Netarsudil

Fixed combination netarsudil-latanoprost for the treatment of glaucoma and ocular hypertension

Sapna Sinha, Daniel Lee, Natasha N. Kolomeyer, Jonathan S. Myers & Reza
M. Razeghinejad

To cite this article: Sapna Sinha, Daniel Lee, Natasha N. Kolomeyer, Jonathan S.
Myers & Reza M. Razeghinejad (2019): Fixed combination netarsudil-latanoprost for the treatment of glaucoma and ocular hypertension, Expert Opinion on Pharmacotherapy, DOI: 10.1080/14656566.2019.1685499
To link to this article: https://doi.org/10.1080/14656566.2019.1685499

Published online: 30 Oct 2019.

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EXPERT OPINION ON PHARMACOTHERAPY
https://doi.org/10.1080/14656566.2019.1685499
DRUG EVALUATION
Fixed combination netarsudil-latanoprost for the treatment of glaucoma and ocular hypertension
Sapna Sinha , Daniel Lee, Natasha N. Kolomeyer, Jonathan S. Myers and Reza M. Razeghinejad
Glaucoma Service, Wills Eye Hospital, Philadelphia, PA, USA

ARTICLE HISTORY
Received 27 August 2019
Accepted 23 October 2019
KEYWORDS
Adherence; fixed- combination netarsudil (AR- 1324)-latanoprost; glaucoma; latanoprost; ocular hypertension; prostaglandin analogues; tolerability

1. Introduction
Glaucoma is a progressive optic neuropathy associated with optic nerve head cupping and characteristic visual field defects. The worldwide glaucoma population is estimated to increase to over 110 million by 2040 [1]. Based on numerous randomized control trials, the only proven treatment for glau- coma is the reduction of intraocular pressure (IOP) [2–4]. First- line intervention for IOP reduction is commonly through the use of pharmacologic drugs, administered as topically-applied eye drops. Current medical treatment options for the lowering of IOP include beta-receptor antagonists, alpha-receptor ago- nists, cholinergic agonists, carbonic anhydrase inhibitors and prostaglandin analogs (PGAs). Beta-blockers and PGAs are commonly used as the first line treatment for lowering the IOP, with evidence indicating that these drugs may reduce IOP by up to 25% and 33%, respectively [5]. Many patients with elevated IOP require co-administration of 2 or even more glaucoma medications to achieve the target IOP. Adherence is critical to effective treatment, and studies suggest that increasing bottles and dosages of medication reduces adher- ence. Additionally, the complexity of glaucoma therapy has a negative association with patient adherence [6].
Fixed-combination drugs are now available and have the advantage of reducing the total number of drops that patients must administer per day and the number of bottles with which the patient must contend. Most fixed-combination drugs require once or twice daily administration; a once-daily

formulation with multimodal mechanisms of action could improve compliance and therefore efficacy of treatment [7].
In recent years, new glaucoma medications have been devel- oped, among them are ROCK inhibitors including ripasudil (K-115), netarsudil (AR-13,324), and AMA0076 [8]. ROCK inhibitors are cytoskeletal-modulating drugs and decrease resistance in the tra- becular meshwork (TM) outflow pathway promoting the reduc- tion of IOP [9]. Netarsudil is the first of this class of glaucoma medications and inhibits both rho-kinase and the norepinephrine transporter [10]. Fixed combination netarsudil 0.02%-latanoprost 0.005% (FCNL) ophthalmic drop is the latest glaucoma eye drops marketed for the reduction of elevated IOP in patients with open- angle glaucoma (OAG) or ocular hypertension (OHTN). Its once- daily dosing schedule is advantageous for individuals who have difficulties with medication adherence, while allowing for multiple pharmacologic targets.

