A multicenter, open-label study of netarsudil for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension in a real-world setting

Abstract

Objective

Assess the real-world efficacy of netarsudil, either as monotherapy or concomitant therapy, in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT) requiring modification of intraocular pressure (IOP)-lowering treatment.

Methods

Multicenter, prospective, interventional, open-label, Phase 4 study, clinical trial registration number: NCT03808688. Netarsudil ophthalmic solution 0.02% was prescribed at the recommended once-daily dosage, with treatment regimens determined by the investigators. Netarsudil could be used alone or in combination with other IOP-lowering medications, consistent with standard clinical practice. Primary efficacy endpoint: percentage reduction from baseline IOP at week 12.

Results

Among 261 enrolled patients, 242 received ≥1 netarsudil dose and had ≥1 follow-up IOP measurement (efficacy population). Mean IOP in patients who were treatment-naïve at baseline and using netarsudil as monotherapy (n = 24) decreased by 16.9%. Netarsudil monotherapy was comparable in efficacy to prior therapy across subgroups, and those who replaced prostaglandin analog (n = 57) monotherapy demonstrated reduction of 2.5% from prostaglandin analog-treated baseline values. Among patients who used netarsudil as concomitant therapy (n = 151), reductions in mean IOP (± standard deviation) to week 12 were seen across subgroups who added netarsudil to a single agent (4.3 ± 2.88 mmHg; 20.5%) or ≥2 classes of concomitant therapy (4.5 ± 4.08 mmHg; 20.9%) and who used netarsudil to replace ≥1 other drug classes (0.4 ± 2.47 mmHg; 1.7%). Of 260 netarsudil-treated patients, 41 (15.8%) discontinued, including 29 (11.2%) due to adverse events.

Conclusions

In the real-world treatment of patients with OAG or OHT, netarsudil consistently maintained IOP control when it replaced previous IOP-lowering therapies and provided additional IOP-lowering efficacy when added to other treatments.

Keywords:

• Glaucoma
• ocular hypertension
• netarsudil
• clinical trial
• intraocular pressure
• pharmacotherapy

Introduction

Glaucoma is a leading cause of visual impairment, accounting for an estimated 3 million cases of blindness and 4 million cases of moderate to severe visual impairment worldwide¹. Elevated intraocular pressure (IOP) is associated with increased risk for progression of visual field loss in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT), and pharmacotherapy to reduce IOP delays progression^2–7. The treatment goal for OAG/OHT patients in clinical practice is to lower IOP to the point that subsequent damage to the optic nerve is prevented, without sacrificing safety or convenience⁸. Topical monotherapy may be insufficient for reaching target IOP, necessitating a change in treatment or initiation of combination treatment. A recent study found that among OAG patients initially prescribed topical monotherapy, 42% required treatment modification within 4 years, 59% of whom started a different monotherapy and 21% of whom initiated combination therapy⁹. The importance of IOP-lowering efficacy is underscored by evidence for the benefits of earlier treatment and lower IOP goals, indicating that every mmHg reduction is significant^3–6.

Netarsudil ophthalmic solution 0.02% (Rhopressa) is the first Rho-kinase (ROCK) inhibitor to be approved by the US FDA, providing a once-daily treatment option with a unique mechanism of action¹⁰. Inhibition of ROCK increases outflow facility by expanding the juxtacanalicular tissue of the trabecular meshwork and dilating episcleral veins, thereby lowering IOP^11–14. Efficacy in monotherapy in the treatment of OAG and OHT was demonstrated in Phase 3 studies in which netarsudil was associated with reductions in IOP of up to 6.1 mmHg, with improvements consistent across a range of baseline IOPs and sustained over 12 months^15–18. The objective of this study was to evaluate the IOP-lowering efficacy of netarsudil in real-world clinical settings when used as monotherapy or concomitantly with other IOP-lowering agents in patients with elevated IOP due to OAG or OHT.

Methods

Design

This was a multicenter, prospective, interventional, open-label, Phase 4 study (NCT03808688). Reflecting real-world practice, participants were not asked to stop their existing IOP-lowering therapy in the weeks prior to being enrolled. Upon enrollment, treatment regimens were determined by the investigators. Netarsudil could be used alone or in combination with any number of available IOP-lowering medications, consistent with the standard practice of clinicians treating OAG/OHT. The study was conducted at 22 clinical sites in the United States and the duration was 12 weeks.

Eligibility criteria

Inclusion criteria were adults (≥18 years) with a diagnosis of OAG or OHT and determined by the treating physician to require additional IOP-lowering treatment with netarsudil 0.02% either as monotherapy, as a replacement for prior IOP-lowering monotherapy, or used concomitantly with other IOP-lowering medication. Patients could participate if they had prior ocular medical treatments or procedures, including any number of IOP-lowering medications, minimally invasive glaucoma surgery (MIGS), glaucoma laser, and/or cataract surgery. Participants were required to indicate their willingness to follow protocol requirements, including signed informed consent, the follow-up schedule, and completion of study-related assessment/measurements.

