Accepted Manuscript

Netarsudil/Latanoprost Fixed-Dose Combination for Elevated Intraocular Pressure: 3-

Month Data From a Randomized Phase 3 Trial

Sanjay Asrani, Alan L. Robin, Janet B. Serle, Richard A. Lewis, Dale W. Usner,
Casey C. Kopczynski, Theresa Heah, On Behalf Of The Mercury-1 Study Group

PII: S0002-9394(19)30284-3
DOI: https://doi.org/10.1016/j.ajo.2019.06.016
Reference: AJOPHT 10995

To appear in: American Journal of Ophthalmology

Received Date: 26 February 2019

Revised Date: 10 June 2019
Accepted Date: 12 June 2019

Please cite this article as: Asrani S, Robin AL, Serle JB, Lewis RA, Usner DW, Kopczynski CC, Heah
T, On Behalf Of The Mercury-1 Study Group, Netarsudil/Latanoprost Fixed-Dose Combination for
Elevated Intraocular Pressure: 3-Month Data From a Randomized Phase 3 Trial, American Journal of
Ophthalmology (2019), doi: https://doi.org/10.1016/j.ajo.2019.06.016.

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 ACCEPTED MANUSCRIPT

ABSTRACT (251/250 words)

• PURPOSE: To compare the ocular hypotensive efficacy and safety of a fixed-
dose combination (FDC) of the Rho kinase inhibitor netarsudil and latanoprost vs
monotherapy with netarsudil or latanoprost.
• DESIGN: Three-month primary endpoint analysis of a randomized, double-
masked, phase 3 clinical trial.

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• METHODS: Adults with open-angle glaucoma or ocular hypertension
(unmedicated intraocular pressure [IOP] >20 and <36 mmHg at 8:00 AM) were
randomized to receive once-daily (PM) netarsudil/latanoprost FDC, netarsudil

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0.02%, or latanoprost 0.005% for up to 12 months. The primary efficacy endpoint
was mean IOP at 8:00 AM, 10:00 AM, and 4:00 PM at week 2, week 6, and month 3.
• RESULTS: Mean treated IOP ranged from 14.8–16.2 mmHg for

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netarsudil/latanoprost FDC, 17.2–19.0 mmHg for netarsudil, and 16.7–17.8 mmHg
for latanoprost. Netarsudil/latanoprost FDC met the criteria for superiority to each
active component at all 9 time points (all P < .0001), lowering IOP by an additional
1.8–3.0 mmHg vs netarsudil and an additional 1.3–2.5 mmHg vs latanoprost. At

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month 3, the proportion of patients achieving mean diurnal IOP ≤15 mmHg was
43.5% for netarsudil/latanoprost FDC, 22.7% for netarsudil, and 24.7% for
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latanoprost. No treatment-related serious adverse event (AE) was reported;
treatment-related systemic AEs were minimal. The most frequent ocular AE was
conjunctival hyperemia (netarsudil/latanoprost FDC, 53.4%; netarsudil, 41.0%;
latanoprost, 14.0%), which led to treatment discontinuation in 7.1%
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(netarsudil/latanoprost FDC), 4.9% (netarsudil), and 0% (latanoprost) of patients.

• CONCLUSIONS: Once-daily netarsudil/latanoprost FDC demonstrated IOP
reductions that were statistically and clinically superior to netarsudil and
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latanoprost across all 9 time points through month 3, with acceptable ocular
safety.
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 ACCEPTED MANUSCRIPT

Netarsudil/Latanoprost Fixed-Dose Combination for Elevated Intraocular

Pressure: 3-Month Data From a Randomized Phase 3 Trial
SANJAY ASRANI,* ALAN L. ROBIN, JANET B. SERLE, RICHARD A. LEWIS, DALE W.
USNER, CASEY C. KOPCZYNSKI, THERESA HEAH, ON BEHALF OF THE
MERCURY-1 STUDY GROUP
From the Duke University School of Medicine, Durham, North Carolina, USA (S.A.);

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Wilmer Institute and Bloomberg School of Public Health, Johns Hopkins University,
Baltimore, Maryland, USA and Kellogg Eye Center, University of Michigan, Ann Arbor,
Michigan, USA (A.L.R.); Icahn School of Medicine at Mount Sinai School, New York,

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New York, USA (J.B.S.); Aerie Pharmaceuticals, Inc., Irvine, California, USA;
Bedminster, New Jersey, USA; and Durham, North Carolina, USA (R.A.L., C.C.K.,
T.H.); Sacramento Eye Consultants, Sacramento, California, USA (R.A.L.); and

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Statistics & Data Corporation, Tempe, Arizona, USA (D.W.U.).