2. Overview on the market
In addition to the major groups of glaucoma medications, recently, nitric oxide donating PGA (latanoprostene bunod) and rho-kinase inhibitors were approved by Food and Drug Administration for the treatment of OHT and OAG [11,12]. To date, PGAs have been most commonly prescribed as the first- line drug of choice due to its superior efficacy and easy once daily dosing [13]. However, nearly 30% of patients started on PGA monotherapy require additional medical treatment within one year [14]. A significant portion of glaucoma patients

© 2019 Informa UK Limited, trading as Taylor & Francis Group

require polytherapy for adequate IOP control. The chronic, cumulative effect of polytherapy has been implicated in ocular surface disorders. Multi-bottle, multi-dose regimens have also been associated with reduced medication adherence leading to suboptimal treatment. As a result, the role of fixed- combination medications has grown in order to reduce the complexity and burden of topical therapy.
Currently available fixed combination medications containing aqueous suppressants are dorzolamide-timolol, timolol- brinzolamide, timolol-brimonidine, and brimonidine- brinzolamide. Fixed combinations of PGAs had not been released in the US but have been widely available in Europe and Asia. These have an ease of once daily administration indicating better com- pliance and tolerability. FCNL is the first medicine combining ROCK inhibition with PGA. (Box 1) It is the only fixed combination agent that improves aqueous outflow via conventional and uveoscleral route.

3. Pharmacokinetic and pharmacodynamics
FCNL is supplied as a sterile, isotonic, buffered aqueous solu- tion of netarsudil mesylate and latanoprost with a pH of approximately 5 and an osmolality of approximately 295 m Osmol/kg. Each mL of FCNL contains 0.20 mg of netarsudil (equivalent to 0.28 mg of netarsudil dimesylate) and 0.05 mg latanoprost. Benzalkonium chloride, 0.02%, is added as a preservative. The inactive ingredients are: boric acid, manni-

was not detectable [16]. The route of excretion has not been determined in humans.
In vitro models studying the outflow facility in human eyes showed time dependent increase in outflow facility with netarsudil M1 (0.3 µM). The outflow facility increased from
0.28 ± 0.05 µL/min/mm Hg at baseline to 0.34 ± 0.05 µL/ min/mm Hg at 30 minutes and 0.43 ± 0.05 µL/min/mm Hg at 3 hours after perfusion with netarsudil M1. The percentage change in outflow facility ranged from 24.66 ± 12.57% at 30 minutes to 59.70 ± 13.65% at 3 hours [17].
Netarsudil is highly protein bound in human plasma and the active metabolite netarsudil M1 is 60% bound to plasma proteins. This leads to low free plasma concentrations of the medication which makes it less likely to have any systemic pharmacological effects after topical application.
ROCK inhibitors can relax vascular smooth muscle cells and consequently decrease blood pressure [18]. There were no clinically significant changes in blood pressure or heart rate in normal subjects receiving topical netarsudil for 8 days [19]. The systemic exposures to netarsudil and its active meta- bolite netarsudil M1, were evaluated in 18 healthy subjects after topical ocular administration of netarsudil 0.02% once daily for 8 days. There were no quantifiable plasma concentra- tions of netarsudil (lower limit of quantitation of 0.100 ng/mL) on day 1 and day 8. Only in one subject the plasma concen- tration at 0.11 ng/mL of the active metabolite was observed on day 8. Netarsudil seems to have a slow onset and pro- longed duration of IOP lowering activity and can produce a 30% reduction in the mean diurnal IOP after 8 days of
once daily treatment [19].

3.2. Pharmacokinetics of latanoprost
Latanoprost is a lipophilic isopropyl ester prodrug and is hydrolyzed by esterases in cornea to latanoprost acid, which

Box 1. Drug summary box.
Drug name Fixed combination netarsudil 0.2%/latanoprost 0.005% (FCNL)
Phase Launched
Indication Open angle glaucoma and ocular hypertension

tol, sodium hydroxide to adjust pH, and water.
This section covers the pharmacokinetic and pharmacody- namics of FCNL and its components: netarsudil and latanoprost.