Patients were excluded if they had any active ocular disease other than OAG or OHT that would interfere with the interpretation of study results; were women of childbearing potential who were pregnant, nursing, or planning a pregnancy and not using a medically acceptable form of birth control; had a known sensitivity or allergy to the study medication or components; had a systemic disease or clinical evidence of any condition which would make the patient, in the opinion of the investigator, unsuitable for the study or could potentially confound the study results; or were currently participating in or had previously participated in any investigational drug or device study within 30 days prior to the baseline visit.

Interventions

All participants received netarsudil ophthalmic solution 0.02% (Aerie Pharmaceuticals, Inc., Durham, NC, USA), and were instructed to use netarsudil at the recommended dosage of 1 drop in each eye once daily in the evening. If netarsudil was to be used concomitantly with other topical ophthalmic drug products to lower IOP, each drug product was administered at least 5 min apart to prevent washout.

Assessments

The study schedule consisted of three visits: baseline visit (day 0), follow-up visit at week 6 (±7 days), and a final visit at week 12 (±7 days). Information collected at baseline included informed consent, demographic information, subject eligibility, a urine pregnancy test for women of childbearing potential, pachymetric data, and medical and IOP history. Data on prior and concomitant medications and procedures were collected at baseline and updated at each subsequent visit.

To evaluate efficacy, IOP was measured in both eyes using a Goldmann applanation tonometer affixed to a slit lamp at the baseline, week 6, and week 12 visits. The same investigator or designee was to complete all tonometric evaluations. After 1 drop of topical anesthetic was administered into each eye, the assessor waited 4 min before evaluating the subject in a seated position. The assessor performed the measurement, read the result, and recorded the IOP. Investigators were requested to schedule study visits at the same time of day.

Exploratory assessments conducted at week 12 included questions for the investigator and patient that assessed feedback on IOP-lowering therapy. Questions for the patient were administered by the investigator or designee to the patient. The assessments, which were not part of a validated questionnaire, were incorporated into electronic case report forms.

Safety measurements conducted at baseline, week 6, and week 12 visit were systemic blood pressure, best-corrected visual acuity for both eyes using a Snellen Visual Acuity Chart, and biomicroscopy for both eyes by slit lamp examination without pupil dilation. Eye structures/surfaces assessed by biomicroscopy included, but were not limited to, lids/lashes, conjunctiva (palpebral and bulbar), cornea, anterior chamber, and lens. Conjunctival hyperemia was scored on a scale ranging from 0 to +3 using the following categories: 0 (none) – normal. May appear blanched to reddish-pink without perilimbal injection. Vessels of palpebral or bulbar conjunctiva easily observed; +0.5 (trace) – minimal flush, reddish color predominantly confined to the palpebral or bulbar conjunctiva; +1 (mild) – a flush, reddish color predominantly confined to the palpebral or bulbar conjunctiva; +2 (moderate) – bright red color of the palpebral or bulbar conjunctiva; 3+ (severe) – deep, bright diffuse redness of the palpebral or bulbar conjunctiva. Adverse events were elicited by the investigator at all follow-up visits and were recorded on a case report form with assessment of severity (mild/moderate/severe), action taken, and relationship to the study medication. Adverse events were coded using Medical Dictionary for Regulatory Activities (MedDRA) version 22.0.

Patients received study medication bottles at baseline and week 6, and used/unused study medication bottles were collected at weeks 6 and 12. If a subject discontinued from the study for any reason after the baseline visit, he/she was requested to return for a final Early Exit visit, at which time all week 12 assessments were performed.

Study endpoints

The primary efficacy endpoint was the percent reduction from baseline IOP at week 12. Questions for investigator and patient feedback were included as exploratory endpoints. Safety and tolerability were also evaluated.

Statistical analyses

Efficacy and safety data are presented descriptively based on observed data, missing data values were not imputed, except when dates were required for calculations. In those instances, partial dates would have either “01” or “Jan” imputed.

Approximately 250 subjects were planned to be enrolled. No sample size calculation was performed, given that no statistical comparisons between treatments were planned. The safety population comprised all subjects who received at least 1 dose of study medication. The modified intention-to-treat (mITT) population, which was used for efficacy analyses, comprised all enrolled subjects who received at least 1 dose of study medication and had at least 1 follow-up visit with a completed IOP measurement.

One eye per subject was included in the efficacy analyses. If both eyes qualified for study inclusion, analyses were provided for the worse eye (i.e. with higher IOP) at baseline. If both study eyes were the same at baseline, then data for only the right eye were analyzed.

Ethical conduct

The study protocol and the informed consent form were reviewed and approved by the institutional review board (Sterling IRB, Atlanta, GA, USA) before subjects were entered into the study. This study was conducted in accordance with the provisions of the Declaration of Helsinki and its amendments and Good Clinical Practice. Subjects were required to read and sign the informed consent form prior to enrollment.