*Correspondence: Sanjay Asrani, Duke University School of Medicine, Box 3802 Med
Center, Durham, NC 27710, USA; Phone: 919-684-8656; E-mail:

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sanjay.asrani@duke.edu.
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Short title (57/60 characters): NETARSUDIL/LATANOPROST FIXED-DOSE COMBINATION
(MERCURY-1)
Supplemental Material available at AJO.com.
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 ACCEPTED MANUSCRIPT

Glaucoma is a progressive optic neuropathy that causes characteristic atrophy of

the optic nerve, which culminates in visual field loss and can eventually lead to
blindness. A major risk factor for glaucomatous visual field loss is elevated intraocular
pressure (IOP).1 Patients diagnosed with ocular hypertension, which are patients with
above-normal pressures yet no conclusive evidence of optic nerve damage or visual
field loss, have a significantly increased risk of developing glaucoma.2 Several clinical
studies support the general conclusion that greater reductions in IOP are associated

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with delays in disease progression in patients with glaucoma or ocular hypertension.1–4
IOP can be reduced using topical ocular hypotensive medications; however, for many
patients, monotherapy is insufficient to achieve target IOP, necessitating the use of

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multiple medications.2,5,6 The increased complexity associated with polypharmacy often
leads to decreased medication adherence,7–9 which may adversely impact clinical
outcomes. Fixed-dose combination (FDC) formulations of ocular hypotensive agents

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simplify treatment. However, the FDC products currently available in the United States
require multiple daily dosing and none contain a prostaglandin analog, the most
effective class of IOP-lowering agents. There is a need for an FDC that provides greater
efficacy than the prostaglandin analogs, with the convenience of once-daily dosing,

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which may improve medication adherence.
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For many patients with primary open-angle glaucoma, IOP is elevated due to an
abnormally high resistance to aqueous humor outflow via the trabecular (conventional)
pathway.10 The causes of increased resistance to trabecular outflow are not fully
understood, but changes in the contractile tone and stiffness of the trabecular
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meshwork, composition of the extracellular matrix, and permeability of the inner wall of
the Schlemm’s canal have been implicated.10,11 Most of the commonly used ocular
hypotensive agents do not specifically target the diseased trabecular meshwork.12,13
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In contrast, the recently approved Rho kinase (ROCK) inhibitor netarsudil14

reduces IOP, potentially through several mechanisms: increasing trabecular outflow,15–
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decreasing aqueous humor production,15,18 and reducing episcleral venous
pressure.18,19 Prostaglandin analogs, the most commonly prescribed of which is
latanoprost, lower IOP primarily by increasing uveoscleral (non-conventional) outflow.20
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Because netarsudil lowers IOP through different mechanisms of action, it may provide
additional IOP-lowering when used in combination with latanoprost. A once-daily FDC
product composed of netarsudil and latanoprost was evaluated for ocular hypotensive
efficacy and safety in the 12-month, phase 3 MERCURY-1 trial. Here, we present ocular
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hypotensive efficacy and safety (ocular and systemic) data from a pre-planned, 3-month
analysis of MERCURY-1, which compared once-daily netarsudil/latanoprost FDC with
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its individual components (once-daily netarsudil 0.02% and once-daily latanoprost

0.005%).
METHODS
Patients and Study Design
The MERCURY-1 study (ClinicalTrials.gov identifier NCT02558400; registered
on September 24, 2015) was a 12-month, double-masked, active-controlled, parallel-
group, randomized, phase 3 trial (56 active sites in 21 states across the United States).
Here we report results of the primary endpoint analysis, which was preplanned to be
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conducted at 3 months. The protocol was reviewed and approved by the institutional
review board/ethics committee, conducted in accordance with Good Clinical Practice
guidelines, and adhered to the Declaration of Helsinki. A list of study investigators is
provided in the online supplement. All patients provided written informed consent and
signed authorization for the Health Insurance Portability and Accountability Act prior to
initiation of any procedures or treatment. The MERCURY-1 trial was undertaken from
August 27, 2015 to June 30, 2017.

