Netarsudil Improves Trabecular Outflow
Facility in Patients with Primary Open Angle
Glaucoma or Ocular Hypertension: A Phase 2
Study
ARTHUR J. SIT, DIVAKAR GUPTA, ARASH KAZEMI, HAYLEY MCKEE, PRATAP CHALLA, KATY C. LIU, JAE LOPEZ,
CASEY KOPCZYNSKI, AND THERESA HEAH
• PURPOSE: Intraocular pressure (IOP) reduction is key
to controlling primary open angle glaucoma (POAG).
Pharmacotherapies for POAG or ocular hypertension
(OHT) commonly lower IOP by increasing uveoscleral
outflow or decreasing aqueous humor production. Netar-
sudil (Rhopressa), a Rho kinase inhibitor, reduces IOP by
improving trabecular outflow facility, which is reduced in
POAG. We investigated the effects of netarsudil on aque-
ous humor dynamics in patients with POAG or OHT.
• DESIGN: Double-masked, randomized, vehicle-
controlled, Phase 2 trial.
• METHODS: Netarsudil 0.02% was instilled in 1 eye and
vehicle into the contralateral eye of 20 patients once daily
in the morning for 7 days. The primary endpoint was
change in mean diurnal outflow facility on day 8 versus
that on day 1 (baseline). Outflow facility was measured
by using Schiøtz tonography, IOP by pneumotonome-
try, and episcleral venous pressure (EVP) by automated
venomanometry.
• RESULTS: Eighteen patients (90%) completed the
study. Mean diurnal outflow facility increased 0.039 ver-
sus 0.007 µL/min/mm Hg from baseline in the netarsudil-
and the vehicle-treated groups, respectively (P < .001 vs.
baseline for netarsudil), a treatment difference of 0.03
µL/min/mm Hg (P ≤ .001). Mean diurnal IOP change
from baseline at day 8 was −4.52 mm Hg for netarsudil
versus −0.98 mm Hg for vehicle, a treatment difference
of −3.54 mm Hg (P < .0001). Mean diurnal EVP change
from baseline was −0.79 mm Hg in the netarsudil-treated
group versus 0.10 mm Hg for vehicle, a treatment differ-
ence of −0.89 mm Hg (P < .001). All patients reporting
an adverse event reported conjunctival hyperemia of mild
or moderate severity.
Accepted for publication January 20, 2021.
From the Department of Ophthalmology, Mayo Clinic, Rochester, Min-
nesota, USA; Department of Ophthalmology, Duke University, Durham,
North Carolina, USA; Aerie Pharmaceuticals, Inc., Durham, North Car-
olina, USA
Inquiries to Arthur J. Sit, Mayo Clinic, Department of Ophthalmol-
ogy, 200 First Street SW, Rochester, Minnesota 55905, USA.; e-mail:
sit.arthur@mayo.edu
© 2021 THE AUTHORS. PUBLISHED BY ELSEVIER INC.
262 THIS IS AN OPEN ACCESS ARTICLE UNDER THE CC BY-NC-ND LICENSE
(HTTP://CREATIVECOMMONS.ORG/LICENSES/BY-NC-ND/4.0/).
• CONCLUSIONS: Netarsudil acts on the conven-
tional outflow pathway, both proximal and distal,
to significantly reduce IOP in POAG and OHT
by improving trabecular outflow facility and decreas-
ing EVP. (Am J Ophthalmol 2021;226: 262–269.
© 2021 The Authors. Published by Elsevier Inc.
This is an open access article under the CC BY-NC-
ND license (http://creativecommons.org/licenses/by-nc-
nd/4.0/))
P
rimary open angle glaucoma (POAG) is the second
leading cause of blindness in the United States and
worldwide.1 , 2 Elevated intraocular pressure (IOP) re-
sulting from increased resistance to aqueous humor outflow
is a critical risk factor for POAG and is, thus far, the only
causative factor that can be modified.3 Randomized con-
trolled clinical trials have demonstrated that IOP reduc-
tion slows the onset and progression of POAG4 , 5 ; there-
fore, pharmacological therapies to reduce elevated IOP are
the most common options for controlling and/or delaying
disease progression.6 , 7
The most common medications used for patients with
POAG or ocular hypertension (OHT) lower IOP by in-
creasing uveoscleral drainage (unconventional outflow
pathway) or by decreasing production of aqueous humor.8
Unfortunately, no IOP-lowering treatment is effective for
all patients, and previous medications that targeted the
trabecular meshwork (the primary site of pathology in