Results

Patient disposition

A total of 261 patients enrolled. The first visit of the first patient occurred on 27 December 2018, and the last visit of the last patient was on 26 July 2019. The disposition of the study participants is shown in Table 1. Because 1 patient dropped out before receiving any study medication, the safety population comprised 260 treated participants (99 who received netarsudil as monotherapy, and 161 who received netarsudil with concomitant therapy). An additional 18 patients were excluded from the mITT population used in efficacy analyses: 16 had a follow-up visit but were no longer treated with study medication when the study visit occurred, and 2 did not have a follow-up visit. Of the 260 treated patients, 41 (15.8%) discontinued from the study, including 29 (11.2%) due to adverse events. Adverse events are reported later in the results section.

Table 1. Patient disposition.

n (%)	Overall population	Netarsudil monotherapy	Netarsudil with concomitant therapy
Enrolled	261
Safety population	260	99	161
mITT population	242	91	151
Per protocol population^a	217	80	137
Treated patients	260	99	161
Completed study	219 (84.2)	81 (81.8)	138 (85.7)
Discontinued study	41 (15.8)	18 (18.2)	23 (14.3)
Treatment-emergent AE	29 (11.2)	12 (12.1)	17 (10.6)
Non–treatment-emergent AE^b	1 (0.4)	1 (1.0)	0 (0.0)
Lost to follow up	2 (0.8)	0 (0.0)	2 (1.2)
Other	9 (3.5)	5 (5.1)	4 (2.5)

Abbreviations. AE, adverse event; mITT, modified intent to treat.

^aPatients in the mITT population who completed 12 weeks of study treatment without significant protocol violations. Two patients who completed the study had protocol deviations considered major and were excluded from the per protocol population; neither patient was taking study medication at the time of the week 6 visit.

^bOne patient discontinued early due to a non–treatment-emergent AE. Onset of the AE occurred after the patient had stopped netarsudil.

Baseline demographic and clinical characteristics

Patient baseline characteristics of the mITT population are shown in Table 2. All demographics and other baseline characteristics were well balanced between the monotherapy and concomitant therapy groups.

Table 2. Baseline demographic and clinical characteristics (mITT population).

	Overall, N = 242	Netarsudil monotherapy, n = 91	Netarsudil with concomitant therapy, n = 151
Age, years
Mean (SD)	67.2 (11.02)	67.2 (11.85)	67.2 (10.53)
Median	69.0	69.0	69.0
Min–max	21–90	21‒88	30‒90
Gender, n (%)
Female	148 (61.2)	57 (62.6)	91 (60.3)
Male	94 (38.8)	34 (37.4)	60 (39.7)
Ethnicity, n (%)
Hispanic or Latino	19 (7.9)	11 (12.1)	8 (5.3)
Not Hispanic or Latino	223 (92.1)	80 (87.9)	143 (94.7)
Race, n (%)
American Indian or Alaska Native	1 (0.4)	1 (1.1)	0 (0.0)
Asian	3 (1.2)	0 (0.0)	3 (2.0)
Black or African American	58 (24.0)	13 (14.3)	45 (29.8)
Native Hawaiian or Other Pacific Islander	0 (0.0)	0 (0.0)	0 (0.0)
White	179 (74.0)	77 (84.6)	102 (67.5)
Other^a	1 (0.4)	0 (0.0)	1 (0.7)
Systolic blood pressure, mmHg
Mean (SD)	133.6 (16.05)	131.1 (13.11)	135.1 (17.45)
Median	132.0	131.0	132.0
Min–max	90‒206	90‒175	101‒206
Diastolic blood pressure, mmHg
Mean (SD)	79.7 (9.77)	78.3 (7.95)	80.6 (10.65)
Median	79.0	79.0	79.0
Min–max	58‒118	59‒106	58‒118
Iris colour, n (%)
Black	1 (0.4)	0 (0.0)	1 (0.7)
Blue	64 (26.4)	29 (31.9)	35 (23.2)
Brown	132 (54.5)	46 (50.5)	86 (57.0)
Green	11 (4.5)	2 (2.2)	9 (6.0)
Grey	2 (0.8)	1 (1.1)	1 (0.7)
Hazel	32 (13.2)	13 (14.3)	19 (12.6)
Central corneal thickness, µm
Mean (SD)	557.8 (45.37)	566.1 (41.77)	552.9 (46.85)
Median	561.0	569.0	553.0
Min–max	427‒737	464‒689	427‒737

^aAmerican Indian or Alaska Native/White.