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Eligible patients had bilateral open-angle glaucoma or ocular hypertension and
were aged ≥18 years with unmedicated IOP >20 and <36 mmHg in both eyes at 8:00
AM at 2 qualification visits (2–7 days apart) and >17 and <36 mmHg in both eyes at

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10:00 AM and 4:00 PM at the second qualification visit. Patients using ocular
hypotensive medications were required to undergo washout prior to study entry: 4
weeks for prostaglandin analogs and β-adrenergic antagonists, 2 weeks for adrenergic

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agonists, and 5 days for muscarinic agonists and carbonic anhydrase inhibitors.21 Best-
corrected visual acuity in each eye was +1.0 logMAR or better by Early Treatment of
Diabetic Retinopathy Study (ETDRS) measurement.
Exclusion criteria included individuals treated with >2 ocular hypotensive

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medications within 30 days of screening, pseudoexfoliation or pigment dispersion
glaucoma, a history of iridocorneal angle closure or narrow angles (including previous
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peripheral iridotomy), previous glaucoma incisional or laser surgery, previous refractive
surgery, central corneal thickness >620 µm, or known hypersensitivity or
contraindications to netarsudil or latanoprost (or their excipients). Patients with clinically
significant ocular disease other than glaucoma in either eye or systemic disease that
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might interfere with the study, and women of childbearing potential who were pregnant,
nursing, planning a pregnancy, or not using a medically acceptable form of birth control
were also excluded.
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Patients were randomized (1:1:1) via an interactive web-based response system

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to receive netarsudil 0.02%/latanoprost 0.005% FDC, single-agent netarsudil

ophthalmic solution 0.02%, or single-agent latanoprost ophthalmic solution 0.005%.
Each study treatment was dosed once daily in the evening. Randomization was
stratified by investigative site and maximum baseline IOP (<25 vs ≥25 mmHg). The
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randomization code was prepared by an independent biostatistician not involved in day-

to-day study conduct. Treatment assignments were masked to the investigator, clinical
study team, and patients. An independent person at the investigative site not
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responsible for performing any study procedure was assigned to dispense, collect, and
store study treatment.
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Endpoints
The primary efficacy endpoint was mean IOP at 8:00 AM, 10:00 AM, and 4:00
PM at week 2, week 6, and month 3. Secondary efficacy endpoints included mean
diurnal IOP, mean change and mean percent change from diurnally-adjusted (time-
consistent) baseline IOP, and percentages of patients achieving prespecified thresholds
for mean, mean change, and mean percent change in mean diurnal IOP. Both eyes
were treated; the study eye was the eye with higher IOP at 8:00 AM on day 1, or the

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right eye in the event that IOP was the same in both eyes. The intent-to-treat population
included all randomized patients who received ≥1 dose of study medication and was the
primary population for efficacy analyses. The per protocol population was the subset of
patients in the intent-to-treat population who did not have major protocol violations and
was the secondary population for efficacy analyses.
Safety outcomes measures were ocular and systemic adverse events (AEs)

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during the 12-month treatment period. The present report summarizes safety data
collected up to the time of the prespecified 3-month primary efficacy analysis; safety
outcomes for the total study duration (12 months) will be reported separately. Safety
and tolerability were assessed using patient responses to open-ended questions (eg,

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“how are you feeling?”) and ophthalmic and systemic examinations. Ocular safety
assessments, which were undertaken at all study time points, included symptoms and
AEs coded per the Medical Dictionary for Regulatory Activities (MedDRA, Version 19.0),

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best-corrected visual acuity (ETDRS measurement), pupil size, biomicroscopy,
pachymetry, visual field and cup-disc ratio measurements, and dilated ophthalmoscopy.
Biomicroscopic examination of the eyelids, conjunctiva, cornea, anterior chamber, lens,