POAG)9-14 either work indirectly or are poorly tolerated
due to side effects. Pilocarpine, a muscarinic receptor ag-
onist, lowers IOP by increasing trabecular outflow facility,
but its pharmacological target tissue is the ciliary muscle
rather than the trabecular meshwork.15 , 16 Ciliary muscle
and pupil sphincter contraction from pilocarpine make the
drug poorly tolerated and limit its current therapeutic use.
Epinephrine reduces IOP by increasing outflow facility and
decreasing aqueous humor production,17 mediated at least
in part by its effect on the trabecular meshwork.18 However,
side effects of epinephrine resulted in poor tolerability, and
it is no longer commercially available. New treatments
0002-9394/$36.00
https://doi.org/10.1016/j.ajo.2021.01.019
are needed that lower IOP by directly targeting the site of
pathological changes in the outflow pathways.
Measurements of aqueous humor dynamics (AHD) en-
able determination of the mechanisms of change in
IOP.19-22 The main contributors to IOP are episcleral ve-
nous pressure (EVP), aqueous humor flow rate, and resis-
tance to outflow. The modified Goldmann equation models
IOP as a function of several variables that include both con-
ventional and unconventional (uveoscleral) outflow path-
ways:
1 Patients using ocular hypotensive medications within 30
IOP = EV P + (Q − U )
c
where EVP is episcleral venous pressure; C is outflow facility
(inverse of resistance); Q is aqueous humor production rate;
and U is the uveoscleral outflow rate.23 , 24
Rho kinase (ROCK) inhibitors are a drug class for the
treatment of POAG and OHT that have been shown in
preclinical studies to lower IOP by increasing trabecu-
lar outflow facility.25-27 Netarsudil, a Rho kinase and nor-
epinephrine transporter inhibitor, significantly lowered
IOP compared with timolol in patients with POAG or
OHT in 2 Phase 3 noninferiority studies and was approved
by the US Food and Drug Administration in December
2017 for the reduction of elevated IOP in those patients.28
A study to determine how netarsudil lowers IOP using per-
fused ex vivo normal human eyes found acutely increased
outflow facility through an expanded trabecular meshwork
and dilated episcleral vessels in the conventional path-
way.29 Further investigations of the mechanism of action
of netarsudil have been performed using animal models30-32
and healthy human volunteers.33 In those studies, netar-
sudil was shown to decrease IOP by increasing trabecu-
lar outflow facility30 , 31 , 33 and by reducing aqueous humor
production31 and EVP.32 , 33 The current study investigated
changes in AHD through measurements of trabecular out-
flow facility, EVP, and IOP in patients with POAG or OHT,
following treatment for 7 days with netarsudil ophthalmic
solution 0.02%.
METHODS
This multicenter, randomized, placebo (vehicle)-
controlled, double-masked Phase 2 study (Study of Ne-
tarsudil Ophthalmic Solution in Subjects With Primary
Open Angle Glaucoma [POAG] or Ocular Hypertension
[OHT]; NCT03233308) was conducted in accordance
with Institutional Review Board reviews of each study site
(Mayo Clinic Institutional Review Board, Rochester, Min-
nesota, USA; and Duke University School of Medicine
Institutional Review Board, Durham, North Carolina,
USA) and Good Clinical Practice regulations. Informed
VOL. 226 EFFECTS OF NETARSUDIL ON AQUEOUS HUMOR DYNAMICS
consent was obtained before any study-specific procedures
were initiated.
Patients attended a total of 3 study visits during which
assessments were made, beginning with a screening visit
(visit 1 [V1]) conducted up to 6 weeks prior to the qualifi-
cation/baseline visit (V2/day 1). Treatment-naïve patients
had the option to return for a qualification visit without
waiting for the washout period. Study drug or vehicle was
administered on days 2 through 7. On day 8 (V3), the final
treatment was administered on site at 8:00 AM, followed