3.1. Pharmacokinetics of netarsudil
Netarsudil is an ester prodrug which is converted to a more potent active metabolite, netarsudil- M1 by the corneal esterases. The half-life of netarsudil incubated in vitro with human corneal tissue is 175 minutes [15]. Clinical studies assessing the in vitro metabolism of netarsudil using human

Pharmacology
Description
Route of administration
Chemical Structure

Fixed Combination Rho-kinase inhibitor and Prostaglandin F2
-alpha receptor agonist Topical ophthalmic drop

Netarsudil Latanoprost

corneal tissue, human plasma, and human liver microsomes and microsomal S9 fractions demonstrated that netarsudil metabolism occurs through esterase activity. Subsequent metabolism of netarsudil’s esterase metabolite, AR-13,503,

Pivotal trial(s) Lewis et al [41]; MERCURY 1 [42] and MERCURY 2 [43] studies showed that FCNL provides clinically and statistically superior ocular hypotensive efficacy relative to its individual active components at the same concentrations.

is biologically active. The peak concentration of the active drug in aqueous humor was detected 1–2 hours after topical instillation and amounted to 15–30 ng/ml. The peak systemic concentration occurred 5 minutes after instillation and this

3.5. Pharmacokinetics of FCNL
The ocular concentrations of Netarsudil 0.02% in treated Dutch belted rabbits were as follows: cornea > conjunctiva
> iris/ciliary body ≫ retina- choroid plexus > aqueous

reached a level of 53 pg/ml. The elimination half-life was
2–3 hours from the eye and 17 minutes from the circulation.

humor > vitreous > lens. The T

1/2

values for netarsudil in

Systemic metabolism occurs in the liver via fatty acid beta oxidation, then the majority is excreted via the urine (88%) and the rest in the feces [20]. The reduction in IOP begins 3–4 hours after topical application and reaches a maximum after 8–12 hours, and is maintained for at least 24 hours [21].

3.3. Pharmacodynamics of netarsudil
Netarsudil is a potent inhibitor of both isoforms of human ROCK 1 and 2 and is also an inhibitor of the norepinephrine transporter (NET) [15,22]. Netarsudil lowers IOP by increasing the trabecular outflow [23,24], decreasing episcleral venous pressure [25] and aqueous humor production [26]. Netarsudil disrupts actin stress fibres and focal adhesions in TM cells and blocks the profibrotic effects of transforming growth factor beta-2 (TGFb-2), producing sustained reduction of IOP for at least 24 hours [15]. Netarsudil increases the cross sectional area of the Schlemm’s canal [27] which may be related to its ability to promote vasodilation [28].
Besides its primary mechanism as a ROCK inhibitor, netar- sudil also functions as an inhibitor of NET [26]. This increases the norepinephrine levels which reduces the aqueous humor secretion via activation of α-2 adrenergic receptors. Topical application of netarsudil in young rats reduced retinal gang- lion cell death and promoted axonal regeneration in optic nerve following optic nerve injury [29].

3.4. Pharmacodynamics of latanoprost
Latanoprost is an ester prodrug analog of prostaglandin F2- alpha, which reduces IOP by increasing uveoscleral outflow [30]. Latanoprost exerts a modulating effect on the extracel- lular matrix both in the ciliary muscle [31–34] and sclera [35,36] leading to a decrease in matrix components subse- quent to decreased synthesis and increased proteolytic degra- dation. This may also cause an alteration in cell shape, influencing the extracellular matrix architecture and subse- quently leading to increased uveoscleral outflow [37]. The predominant effects of latanoprost were demonstrated on the compact anterior longitudinal muscle fibres of the ciliary body which represents the entrance to the uveoscleral outflow [31]. The combination of reorganization of the collagen bun- dles with decreased extracellular matrix and ciliary muscle relaxation increases the porosity and hydraulic conductivity through the ciliary muscle [31,37,38].
Though prostaglandins decrease IOP predominantly by increasing the uveoscleral outflow, a few laboratory studies have demonstrated an effect on the trabecular flow as well. Morphological studies demonstrated the presence of prosta- glandin receptors in TM may contribute to the increased out- flow via the conventional pathway as well [37,39].