Regarding ophthalmic medical history (Table 3), 205/242 (84.7%) of the mITT population were diagnosed with glaucoma (191 [78.9%] with open-angle glaucoma and 14 [5.8%] with other glaucoma), and 107 (44.2%) had elevated IOP for 11 or more years. Investigators reported having a difficult time controlling IOP in 49/242 (22.7%) of subjects overall, ranging from 6/67 (9.5%) of subjects in the treatment-replaced monotherapy group to 41/151 (28.7%) in the concomitant therapy group (Supplementary Table 1). Investigators also reported that 45/242 (18.6%) of subjects overall had potential for IOP-lowering surgery in the next 6–12 months, ranging from 3/24 (12.5%) of subjects in the previously treatment-naive group to 13/67 (19.4%) in the treatment-replacement monotherapy group. In the overall population, 146/242 (60.3%) had at least 1 previous ocular surgery, including 90 (37.2%) with a history of glaucoma laser surgery (argon laser trabeculoplasty/selective laser trabeculoplasty/iridotomy), which was the most common procedure, followed by cataract surgery (n = 87; 36.0%) and MIGS (n = 12; 5.0%).

Table 3. Ophthalmic medical history (mITT population).

	Overall, N = 242	Netarsudil monotherapy, n = 91	Netarsudil with concomitant therapy, n = 151
Glaucoma diagnosis, n (%)
Ocular hypertension	37 (15.3)	18 (19.8)	19 (12.6)
Open-angle glaucoma	191 (78.9)	72 (79.1)	119 (78.8)
Closed-angle glaucoma with patent iridotomy	2 (0.8)	0 (0.0)	2 (1.3)
Pseudoexfoliative glaucoma	2 (0.8)	0 (0.0)	2 (1.3)
Pigmentary glaucoma	4 (1.7)	1 (1.1)	3 (2.0)
Other^a	6 (2.5)	0 (0.0)	6 (4.0)
Years with elevated IOP, n (%)
Newly diagnosed	25 (10.3)	15 (16.5)	10 (6.6)
1–3 years	32 (13.2)	10 (11.0)	22 (14.6)
4–5 years	28 (11.6)	10 (11.0)	18 (11.9)
6–10 years	50 (20.7)	16 (17.6)	34 (22.5)
11–20 years	78 (32.2)	30 (33.0)	48 (31.8)
>20 years	29 (12.0)	10 (11.0)	19 (12.6)
Historical untreated IOP, mmHg
N	208	83	125
Mean (SD)	25.9 (5.67)	24.4 (4.26)	26.9 (6.25)
Median	25.0	24.0	27.0
Min–max	14–48	14–36	14–48
Historical maximum treated IOP, mmHg
N	229	81	148
Mean (SD)	22.9 (5.94)	21.8 (4.52)	23.5 (6.52)
Median	22.0	22.0	23.0
Min–max	8–50	15–36	8–50
Previous procedures – study eye, n (%)^b
None	96 (39.7)	44 (48.4)	52 (34.4)
Glaucoma laser (ALT/SLT/iridotomy)	90 (37.2)	26 (28.6)	64 (42.4)
Cataract surgery	87 (36.0)	31 (34.1)	56 (37.1)
MIGS	12 (5.0)	2 (2.2)	10 (6.6)
Retinal surgery	10 (4.1)	4 (4.4)	6 (4.0)
Refractive surgery	8 (3.3)	2 (2.2)	6 (4.0)
Trabeculectomy or valve	8 (3.3)	0 (0.0)	8 (5.3)
Oculoplastic surgery	7 (2.9)	4 (4.4)	3 (2.0)
Corneal surgery	1 (0.4)	0 (0.0)	1 (0.7)

Abbreviations. ALT, argon laser trabeculoplasty; IOP, intraocular pressure; MIGS, minimally invasive glaucoma surgery; SLT, selective laser trabeculoplasty.

^aOther includes 1 subject with glaucoma suspect, 1 subject with low-tension glaucoma, and 4 subjects with normal-tension glaucoma.

^bPatients may have had more than 1 previous ocular procedure.

At baseline, 218/242 (90.1%) patients used at least 1 IOP-lowering medication. Twenty-four subjects (9.9%) were not taking IOP-lowering medication at baseline visit and were classified as treatment naïve. Twelve percent of patients (29/242) used at least 1 other concomitant ocular medication that was not an IOP-lowering drug. In addition, 84.7% of subjects (205/242) at baseline used at least 1 concomitant systemic medication (that was not prescribed for IOP lowering). The most common non-ocular conditions (by MedDRA preferred term) in the patient medical history were hypertension in 147/242 patients (60.7%), hypercholesterolemia in 81 (33.5%), type 2 diabetes and postmenopause in 45 each (18.6%), gastroesophageal reflux disease in 38 (15.7%), and seasonal allergy in 37 (15.3%).