by post-treatment assessments on that visit day.
days prior to screening underwent specific washout peri-
ods prior to the qualification visit (V2) according to the
medication(s) taken. Prostaglandins and β-adrenergic an-
tagonists had a minimum washout period of 4 weeks; α-
adrenergic agonists had a washout period of 2 weeks; and
muscarinic agonists and carbonic anhydrase inhibitors had
a washout period of 5 days.
Patients 18 years of age or older whose condition was di-
agnosed as POAG or OHT in both eyes were included in
the study; it was not necessary to have the same diagnosis
in both eyes. Patients were either treatment-naïve or being
treated with topical ocular hypotensive medications. For
patients to be enrolled, unmedicated (ie, post-washout or
treatment-naïve) IOP was required to be >20 and <30 mm
Hg at 8:00 AM, and >17 and <30 mm Hg at 1:00 PM and
4:00 PM in both eyes on V2 (day 1/baseline). Best-corrected
visual acuity was required to be equivalent to 20/200 or bet-
ter in each eye.
Exclusion criteria included clinically significant ocular
disease other than POAG or OHT. Patients with previ-
ously diagnosed pseudoexfoliation or pigment dispersion
glaucoma, angle closure glaucoma, or narrow angles were
excluded. Patients were also excluded if the intereye differ-
ence in IOP was >4 mm Hg (unmedicated) at any base-
line timepoint or if more than 2 ocular hypotensive medi-
cations were used within 30 days of screening. Patients with
previous glaucoma surgery or glaucoma laser procedures in
either eye, keratorefractive surgery in either eye, or previ-
ous peripheral iridotomy were also excluded, as well as those
with mean central corneal thickness >620 µm in either eye
at screening and those with recent or current ocular infec-
tions, clinically significant systemic disease, or any abnor-
mality preventing reliable applanation tonometry of either
eye.
Eyes were randomized to receive drug or vehicle control,
and patients were masked to treatments. For each patient, a
single drop of netarsudil ophthalmic solution 0.02% was in-
stilled into 1 eye, and the contralateral eye received vehicle
(placebo) once daily between 8:00 and 10:00 AM.
The primary efficacy endpoint of the study was change in
mean diurnal trabecular outflow facility on day 8 compared
with that on baseline (day 1). Mean diurnal outflow facil-
ity was defined as the average of facility measurements at
1:00 and 4:00 PM. Secondary objectives of the study were
263
to evaluate the effect of the study drug on IOP and EVP
compared with effects of the vehicle, and to evaluate ocu-
lar and systemic safety. Missing data were not imputed.
Outflow facility was measured noninvasively using
Schiøtz tonography34 (a custom digital tonometer was
used at Mayo Clinic and a tonometer manufactured by
V. Mueller and Co., Chicago, Illinois, USA, was used at
Duke University). A 5.5-g weight was used, and a pressure-
decay curve was obtained over 4 minutes.35 Outflow facility
was determined as described by the Grant equation34 and
Friedenwald table based on the Schiøtz scale change over 4
minutes.36
IOP was measured at each study visit and time point us-
ing a pneumotonometer (Model 30 Classic; Reichert, De-
pew, New York, USA). Two consecutive IOP measurements
of each eye were taken. If the 2 measurements differed by
more than 2 mm Hg, a third measurement was taken. Each
tonometry value was read as an integer and analyzed as the
mean of 2 or 3 measurements.
EVP was measured noninvasively using a custom-
designed slit-lamp-mounted computerized venomanome-
ter and assessments were made at the Mayo Clinic site
only.37 An inflatable bulb was placed over an episcleral vein
and pressure was automatically increased until blanching
of the episcleral vein was observed, which indicated com-
plete vessel collapse. Video recordings of the vessel col-
lapse were synchronized with pressure transducer measure-
