arsudil’s selection as first-line therapy for OHT or OAG. Similarly, phase 3 trials comparing netarsudil against topi- cal carbonic anhydrase inhibitors and -adrenergic agonists would be valuable to elucidate netarsudil’s role as add-on therapy for refractory cases. Results from clinical trials of the latanoprost-netarsudil combination product will also contribute meaningful information about netarsudil’s capac- ity as add-on therapy.

Netarsudil’s convenient once daily dosing was some- what overshadowed by its clinical safety data versus com- petitors in clinical trials. Conjunctival hyperemia was observed in approximately half of all patients treated with netarsudil. This side effect was mostly mild, transient, and self-resolving with continuous therapy. Conversely, corneal verticillata did not spontaneously resolve for almost a quar- ter of the patients who developed these corneal deposits. The adverse reaction surfaced after 3 months of treatment and only resolved on discontinuation of the medication, even though it did not cause any visual disturbances or visual loss. Netarsudil also induced mild to moderate self- limiting conjunctival hemorrhage in 15% to 20% of patients. It is currently unclear if there are long-lasting consequences of these hemorrhages or, outside of medication discontinu- ation, if there are any acute management strategies that may be implemented. Collectively, netarsudil’s tolerability and safety concerns are pronounced. At least 1 study demon- strated that 28% of the patients receiving netarsudil with- drew enrollment because of adverse events.22 The results of the ROCKET-3 trial are unpublished; however, it was designed as a phase 3 safety trial, the results from which could have provided more comprehensive information regarding netarsudil’s tolerability and safety concerns.34

Another Rho kinase inhibitor, ripasudil, was approved for use in Japan in 2014. The Asia-Pacific Glaucoma Society guidelines include ripasudil in their treatment algo- rithm, citing an average IOP-lowering efficacy around 20%.35 This document is similar in its recommendations to that of the AOA and European Glaucoma Society in that prostaglandin analogues and topical -blockers may be considered as first-line treatment options. Because of the paucity of published primary literature, it is possible that evidence-based guidelines will wait for more data before issuing a formal recommendation regarding the routine use of Rho kinase inhibitors.

Netarsudil is currently being studied for the prophylaxis of steroid-induced IOP elevation and has also received FDA approval coformulated with latanoprost for the treatment of OHT and OAG.36,37 The outlook of netarsudil will become clearer as more postmarketing analyses elucidate its tolera- bility and safety profile, support its clinical utility, and determine its place within OAG and OHT management.

Relevance to Patient Care and Clinical Practice

Patient-specific medication selection for the management of OAG and OHT is rooted in the medication’s adverse effect profile, interactions, contraindications, IOP- lowering efficacy, and administration frequency. Netarsudil decreases IOP by between 20% and 40%, akin to guide- line-recommended first-line therapies for OHT and OAG. However, this effect is diminished in patients with baseline IOP greater than 25 mm Hg, and thus, prostaglandin ana- logues should be recommended in these cases.3 Patient adherence to ocular medications may be as low as 65% to 73%, and adherence wanes with the increasing need to use several ocular hypotensive medications.38,39 Netarsudil’s once-nightly dosing may improve adherence either as monotherapy or as a component in a multidrug regimen. It is an option for patients who are allergic or unresponsive to one or more medications and, thus, need an alternative pharmacological approach. For example, patients with sulfonamide hypersensitivity should avoid carbonic anhy- drase inhibitors because of the potential for allergenicity, and patients with chronic lung disease should avoid topical -blockers because of risks for bronchoconstriction; netar- sudil could be prescribed in these situations. Nonsteroidal anti-inflammatory drugs antagonize the IOP-lowering effects of first- and second-line ocular hypotensive medi- cations.40 Although netarsudil’s product labeling does not currently list any drug-drug interactions, it is plausible that its efficacy is also susceptible, and thus, the premise for reduced interactivity requires further investigation before ubiquitous prescribing.13 Netarsudil is currently available only as a branded medication and may be cost prohibitive to many patients. Conservative estimates suggest that the per-dose cost (assuming 1 drop is equivalent to 0.05 mL) of ocular hypotensive medications are as follows: $6.53 for netarsudil, $0.30 for latanoprost, $0.07 for timolol (0.5% ophthalmic solution), and $0.13 for brimonidine (0.2% ophthalmic solution).41

Conclusion

Netarsudil is a Rho kinase inhibitor that may be inferior to prostaglandin analogues and noninferior to topical - blockers in the treatment of OAG and OHT. Additional head-to-head phase 3 clinical trials and evidence-based guidelines are necessary to determine netarsudil’s position as first-line therapy in the treatment of OAG and OHT.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, author- ship, and/or publication of this article.

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