Efficacy

Patients receiving netarsudil monotherapy (n = 91) had a mean baseline IOP (± standard deviation [SD]) of 19.4 ± 4.46 mmHg (range, 11.0–34.0 mmHg) in the study eye. Of 91 netarsudil monotherapy patients, 67 (73.6%) were receiving IOP-lowering therapy at baseline and used netarsudil to replace either a prostaglandin analog (n = 57), a fixed-dose combination or 2 concomitant therapies (n = 6), or non-prostaglandin analog monotherapy (n = 4). At week 12, each of these subgroups achieved IOP reductions comparable to their prior therapies (changes from baseline of −0.6 ± 3.14, 0.0 ± 1.55, and 0.5 ± 0.71 mmHg, respectively). The subgroup that used netarsudil to replace prostaglandin analog therapy demonstrated a 2.5% IOP reduction from prostaglandin analog-treated baseline and 1–8% improvement in the percentage of patients meeting the IOP thresholds of ≤14 mmHg through ≤18 mmHg at week 12 (Figure 1(B)). Patients who used netarsudil monotherapy as replacement for multiple therapies (a fixed-dose combination or 2 agents; n = 6 patients) or as a replacement for non-prostaglandin analog monotherapy (n = 4 patients) showed no uniform trend in meeting IOP thresholds due to small subgroup sizes. While the majority of participants replaced either a prostaglandin analog or 2 agents with netarsudil, among netarsudil monotherapy patients overall, 8–12% more patients achieved IOP thresholds of ≤14 mmHg through ≤18 mmHg after 12 weeks of treatment compared to baseline (Figure 1(A)). In the subgroup of treatment-naïve patients receiving netarsudil monotherapy, a mean IOP reduction of 3.9 ± 3.57 mmHg (16.9%) occurred after 12 weeks of netarsudil, with 18–27% patients in this subgroup achieving IOP thresholds of ≤14 mmHg through ≤18 mmHg at week 12 versus baseline (Figure 1(C)).

Figure 1. Percentages of netarsudil monotherapy patients who achieved intraocular pressure thresholds in the study eye at week 12 (mITT population). (A) All netarsudil monotherapy patients; (B) netarsudil monotherapy replaced prostaglandin analog therapy; (C) treatment-naïve netarsudil monotherapy patients.

Figure 2. Percentages of patients receiving concomitant therapy who achieved intraocular pressure thresholds in the study eye at week 12 (mITT population). (A) all concomitant therapy patients; (B) netarsudil added to a prostaglandin analog; (C) netarsudil added to multiple drug classes; (D) netarsudil replaced 1 drug class or multiple drug classes (i.e. 2-agent fixed dose combinations) as concomitant therapy.

Patients receiving netarsudil as concomitant therapy (n = 151) had a treated mean baseline IOP of 20.3 ± 4.96 mmHg (range, 10.0–49.0 mmHg) in the study eye. All patients in this subgroup (including those at the high end of the baseline IOP range) received netarsudil with other IOP-lowering therapies in regimens decided by the treating investigator. Most patients were taking (in addition to netarsudil) either a prostaglandin analog (43.0%), a fixed-dose combination plus a prostaglandin analog (20.5%), or a fixed-dose combination (14.6%). As shown in Table 4, reductions in mean IOP (± SD) of the study eye occurred at week 12 in patients who added netarsudil to monotherapy (4.3 ± 2.88 mmHg; 20.5%), patients who added netarsudil to 2 or more classes of concomitant therapy (4.5 ± 4.08 mmHg; 20.9%), and in those who replaced 1 or more classes within concomitant therapy with netarsudil (0.4 ± 2.47 mmHg; 1.7%). Results for the group who added netarsudil to monotherapy are presented by baseline monotherapy (prostaglandin analog or beta blocker) in Supplementary Table 2, which shows a reduction at Week 12 of 5.5 ± 4.95 mmHg (27.5%) for the beta blocker group (n = 2) and 4.3 ± 2.84 mmHg (20.2%) for the prostaglandin analog group (n = 55).

Table 4. Intraocular pressure of the study eye in patients receiving concomitant therapy (mITT population).

	Netarsudil added to monotherapy (added to PGA or BB)	Netarsudil added to concomitant therapy (added to ≥ 2 classes concomitant therapy)	Netarsudil replaced ≥1 class in concomitant therapy
Baseline
n	57	64	30
Mean (SD), mmHg	21.2 (4.49)	20.6 (5.81)	18.2 (2.96)
Min–max, mmHg	10.0–35.0	12.0–49.0	13.0–23.0
Week 6
n	57	64	30
Mean (SD), mmHg	17.1 (4.25)	16.9 (5.16)	16.8 (3.89)
Mean change (SD), mmHg	−4.0 (2.82)	−3.7 (2.92)	−1.4 (3.34)
Mean % change (SD), mmHg	−18.8 (12.72)	−17.5 (15.43)	−7.0 (18.24)
Week 12
n	54	61	28
Mean (SD), mmHg	16.9 (4.45)	16.2 (5.86)	17.8 (3.39)
Mean change (SD), mmHg	−4.3 (2.88)	−4.5 (4.08)	−0.4 (2.47)
Mean % change (SD), mmHg	−20.5 (12.94)	−20.9 (17.62)	−1.7 (12.90)

Netarsudil added to concomitant therapy group includes fixed-dose combination (brinzolamide/brimonidine, dorzolamide/timolol, brimonidine/timolol, brimonidine/dorzolamide/timolol) and/or PGA (bimatoprost, travoprost, latanoprost, latanoprostene bunod, tafluprost) and/or alpha agonist (brimonidine) and/or BB (timolol, levobunolol, betaxolol) and/or carbonic anhydrase inhibitor (methazolamide, dorzolamide, brinzolamide). Abbreviations. BB, beta blocker; PGA, prostaglandin analog.