ments. Image analysis software was used to determine the
point at which venous collapse began, which corresponded
to EVP.
Primary safety measurements were visual acuity and
biomicroscopy and dilated ophthalmoscopy results, and
treatment-emergent adverse events (TEAEs). Systemic
safety measurements were also included, such as heart rate,
blood pressure, and a urine test for pregnancy in females of
childbearing potential.
The modified intent-to-treat population (n = 18) in-
cluded all randomized patients who met the following cri-
teria: 1) at least 1 dose of study medication was adminis-
tered; 2) all baseline measurements and post-baseline mea-
surements for outflow facility were collected; and 3) mean
diurnal IOP was at least 2 mm Hg lower than baseline mean
diurnal IOP in the same eye treated with netarsudil (respon-
ders). For measurements of AHD, if results were missing in 1
eye, then the results for the contralateral eye were assumed
to be missing at the same time point. Baseline values for
all AHD (trabecular outflow facility, IOP, EVP) were col-
lected at 1:00 and 4:00 PM on day 1/V2. AHD measure-
ments from the same time point were compared (eg, the
measurement at 1:00 PM on visit 2 was the baseline for the
measurement at 1:00 PM on day 8/V3). All safety analyses
were conducted using the safety population (n = 20) of all
patients who received at least 1 dose of study drug.
Differences between treatment groups in terms of efficacy
variables were tested with paired t-tests. All statistical tests
were performed with a significance level of 5% (1-tailed).
264 AMERICAN JOURNAL OF OPHTHALMOLOGY
TABLE 1. Patient Demographics and Baseline
Characteristics (Randomized Population).
All Patients
Sex
Females 14 (70)
Males 6 (30)
Race
African American 5 (25)
White 14 (70)
Asian 1 (5)
Eye receiving netarsudil
Left 10 (50)
Right 10 (50)
Mean ± SD age, y 63.0 ± 12.5
Age range, y 28-77
Range of central corneal thickness, μm 502.0-618.5
Baseline ocular diagnosis 15 OHT/5 POAG
OHT = ocular hypertension; POAG = primary open-angle
glaucoma; SD = standard deviation.
Table data are mean ± SD, number range, or n (%).
RESULTS
Twenty patients were randomized to and received at least
1 dose of study drug. Eighteen patients (90%) completed
the study; all patients were responders. Two patients dis-
continued the study; 1 for an adverse event of conjunctival
hyperemia and the other for a protocol violation. Baseline
characterisitics are shown in Table 1.
Baseline mean ± SD diurnal outflow facility values were
0.126 ± 0.038 and 0.133 ± 0.043 µL/min/mm Hg in the ne-
tarsudil and vehicle groups, respectively (Table 2). At day
8, the absolute change from baseline was 0.039 ± 0.040
µl/min/mm Hg (P < .001 vs. baseline) for the netarsudil-
treatment group versus 0.007 ± 0.028 µL/min/mm Hg for
the vehicle-treatment group, a 0.03 µL/min/mm Hg differ-
ence between groups (P ≤ .001 vs. vehicle). The percent-
age change in mean diurnal outflow facility from baseline
was significantly greater in the netarsudil group (P < .001
vs. baseline) than in the vehicle group (34.6 ± 34.6% vs.
9.6 ± 25.6%, respectively), with a difference between the
treatment and control groups of 25.0% (P ≤ .01 vs. vehicle)
(Table 2).
Baseline IOP values were comparable between treatment
groups (∼22.95 mm Hg) (Table 3). The absolute change
in mean diurnal IOP from baseline to day 8 was −4.52 ±
1.58 mm Hg in the netarsudil group (P < .0001 vs. base-
line) and −0.98 ± 1.60 mm Hg in the vehicle group (P <
.01 vs. baseline), with a −3.54 mm Hg difference between
groups (P < .0001 vs. vehicle). The percentage of change
in mean diurnal IOP from baseline was significantly greater
in netarsudil-treated eyes (P < .0001 vs. baseline) than in
JUNE 2021
 TABLE 2. Netarsudil Effects on Mean Diurnal Outflow Facility Relative to Baseline and Placebo (Vehicle)-Treated Contralateral
Eyes (mITT Population).