cornea, conjunctiva and vitreous, in addition to blood, plasma, liver, and kidney ranged from 12 to 27 hours. Elimination of netarsudil from the retina-choroid- plexus, lens and iris/ciliary body was much slower with T1/2 values ranging from 68 to 112 hours. The maximum systemic con- centrations in blood, plasma, liver and kidney were 200 to
300 folds lower than in the cornea and conjunctiva. Netarsudil dosing produced a maximum aqueous humor drug concentration at 8 hours after dosing [15].
The effect of latanoprost in monkey eyes revealed peak con- centrations in the iris, anterior chamber and ciliary body 1 hour post dose with an elimination half-life from eye tissues of 3–4 hours. Latanoprost is 90% bound to plasma proteins in the first few minutes after intravenous administration, although this decreases over time (60% by 2 hours post dose) [40].

3.6. Pharmacodynamics of FCNL
In the FCNL, netarsudil’s IOP reduction through increased trabecular outflow, decreased aqueous secretion, and reduced episcleral venous pressure, is further complemented by lata- noprost which lowers the IOP by increasing uveoscleral out- flow. Trials have shown a greater reduction of IOP with the combination when compared to the either of the drugs alone [41].

4. Efficacy
Efficacy of FCNL can be summarized using the recently pub- lished phase II and III trials (Table 1). Post-marketing surveil- lance studies, when available, will add to our understanding.
Lewis et al. conducted a phase II double-masked randomized parallel comparison study of 297 patients with OAG or OHTN with four treatment arms: FCNL 0.01%, FCNL 0.02%, latanoprost 0.005%, or netarsudil 0.02%, each dosed once daily at night for 28 days [41]. Mean (±standard deviation) of unmedicated diurnal IOP prior to study was 25.1 ± 2.3, 25.1 ± 2.4, 26.0 ± 2.8 and
25.4 ± 2.7 mm Hg in each group, respectively, with no significant difference among treatment groups (p = 0.11). On day 29, mean diurnal IOP decreased to 17.3 ± 2.8, 16.5 ± 2.6, 18.4 ± 2.6 and
19.1 ± 3.2 mm Hg, respectively. Based on mean diurnal IOP at day 29, both fixed-combinations met the criteria for statistical super- iority compared to both latanoprost and netarsudil. The lower concentration (0.01%) provided additional 1.1 (p = 0.0071) and
1.8 mmHg (p = 0.0002) IOP lowering, vs. latanoprost and netar- sudil respectively; the higher concentration (0.02%) provided additional IOP lowering of 1.9 and 2.6 mm Hg, respectively (p < 0.0001). The Mercury-I study was a double-masked randomized phase III multicenter trial comparing FCNL, with netarsudil 0.02% and latanoprost 0.005% in 718 patients with bilateral OAG or OHTN [42]. The main outcome measure was mean IOP at 8:00 AM, 10:00 AM, and 4:00 PM at week 2, week 6, and Table 1. Trials comparing the efficacy of fixed combination netarsudil-latanoprost with latanoprost and netarsudil. Study Netarsudil 0.02% + Latanoprost 0.05% Latanoprost 0.005% Netarsudil 0.02% Lewis et al [41] n = 73 n = 73 n = 78 Mean baseline IOP (mm Hg± SD) 25.1 ± 2.4 26.0 ± 2.8 25.4 ± 2.7 Mean IOP at 28 days (mm Hg± SD) 16.5 ± 2.6 18.4 ± 2.6 19.1 ± 3.2 Mean IOP ≤ 18 mm Hg 69% 47% 39% MERCURY-1 [42] n = 238 n = 236 n = 244 Mean baseline IOP (mm Hg) 23.7 23.5 23.6 Mean IOP at 3 months (mm Hg) 15.6 17.1 18.1 Absolute reduction from baseline (mm Hg) 7.2–9.2 5.3–7.1 5.1–6.1 Percentage reduction from baseline 39.9–36.7% 23.3–28.8% 21.8–24.9% Mean IOP ≤ 18 mm Hg 82% 69.1% 53.5% ≥ 30% reduction of IOP from baseline 64.5% 37.2% 28.8% MERCURY-2 [43] n = 245 n = 250 n = 255 Mean baseline IOP (mm Hg) 23.5 23.5 23.6 Mean IOP at 3 months (mm Hg) 15.9 17.5 18.6 Absolute reduction from baseline (mm Hg) 6.8–8.6 5.5–6.8 4.8–5.4 Percentage reduction from baseline 30.3–34.8% 23.6–27.3% 19.5–23% Mean IOP ≤ 18 mm Hg 76.5% 66.0% 46.1% ≥ 30% reduction of IOP from baseline 58.8% 29.4% 20.6% IOP- Intraocular pressure; SD-Standard deviation month 3. FCNL met the criteria for superiority to each active component at all 9 time points (all p < .0001) in the first three months. Based on mean IOP reduction from baseline at 2 weeks to 3 months, FCNL