Among all patients using netarsudil with concomitant therapy, 19–40% more patients achieved IOP thresholds of ≤14 mmHg through ≤18 mmHg 12 weeks after incorporating netarsudil into their treatment regimens (Figure 2(A)). Improvements at week 12 were observed regardless of whether netarsudil was added to a prostaglandin analog, added to multiple drug classes, or replaced 1 or more drug classes as concomitant therapy (Figures 2(B–D)), as well as in the small group (n = 2) who added netarsudil to a beta blocker. Each of the subgroups using netarsudil as add-on therapy experienced a 15.5–20.4% reduction in IOP at week 6 and an 18.2–22.6% reduction at week 12. Of the 30 patients who replaced 1 or more drug classes with netarsudil, 25 replaced a single agent (15 who replaced prostaglandin analog monotherapy and 10 who replaced non-prostaglandin analog monotherapy) and 5 replaced at least 2 agent fixed-dose combination therapies. As with the patients who replaced previous prostaglandin analog monotherapy with netarsudil, those who replaced part of a concomitant therapy regimen with netarsudil achieved IOP thresholds at rates better than with their prior regimens (Figure 2(D)).

Safety and tolerability

Blood pressure was measured after subjects had been at rest in a sitting position for 5 min at baseline and follow-up visits. Mean systolic blood pressure (±SD) at baseline was 133.8 ± 16.43 mmHg and at week 12 was 130.6 ± 14.70 mmHg, mean diastolic blood pressure at baseline was 79.8 ± 9.97 mmHg and at week 12 was 78.2 ± 10.47 mmHg. No clinically significant changes in blood pressure were observed during the study in monotherapy or concomitant therapy groups.

Slit lamp grading of study eyes was completed for eyelids/lashes, conjunctiva, cornea, anterior chamber, and lens status/appearance, at each visit using standardized scales. The predominant finding on biomicroscopy was conjunctival hyperemia. In the majority of subjects with conjunctival hyperemia, the hyperemia occurred sporadically (162/260 [62.3%] subjects) rather than occurring at consecutive visits (61/260 [23.5%] subjects), and 34/260 (13.1%) experienced no conjunctival hyperemia. Mean conjunctival hyperemia assessed via biomicroscopy remained under 1.0 on a scale of 0–3 through week 12.

Similar percentages of patients in the monotherapy and concomitant therapy groups, respectively, experienced adverse events of any kind (37.4 and 42.2%), ocular adverse events (34.3 and 34.8%), and ocular adverse events related to treatment (28.3 and 33.5%) (Table 5). Most subjects (96.2%) who experienced adverse events (ocular and non-ocular) had a maximum of mild or moderate severity. Adverse events occurring at a frequency of ≥5% included conjunctival hyperemia (20.8%), vision blurred (7.3%), conjunctival hemorrhage (5.4%), and instillation site pain (5.4%), with incidences similar between monotherapy and concomitant therapy groups.

Table 5. Summary of adverse events.

n (%)	Overall, N = 260	Netarsudil monotherapy, n = 99	Netarsudil with concomitant therapy, n = 161
Patients with ≥1 AE	105 (40.4)	37 (37.4)	68 (42.2)
Patients with ≥1 ocular AE	90 (34.6)	34 (34.3)	56 (34.8)
Patients with ≥1 treatment-related AE^a	83 (31.9)	29 (29.3)	54 (33.5)
Patients with ≥1 ocular treatment-related AE	82 (31.5)	28 (28.3)	54 (33.5)
Patients with AEs leading to discontinuation^b	29 (11.2)	12 (12.1)	17 (10.6)
Patients with ocular-related AEs leading to discontinuation^b	26 (10.0)	9 (9.1)	17 (10.6)
Serious AEs	3	2	1
Ocular serious AEs	1	1	0
Treatment-related serious AEs	0	0	0
Deaths	0	0	0
AEs reported by ≥5% of patients
Conjunctival hyperemia	54 (20.8)	22 (22.2)	32 (19.9)
Vision blurred	19 (7.3)	9 (9.1)	10 (6.2)
Conjunctival hemorrhage	14 (5.4)	6 (6.1)	8 (5.0)
Instillation site pain	14 (5.4)	6 (6.1)	8 (5.0)

Abbreviation. AE, adverse event.

^aEach adverse event was evaluated by the investigator as not related, unlikely related, possibly related, or related to treatment. The patients shown here experienced adverse events assessed as unlikely related, possibly related, or related to treatment.