Mean ± SD Mean ± SD Day 8

Netarsudil Ophthalmic Solution 0.02% Vehicle Netarsudil Difference from
(n = 18) (n = 18) Vehicle

Day 1 (baseline) observed, µL/min/mm Hg 0.126 ± 0.038 0.133 ± 0.043 —

Day 8 observed, µL/min/mm Hg 0.164 ± 0.053 0.139 ± 0.041 0.02a
Day 8 change from baseline, µL/min/mm Hg 0.039 ± 0.040c 0.007 ± 0.028 0.03c
Day 8 percentage change from baseline 34.6 ± 34.6c 9.6 ± 25.6 24.99b

mITT = modified intent-to-treat population; SD = standard deviation.

a
P < .05
b
P ≤ .01
c
P ≤ .001.

TABLE 3. Netarsudil Effects on Mean Diurnal Intraocular Pressure Relative to Baseline and Placebo (Vehicle)-Treated Contralateral
Eyes (mITT population).

Mean ± SD Netarsudil Mean ± SD Day 8

Ophthalmic Solution 0.02% Vehicle Netarsudil Difference from
(n = 18) (n = 18) Vehicle

Day 1 (baseline) observed, mm Hg 22.94 ± 1.64 22.95 ± 1.40 —

Day 8 observed, mm Hg 18.42 ± 1.57 21.97 ± 1.98 -3.56b
Day 8 change from baseline, mm Hg −4.52 ± 1.58b −0.98 ± 1.60a −3.54b
Day 8 percentage change from baseline −19.6 ± 6.1b −4.2 ± 7.0a −15.3b

mITT = modified intent-to-treat population; SD = standard deviation.

a
P < .01
b
P < .0001.

TABLE 4. Netarsudil Effects on Mean Diurnal Episcleral Venous Pressure Relative to Baseline and Placebo (Vehicle)-Treated
Contralateral Eyes (mITT Population).

Mean ± SD
Netarsudil Ophthalmic Solution Mean ± SD Day 8
0.02% Vehicle Netarsudil Difference from
(n = 9) (n = 9) Vehicle

Day 1 (baseline) observed, mm Hg 7.68 ± 1.31 7.35 ± 2.02 —

Day 8 observed, mm Hg 6.90 ± 1.01 7.45 ± 1.47 -0.55
Day 8 change from baseline, mm Hg −0.79 ± 0.84a 0.10 ± 0.71 −0.89c
Day 8 percentage change from baseline −9.5 ± 9.5b 3.10 ± 7.7 −12.6c

mITT = modified intent-to-treat population; SD = standard deviation.

a
P < .05
b
P < .01
c
P < .001.

vehicle-treated eyes after 7 days of treatment (−19.6 ±
6.1% vs. −4.2 ± 7.0%, respectively), with a difference be-
tween treatment groups of −15.3% (P < .0001 vs. vehicle).
The baseline mean diurnal EVP was slightly higher in the
netarsudil group than in the control group (7.68 ± 1.31 vs.
7.35 ± 2.02 mm Hg, respectively) (Table 4). The day-8 ab-
solute change in EVP from baseline was −0.79 ± 0.84 mm
Hg in the netarsudil group (P < .05 vs. baseline) versus 0.10
± 0.71 mm Hg in the vehicle group, with a treatment differ-
ence of −0.89 mm Hg (P < .001 vs. vehicle) (Table 4). The
percentage of change in EVP from baseline was a decrease
in the netarsudil group of −9.5% (P < .01 vs. baseline) and

VOL. 226 EFFECTS OF NETARSUDIL ON AQUEOUS HUMOR DYNAMICS 265

 TABLE 5. Adverse Events Associated with Once-Daily Morning Dosing by Maximum Severity.