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iris, and pupil of both eyes was performed at every study visit. Systemic safety
assessments included measurements of heart rate, blood pressure, and clinical
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laboratory findings.
Statistics
The cut-off date for this pre-planned 3-month analysis was September 23, 2016.
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The primary efficacy analysis was performed on the intent-to-treat population and
employed a linear model with mean study eye IOP at a given visit and time point as the
response, baseline IOP as a covariate, and treatment as a main effect factor. Missing
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data were imputed using Markov Chain Monte Carlo multiple imputation techniques.
Statistical superiority was concluded if the P-value for the comparison of
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netarsudil/latanoprost FDC with each of its active components was <.05 and the point
estimate (netarsudil/latanoprost FDC minus comparator) was <0 for all time points at all
study visits. Statistical superiority for the primary endpoint required statistical
significance at all time points and visits; therefore, multiple comparison adjustments for
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Type I error was unnecessary. Assuming a true mean difference of 1.5 mmHg vs
latanoprost and 2.0 mmHg vs netarsudil at each of the 9 study time points, a 2-tailed
alpha of 0.05, a common standard deviation (SD) of 3.5 mmHg at each time point, and
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independence among time points (power increases with increasing correlation), 196
patients per treatment arm were needed to have ≥90% and >99% power to conclude
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the statistical superiority of netarsudil/latanoprost FDC to latanoprost and netarsudil,

respectively. Similar analyses were performed for the secondary endpoints of mean
diurnal IOP and mean change from diurnal and diurnally-adjusted (time-consistent)
baseline IOP.
Secondary analyses of the primary endpoint and continuous secondary
endpoints, as well as the percent change from diurnally-adjusted (time-consistent)
baseline IOP, were performed using 2-sample t-tests and 95% t-distribution confidence
intervals of the difference (netarsudil/latanoprost FDC minus comparator) between
netarsudil/latanoprost FDC and each of its active components at each time point and

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study visit. Mean diurnal IOP values were calculated by averaging the 3 diurnal IOP
measurements collected at each study visit. The numbers/proportions of patients
achieving mean diurnal IOP reductions from baseline ranging from ≥20% to ≥40%
(increments of 5%) and mean diurnal IOP ranging from ≤18 to ≤14 mmHg (increments
of 1 mmHg) at week 2, week 6, and month 3 were determined. Fisher’s exact test (2-
sided P-values) was used to test the pair-wise differences between
netarsudil/latanoprost FDC and each comparator for each category at each visit; only

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observed data were analyzed.
The safety analysis included all randomized patients who received ≥1 dose of
study medication (safety population). Safety outcomes were described using summary

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statistics. All statistical analyses were performed using SAS® version 9.4.
RESULTS

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Patient Demographics and Disposition
A total of 718 patients were enrolled. Baseline demographics were similar across
treatment groups (Table 1). The majority (75.2%, 540/718) of patients had a primary

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study eye diagnosis of open-angle glaucoma; the remaining patients had a primary
study diagnosis of ocular hypertension. Mean (SD) time from study eye diagnosis to
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baseline was 359.0 (389.6) weeks. In total, 73.8% (530/718) of patients were receiving
a glaucoma medication at or within 30 days of screening, with 55.3% (397/718), 7.0%
(50/718), and 11.6% (83/718) receiving prostaglandin monotherapy, other monotherapy,
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or combination therapy, respectively. Mean (SD) time on current ocular hypotensive

therapy was 181.1 (221.8) weeks. Most randomized patients (87.0%, 625/718)
completed 3 months of treatment (netarsudil/latanoprost FDC, 84.5% [201/238];
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netarsudil, 82.4% [201/244]; latanoprost, 94.5% [223/236]). Reasons for treatment

discontinuation are provided in Figure 1.
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Efficacy
Mean baseline IOP across the 3 diurnal time points (8:00 AM, 10:00 AM, and
4:00 PM) ranged from 22.4–24.8 mmHg for the 3 treatment groups. Between week 2
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and month 3, mean IOP ranged from 14.8–16.2 mmHg for netarsudil/latanoprost FDC,
17.2–19.0 mmHg for netarsudil, and 16.7–17.8 mmHg for latanoprost (Figure 2).
Netarsudil/latanoprost FDC met the criteria for superiority to each active component at
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all 9 time points (all P < .0001). Compared with netarsudil, netarsudil/latanoprost FDC
lowered IOP by an additional 1.8–3.0 mmHg, and compared with latanoprost,
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netarsudil/latanoprost FDC lowered IOP by an additional 1.3–2.5 mmHg (Figure 2).