^bOne patient was excluded from this table because of early discontinuation due to a non–treatment-emergent event.

Twenty-nine subjects (11.2%) experienced adverse events that led to discontinuation, 12/99 (12.1%) in the monotherapy group and 17/161 (10.6%) in the concomitant therapy group. The adverse events leading to discontinuation were conjunctival hyperemia (n = 8; 3.1%), vision blurred (n = 8; 3.1%), instillation site pain (n = 4; 1.5%), conjunctival hemorrhage (n = 3; 1.2%), eye pruritus (n = 3; 1.2%), eye irritation (n = 1; 0.4%), noninfective conjunctivitis (n = 1; 0.4%), and pneumonia (n = 1; 0.4%). Two subjects from the netarsudil monotherapy group experienced a serious adverse event (1 case of malignant melanoma of the eyelid, 1 case of pneumonia), as did 1 subject from the concomitant therapy group (1 case of cellulitis of lower left extremity). None of the serious adverse events was considered related to treatment.

Patient and investigator assessment of treatment

At week 12 (or Early Exit visit), patients and investigators provided feedback to questions on prior and current IOP-lowering therapy. When asked “How well are you able to tolerate the study eye medication(s)?,” 89.1% of patients overall tolerated the study medication at least well (including 20.2% well, 23.9% mostly well, and 45.0% very well), with 2.9% not able to tolerate it. Responses were similar across the monotherapy (90.0%) and concomitant therapy (88.5%) subgroups. When asked “How much eye redness do you notice from using the study eye medication(s)?,” approximately two-thirds (67.2%) of subjects overall thought the study medication caused mild (22.7%), trace (21.0%), or no (23.5%) eye redness; this breakdown was similar across both subgroups, with 63.3% in the monotherapy subgroup and 69.6% in the concomitant therapy subgroup considering the redness to be mild, at most. Subjects who reported redness were also asked “How much are you bothered by eye redness?” Approximately three-quarters (77.5%) of subjects overall and of subjects in both subgroups (monotherapy 77.2%; concomitant therapy 77.6%) were not at all or only a little bothered by the redness. Among the investigators, 67.8% rated their subjects’ acceptability and tolerability of netarsudil as good or excellent. In comparison, 64.4% of investigators gave an overall rating of good or excellent acceptability and tolerability to their patients’ baseline IOP-lowering therapy. At the end of the study, investigators classified 15.9% of subjects as potential candidates for IOP-lowering surgery in the next 6–12 months, compared with 18.6% of subjects at baseline. Classifications were based on investigator judgment, from baseline to week 12.

Discussion

In this trial of patients with OAG or OHT who required IOP-lowering treatment in the real-world clinical setting, netarsudil demonstrated efficacy and tolerability across a wide range of treatment regimens. Netarsudil previously demonstrated IOP-lowering efficacy with an acceptable safety profile in clinical trials evaluating use as monotherapy or in combination with latanoprost for the treatment of OAG and OHT^15–18. Given the carefully controlled nature of pre-approval Phase 3 studies, those results may not always reproducibly reflect the conditions of daily practice, and real-world data are needed to more fully characterize IOP-lowering agents. This study of netarsudil enrolled a population with OAG or OHT treated at physician discretion in accordance with prevailing standards of practice. Participants required IOP lowering at baseline under commonly encountered scenarios using a variety of treatment regimens, including patients who were treatment-naïve or already using monotherapy or up to 5 agents. Investigators chose the IOP-lowering regimen provided to subjects, with netarsudil used as either monotherapy or part of a concomitant therapy regimen. While as a group, subjects had a relatively low mean (treated) IOP at baseline of 20.0 mmHg (baseline IOP ranging from 10 to 49 mmHg), the results demonstrated the consistent IOP-lowering efficacy of netarsudil, whether used as monotherapy or in conjunction with other medications.

Netarsudil decreased mean IOP from baseline in the monotherapy group overall, and subgroup analyses of the monotherapy group showed that netarsudil monotherapy decreased IOP in previously treatment-naïve patients and demonstrated comparable IOP control in patients replacing prostaglandin analogs (i.e. a 2.5% IOP reduction from previous prostaglandin analog treatment), which are among the most effective IOP-lowering agents⁸. Netarsudil used concomitantly with other agents showed a similar pattern, exhibiting the ability to reduce IOP when added to existing therapy and to achieve comparable IOP control when replacing part of a concomitant therapy regimen, in most cases replacing a prostaglandin analog or fixed-dose combination. Not only did netarsudil provide additive efficacy regardless of the class of drug to which it was added, but it provided a substantial and consistent IOP-lowering benefit regardless of the number of currently used antiglaucoma medications, up to and including maximal medical therapy, suggesting that netarsudil can override the principle of diminishing returns demonstrated in previous adjunctive use studies^19–21. This finding is consistent with the results of retrospective cohort studies that indicated no attenuation in efficacy when netarsudil was added to multiple IOP-lowering medications^22–24. In addition to its distinct mechanism of action of increasing trabecular outflow, netarsudil decreases episcleral venous pressure^11–14. Episcleral venous pressure plays an important role in determining IOP, and thereby netarsudil may be able to offer consistent IOP-lowering efficacy whether it is used as a first, second, third, or fourth IOP-lowering agent.