Severity

Adverse Events Mild Moderate Severe Total AEs

Any TEAE (%)a 8 (40) 5 (25) 0 13 (65)

Eye disorders (%)a 8 (40) 5 (25) 0 13 (65)
Conjunctival hyperemia 9b (45) 4 (20) 0 13 (65)
Eye irritation 1 (5) 2 (10) 0 3 (15)
Vision blurred 1 (5) 1 (5) 0 2 (10)
Eye swelling 0 1 (5) 0 1 (5)
Photophobia 0 1 (5) 0 1 (5)

AE = adverse event; TEAE = treatment-emergent adverse event.

a
Patients having >1 adverse event within the category were counted only once for that category at the maximum adverse event severity.
b
One patient experienced mild conjunctival hyperemia and moderate eye irritation, hence was counted only once for the categories “Any
TEAE” and “Eye disorders,” under “Moderate” severity.
(Values).

an increase in the vehicle-treated group of 3.1% (P = .87 vs.
baseline), with a between-treatment difference of −12.6%
(P < .001 vs. vehicle) (Table 4).
• SAFETY: Once-daily treatment with netarsudil oph-
thalmic solution 0.02% in the morning for 7 days demon-
strated tolerable ocular safety (Table 5). All adverse events
were ocular in nature and reported only in netarsudil-
treated eyes. Adverse events were reported by 13 patients
(65.0%) and were mild or moderate in severity. No serious
adverse events were reported in the study.
The 13 patients who reported an adverse event reported
conjunctival hyperemia of mild or moderate severity. One
patient discontinued the study due to conjunctival hyper-
emia that was graded on biomicroscopy examination to be
mild in severity.
DISCUSSION
In our study of patients with POAG or OHT, once-daily
dosages of netarsudil ophthalmic solution 0.02% for 7 days
lowered IOP by improving outflow facility and reducing
EVP. Trabecular outflow facility increased by approximately
35% from baseline and 25% versus vehicle-treated controls
with netarsudil treatment. The change from baseline in tra-
becular outflow facility accounts for approximately 80% of
the mean change in IOP in the treatment group, which
decreased nearly 20% after 7 days of once-daily netarsudil
treatment. Netarsudil treatment also resulted in an approxi-
mately 10% decrease in EVP from baseline, which accounts
for approximately 20% of the change in the mean IOP for
the treatment group.
The increase in trabecular outflow facility is consistent
with the results from previous studies of cadaver eyes, ani-
mal models, and healthy human volunteers. In an ex vivo
study of normal human eyes, netarsudil was shown to signif-
icantly increase outflow facility by expansion of the juxta-
canalicular tissue of the trabecular meshwork and dilation
of episcleral veins, which enabled aqueous humor outflow
through a larger area of the inner wall of Schlemm’s canal.29
Animal studies also showed an increase in outflow facility
with netarsudil treatment, but the magnitude of effect ap-
pears to vary by species, with a study of normotensive mon-
keys demonstrating a much larger increase, 53% at 6 hours
after a single administration.31 However, that study used a
higher concentration of netarsudil (0.04% vs. 0.02% in our
study), and 2 drops (instead of a single drop) were given in
each eye.
The decrease in EVP with netarsudil treatment is also
consistent with previous human and animal studies. The
mean decrease in EVP in the current study was 9.5% com-
pared to baseline in the netarsudil treatment group. This is
similar to the results of our previous study of healthy human
subjects, which found a mean decrease in EVP of 10% com-
pared to baseline in the netarsudil-treated group.33 This is
not surprising given that baseline EVP values in both stud-
ies were similar (7.9 mm Hg in healthy human subjects vs.
7.7 mm Hg in our current study of POAG/OHT patients).
However, as with outflow facility, the effect of netarsudil
on EVP appears to be species-dependent. A study in Dutch
Belted rabbits reported a marked reduction (35%) in EVP
with netarsudil treatment,32 and the larger effect may be
related to a higher baseline IOP (33.2 ± 8.3 mm Hg) and
EVP (16.3 ± 3.4 mm Hg) compared to human subjects. It is
also possible that the difference in effect could be attributed
to differences in the method of measurement, as the rabbit
study involved removal of the overlying conjunctiva and
penetration of the vessel with a glass cannula for direct mea-
surement of EVP. These procedures could potentially af-
fect absorption of netarsudil into the episcleral vasculature.