lowered IOP by an additional 1.8–3.0 mmHg and 1.3–2.5 mmHg, compared with netarsudil and latanoprost, respectively. Absolute reductions from base- line in mean IOP during this time ranged from 7.2–9.2 mmHg, 5.1–6.1 mmHg, and 5.3–7.1 mmHg for FCNL, netarsudil, and latanoprost, respectively (p < .0001 for all comparisons), cor- responding to percentage reductions from baseline mean IOP of 30.9–36.7%, 21.8–24.9%, and 23.3–28.8%, respectively. Mercury-II was another double-masked randomized phase III multicenter trial in patients with bilateral OAG or OHTN, compar- ing FCNL with its constituents as monotherapy [43]. Similar to Mercury-I, FCNL met the criteria for superiority to each active component at all 9 time points (p < 0.0001), lowering IOP by an additional 2.2–3.3 mmHg versus netarsudil and an additional 1.5–2.4 mmHg versus latanoprost [43]. Notably, at month three, the proportion of patients achieving mean diurnal IOP ≤15 mmHg was 42.1% for FCNL, compared to 15.8% and 18.3% for netarsudil and latanoprost, respectively. Mercury-III is underway and will compare FCNL with FC bimatoprost 0.03%- timolol 0.5%. 5. Side effects The most frequently reported minor side effect is conjunctival hyperemia. In the phase II trial with four-treatment arms (FCNL 0.01%, FCNL 0.02%, latanoprost, and netarsudil), the incidence of conjunctival hyperemia was similar in all arms, with the following reported rates: 41%, 40%, 14%, and 40%, respectively [41]. The severity of hyperemia was mild in most patients (76–100%). Three month data from the phase III Mercury I trial reported similar rates of hyperemia (53.4–54.5% for FCNL, 41–42.7% for netarsudil, and 14–22.3% for latanoprost) [42,43]. The presumed mechanism of hyperemia is ROCK-inhibition related vascular smooth muscle relaxation [23]. Conjunctival hemorrhage of varying severity was noted in 8.6–10.5% of FCNL patients, compared to 11–13.9% and 0.4–0.8% in netarsudil and latanoprost groups, respectively [42,43]. Two patients (both in the netarsudil group) discontin- ued the medication due to conjunctival hemorrhage in Mercury-I, however no patients discontinued treatment for this reason in Mercury-II. Cornea verticillata was reported in 5.0–13.1% of FCNL patients, 4.1–9.8% of netarsudil-treated patients, and none in latanoprost-treated patients [42,43]. Most reported verticillata were considered mild. All cases were asymptomatic with no apparent change in visual acuity; however, in the two phase III studies investigators chose to discontinue the medication due to corneal verticillata in three total patients (two on FCNL, one on netarsudil). Additionally, instillation site pain was noted in 19.3% of FCNL patients, compared to 20.9% and 6.4% for netarsudil and latanoprost, respectively [42]. Eye pruritis was reported in 7.6% of FCNL and 7.0% and 1.3% of netarsudil and latano- prost, respectively. Increased lacrimation was reported in 5.9% of FCNL and 6.1% and 0.4% of its constituents respectively. In Mercury-II, ocular discomfort was rated as none or mild in a majority (93% or higher) of patients, based on the Ocular Comfort Survey; FCNL and netarsudil were slightly less com- fortable at the individual visits compared to latanoprost (92.- 5–96.5% compared to 100%, respectively) [43]. Based on these studies, most ocular adverse events for FCNL had rates similar to netarsudil alone. In the phase III studies, 6–10% of patients in the FCNL and netarsudil treat- ment groups discontinued the medication prior to month three due to adverse events, whereas the rate of discontinua- tion was 0–1.6% in the latanoprost group [42,43]. In the phase II and III studies thus far, no serious adverse events were attributed to the medication. The safety profile for FCNL seems to be consistent with its constituents, with thus far no new adverse events related to the fixed combination. 