Major clinical studies in glaucoma have demonstrated that more aggressive IOP control, with treatment targets <20 mmHg, decreases the risk of visual field loss progression^2,5,25,26. Additionally, eyes with stricter IOP control over follow-up visits had a smaller chance of exhibiting fast deterioration²⁷. Accordingly, it is a notable finding of this study that substantial proportions of patients receiving netarsudil as monotherapy or concomitant therapy, overall and across the different therapy subgroups, had IOP under thresholds of ≤14 to ≤18 mmHg.

Netarsudil was associated with manageable ocular tolerability and a low incidence of systemic adverse events. Consistent with previous findings^15–18, ocular hyperemia was the most common adverse event and is a known vasodilatory side effect of ROCK inhibitors²⁸. The vast majority of subjects reported tolerating netarsudil well; this was also reported by most investigators. Although approximately one-third of subjects experienced treatment-related adverse events (most commonly, conjunctival hyperemia), none of these were serious adverse events, and only 11% of subjects discontinued the study due to adverse events. The discontinuation rate is comparable to the 3-month netarsudil dropout rates from the pooled ROCKET monotherapy trials (66/494 subjects [13.4%]) and the pooled monotherapy arms of the MERCURY-1 and 2 trials (70/499 subjects [14.0%])^29,30. Hyperemia was generally mild and sporadic, with only 1 case of severe hyperemia. Other common adverse events in this study with netarsudil (conjunctival hemorrhage, blurred vision, instillation site pain) are consistent with those reported in randomized, controlled netarsudil trials¹⁵. No new safety signals were discovered for netarsudil 0.02% in patients with OAG or OHT.

Several retrospective analyses of medical data collected from real-world clinical settings evaluated the effects of adding netarsudil to the treatment regimens of OAG or OHT patients with inadequate IOP control^{22,23,31–33}. Results consistently demonstrated significant decreases in IOP (ranging from 2.2 to 3.9 mmHg) beyond levels achieved with previous therapy, regardless of the number of IOP-lowering medications in the patient regimen^22,23,32,33. The present study substantiates these earlier findings with a prospective design and prespecified assessments, which are more likely to capture adverse events that may not be reported in routine practice. Further, the earlier studies did not specifically assess the use of netarsudil as replacement therapy, a commonly encountered situation in which a new agent is substituted for a previous monotherapy or for one or more components of a multi-treatment regimen.

Limitations of this study include the open-label design, the absence of a comparator group, and the possibility of improved medication adherence during study participation relative to pre-enrollment. By design, the study population was heterogenous in terms of medical history and treatment regimen, which resulted in small numbers of patients in some subgroups and precluded making statistical comparisons between treatment groups. As the study was conducted in the real-world setting, investigators were requested to schedule IOP assessments at the same time of day for each study visit, however, IOP checkpoints were not standardized across sites, raising the possibility that IOP at different visits was affected by diurnal fluctuations. Missing data were not imputed as part of the statistical analysis plan, therefore, the week 12 IOP data includes only patients who attended that study visit.

Conclusions

In summary, the results indicate that under conditions of routine clinical practice, incorporating netarsudil ophthalmic solution 0.02% into the treatment of OAG and OHT patients with insufficient IOP control was effective with manageable ocular tolerability. The introduction of netarsudil treatment as monotherapy or an adjunct to other topical treatments achieved clinically meaningful reductions in IOP, and the replacement of prior agents with netarsudil resulted in IOP control comparable to levels obtainable with established treatments such as prostaglandin analogs. Therefore, results from this study demonstrate that the benefits and safety of netarsudil, which were shown in rigorously controlled clinical trials, translate to the real world when used in the clinical practices of a diverse group of physicians.

Transparency

Declaration of funding

This work was funded by Aerie Pharmaceuticals, Inc., Durham, NC, which designed and conducted the study including data collection, management, and interpretation, as well as preparation, review, and approval of the manuscript.

Declaration of financial and other relationships

F. Z.: grant/research: Allergan, Aerie, Nicox; consultant/advisor: Ivantis, New World Medical; speaker bureau: Aerie, Allergan. S. C. G.: nothing to declare. G. F. S.: speaker: Aerie, Allergan; consulting fees: Allergan; research funding: Aerie (for the present study). C. S. and J. M. W. are employees of Aerie Pharmaceuticals, Inc., Durham, NC. Peer reviewers on this manuscript have received an honorarium from CMRO for their review work but have no other relevant financial relationships to disclose.

Acknowledgements

Medical writing and editorial assistance were provided by BioScience Communications, New York, NY, funded by Aerie Pharmaceuticals, Inc.