266 AMERICAN JOURNAL OF OPHTHALMOLOGY JUNE 2021

Nevertheless, our results and those of previous studies sug-
gest an effect of netarsudil on the distal portion of the con-
ventional outflow pathway beyond Schlemm’s canal. Al-
though the mean reduction in EVP was modest (0.79 mm
Hg), even small reductions in IOP can be clinically signifi-
cant, as shown in the Early Manifest Glaucoma Trial, which
found that the risk of progression decreased by about 10%
with each mm Hg of IOP reduction.38
Although the present study did not assess aqueous hu-
mor production, a previous clinical study in healthy normal
volunteers did not detect a significant change in aqueous
humor flow rate with netarsudil.33 Again, there may be
species differences in the effect of netarsudil. A study on
normotensive monkeys reported a 23% decrease in aqueous
humor flow rate, as measured by fluorophotometry, 6 hours
after a single administration.31
Although the purpose of this study was not to determine
clinical efficacy, an understanding of the mechanisms of ac-
tion of netarsudil provides a rationale for its placement in
the glaucoma treatment algorithm. Previous clinical trials
have described the efficacy of netarsudil and shown non-
inferiority to timolol.28 , 39 Nevertheless, it is anticipated
that netarsudil will be used as second-line therapy or in
combination with prostaglandin analogs. As prostaglandin
analogs act primarily on the uveoscleral pathway,40-43 com-
pounds that act on the trabecular meshwork would be ex-
pected to have a complementary effect, and this has been
validated by the efficacy of fixed combinations of netarsudil-
latanoprost.44 We also anticipate that netarsudil and aque-
ous humor suppressant medications would have comple-
mentary effects, but this remains to be validated. The small
but statistically significant reduction in EVP in both glau-
coma patients and normal subjects suggests a possible role
for netarsudil in patients who already have IOP in the nor-
mal range but require further reduction, but this again re-
mains to be demonstrated.
The safety profile of netarsudil was consistent with those
of previous studies, although morning doses in the cur-
rent study produced a higher frequency of hyperemia (65%)
than reported for evening doses in previous registration
studies (50%-53%).28 The 13 patients who reported an ad-
verse event experienced mild or moderate conjunctival hy-
peremia.
In conclusion, once daily dosing of netarsudil ophthalmic
solution 0.02% in POAG and OHT patients lowered
IOP through multiple mechanisms of action, including in-
creased trabecular outflow facility and decreased EVP. Ne-
tarsudil appears to have a combination of mechanisms that
impact both the proximal and the distal portions of the con-
ventional outflow pathway.

ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST.
Funding/Support: This work was funded by Aerie Pharmaceuticals, Inc., Durham, NC, which designed and conducted the study including data collec-
tion, management, and interpretation, as well as preparation, review, and approval of the manuscript.
Financial Disclosures: Arthur J. Sit receives research support from Aerie Pharmaceuticals; and has a personal financial interest in Injectsense; and is a
consultant for Aerie Pharmaceuticals, Allergan, Bausch Health, Injectsense, and PolyActiva. Pratap Challa owns stock in Aerie Pharmaceuticals. Theresa
Heah is an employee of AsclepiX Therapeutics, and was an employee of Aerie Pharmaceuticals, at the time of the study. Divakar Gupta, Arash Kazemi,
and Katy C. Liu have no disclosures to report.
Acknowledgements: Medical writing and editorial assistance were provided by BioScience Communications, New York, New York, funded by Aerie
Pharmaceuticals, Inc.

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