6. Safety in pregnancy, childhood, and lactation The tolerability and effectiveness of FCNL has yet to be deter- mined in pregnancy, lactation, and children. The following section will discuss tolerability of netarsudil and latanoprost separately. In the studies conducted on the efficacy and safety of netarsudil, pregnant and nursing women were excluded and only a small number of pediatric subjects (n = 2; one 11 years old and one 14 years old) were enrolled [16]. There are no case reports about this medication in pregnant or lactating women. Information in this regard is limited to the studies of netarsudil conducted on animals. Studies with systemic administration of netarsudil in rats showed dose dependent increases in embryo and fetus toxi- city such as early resorptions and post-implantation loss, decreases in litter size, number of mothers with viable fetuses, and number of viable fetuses. Offspring anomalies were limited to a slight increase in the mean number of ossified caudal vertebrae at ≥0.1 mg/kg/day and forelimb phalanges at ≥0.03 mg/kg/day. There were no netarsudil- related fetal external, soft tissue, or skeletal fetal malforma- tions or variations at any dose in rabbits. No fetal abnormal- ities were observed at plasma exposures that were at least 40 times (rat) and 1330 times (rabbit) higher than the human plasma exposure with topical ocular dosing of netarsudil 0.02% once a day. With topical application of netarsudil the serum level generally is below the lower limit of quantitation of 0.100 ng/mL at the recommended clinical dose, there is low risk for embryofetal toxicity to be observed at the intended dosing regimen [16]. Theoretically prostaglandins increase uterine tone and may lead to premature labor. However, the dosage used to stimulate abortion would be the equivalent of 400 cc of the ocular for- mulation of latanoprost [44]. Additionally, the half-life of latano- prost is only 17 minutes [44–47]. The manufacturer reported no adverse effects on the embryo with up to 15 times the human dosage [48]. One of 10 pregnant women who received latano- prost in the first trimester had a miscarriage. All other 9 patients had a normal pregnancy course and outcome without neonatal malformations. The miscarriage occurred in an older patient (46 years old) which is considered a risk factor for abortion [49]. There are debates regarding the use of latanoprost in pregnancy, but it has been claimed that ocular PGAs have insufficient active ingredients to induce adverse effects on the fetus [50]. However, some believe that its use is contra-indicated in pregnant women [51,52]. There is no formal data available on whether significant netarsudil or latanoprost levels could be present in human milk following ocular administration, or their effects on the breastfed infants or milk production. Systemic exposure to netarsudil following topical ocular administration is low, and it is not known whether measurable levels of netarsudil would be present in maternal milk following topical ocular adminis- tration. After topical dosing of netarsudil in animal studies the maximum concentration was detected in the cornea with a half-life of 0.5 hour. The maximum systemic concentrations of netarsudil in blood, plasma, liver, and kidney were about 200- to 3000-fold lower than in the cornea [15]. The fetal safety, development and health benefits of breastfeeding along with the mother’s glaucoma severity and need for the drug and any potential adverse effects on the child should be taken into account prior to offering this medication to preg- nant or lactating women. 7. Conclusion FCNL is a potent fixed combination anti-glaucoma medication for the reduction of IOP in patients with OAG and OHTN. FCNL targets multiple pathways and lowers IOP effectively. Latanoprost is a prostaglandin agent lowering the IOP by increasing the uveoscleral outflow. Netarsudil exerts its thera- peutic effect through improved trabecular outflow, decreased episcleral venous pressure, and reduced aqueous fluid produc- tion. FCNL is more effective than either latanoprost or netarsudil alone and is non-inferior to the concomitant administration of latanoprost and netarsudil. The systemic safety profile of FCNL is excellent with no major reported drug related events. Local side effects include conjunctival hyperemia, cornea verticillata, and subconjunctival hemorrhages which are generally mild with low rates of discontinuation in studies. 8. Expert opinion A significant portion of glaucoma patients require multiple medications to adequately control their disease. Patients on chronic polytherapy with complex dosing regimens are at particular risk for developing ocular surface issues due to the cumulative effect of preservatives such as benzalkonium chlor- ide which has been shown to be cytotoxic to human ocular epithelial cells in culture [53]. There is also a strong correlation between the number of medications and reduced treatment adherence [6]. With this in mind, ophthalmologists increas- ingly turn to fixed combination medications in order to reduce the overall preservative burden and improve compliance with a more simplified and streamlined treatment regimen. FCNL is unique among currently available glaucoma medica- tions as it is the only non-beta blocker fixed combination med- ication containing a PGA. Netarsudil exerts its therapeutic effect through multiple pathways. It primarily works by reducing out- flow resistance at the TM. In addition, episcleral venous pressure is reduced and aqueous fluid production is suppressed via NET inhibition. The combination of latanoprost and netarsudil mod- ulates all known targets for IOP reduction in a single drop. The side effect profile of FCNL in trials has been mostly mild topical side effects. The lack of systemic contraindications makes this an attractive agent for patients with beta blocker contra- indications, those with sulfa allergies, and those on systemic beta-blockers. Topical beta-blockers have been reported to be less effective in patients on systemic beta-blockers [54]. Patients should be counseled before initiating ROCK inhibitors that con- junctival hyperemia is fairly common, but that for most patients this will be mild if the drug is continued. Elevated IOP is the result of reduced aqueous fluid transmission through the TM. Therefore, improving flow through the TM targets the site of the pathology. There is an emerging school of thought that places a high priority on restoring trabecular outflow early in the disease course. The hypothesis is that chronically reduced aqueous flow through the distal outflow vessels may be detri- mental to their health leading to increased distal resistance. This is supported by the observation that 360 degree goniotomy fails more often in patients with more advanced disease and older individuals [55]. Similarly, success rates following selective laser trabeculoplasty were negatively correlated with increasing age and disease severity [56]. From this standpoint, netarsudil’s effect on improving outflow through the TM potentially could change the long-term course, possibly making FCNL a favorable early treatment option. The published trials do demonstrate already that for most patients FCNL is effective and well tolerated and may achieve low IOPs reducing the need for multidose therapy. Funding This manuscript was not funded. Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Reviewer Disclosures One referee is a consultant for Santen and is also involved with the Aerie MERCURY 4 investigation which is currently ongoing. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose. ORCID Sapna Sinha http://orcid.org/0000-0001-9904-2371 Reza M. Razeghinejad http://orcid.org/0000-0001-7961-8425 References Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers. 1. Tham YC, Li X, Wong TY, et al. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology. 2014;121(11):2081–2090. 2. Kalouda P, Keskini C, Anastasopoulos E, et al. Achievements and limits of current medical therapy of glaucoma. Dev Ophthalmol. 2017;59:1–14. 3. Gordon MO, Beiser JA, Brandt JD, et al. The ocular hypertension treatment study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120(6):714–720. dis- cussion 829-730. 4. Schulzer M. Intraocular pressure reduction in normal-tension glau- coma patients. 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