Absolute reductions from baseline in mean IOP ranged from 7.2–9.2 mmHg, 5.1–6.1
mmHg, and 5.3–7.1 mmHg for netarsudil/latanoprost FDC, netarsudil, and latanoprost,
respectively (P < .0001 for all comparisons), corresponding to percentage reductions
from baseline in mean IOP of 30.9–36.7%, 21.8–24.9%, and 23.3–28.8%, respectively
(Table 2). The results of per protocol efficacy analyses did not differ substantially from
those of the primary intent-to-treat analyses.
In a prespecified responder analysis (observed data only), 82.0% (164/200) of
netarsudil/latanoprost FDC-treated patients achieved mean diurnal IOP ≤18 mmHg at

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month 3 vs 53.5% (106/198) of netarsudil-treated patients (P < .0001) and 69.1%

(154/223) of latanoprost-treated patients (P = .0023) (Figure 3, top). The proportions of
patients who achieved mean diurnal IOP ≤16 mmHg at month 3 were 61.0% (122/200),
31.8% (63/198), and 38.6% (86/223) for netarsudil/latanoprost FDC, netarsudil, and
latanoprost, respectively (P < .0001 for netarsudil/latanoprost FDC compared with each
component in both analyses). The proportion of patients achieving mean diurnal IOP
≤15 mmHg at month 3 was 43.5% for netarsudil/latanoprost FDC, 22.7% for netarsudil,

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and 24.7% for latanoprost (P < .0001 for netarsudil/latanoprost FDC compared with
each component in both analyses). The proportion of patients who achieved ≥30%
reduction from baseline in diurnal IOP at month 3 was 64.5% (129/200) for

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netarsudil/latanoprost FDC vs 28.8% (57/198) for netarsudil and 37.2% (83/223) for
latanoprost (P < .0001 for each comparison) (Figure 3 bottom). In addition, significantly
greater proportions of netarsudil/latanoprost FDC-treated vs netarsudil-treated or

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latanoprost-treated patients achieved mean diurnal IOP ≤14 mmHg at month 3 (Figure 3
top) and ≥40% reduction in mean diurnal IOP between baseline and month 3 (Figure 3
top).

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Safety
Over 3 months of treatment, 73.5% (175/238), 63.1% (154/244), and 40.7%
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(96/236) of patients treated with netarsudil/latanoprost FDC, netarsudil, and latanoprost,
respectively, experienced an AE. In total, ocular AEs were reported in 71.4% (170/238),
60.7% (148/244), and 30.9% (73/236) of patients treated with netarsudil/latanoprost
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FDC, netarsudil, and latanoprost, respectively. The corresponding values reported for
patients with a non-ocular AE were 14.3% (34/238), 12.3% (30/244), and 18.2%
(43/236), respectively. For the majority of patients with an AE, the maximum severity
was mild (netarsudil/latanoprost FDC, 81.1% [142/175]; netarsudil, 82.5% [127/154];
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latanoprost, 82.3% [79/96]). Serious AEs were reported in 2 netarsudil/latanoprost FDC-

treated patients, 2 netarsudil-treated patients, and 1 latanoprost-treated patient; none
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was considered related to treatment. Systemic treatment-related AEs were minimal;

most treatment-related AEs were reported in system organ class “eye disorders”
(netarsudil/latanoprost FDC, 87.4% [125/143]; netarsudil, 86.7% [111/128]; latanoprost,
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71.4% [40/56]). By month 3, 16.8% (40/238) of patients in the netarsudil/latanoprost

FDC group, 14.3% (35/244) of those in the netarsudil group, and no patient in the
latanoprost group discontinued study treatment due to an AE.
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The most frequent ocular AE was conjunctival hyperemia, which was reported in
53.4% (127/238), 41.0% (100/244), and 14.0% (33/236) of patients administered
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netarsudil/latanoprost FDC, netarsudil, and latanoprost, respectively (Table 3). Based

on AE reporting, conjunctival hyperemia was graded as mild in the majority of affected
patients (netarsudil/latanoprost FDC, 85.8% [109/127]; netarsudil, 89.0% [89/100];
latanoprost, 97.0% [32/33]). In most affected patients who completed 3 months,
conjunctival hyperemia (when reported as an AE) occurred intermittently
(netarsudil/latanoprost FDC, 63.0% [63/100]; netarsudil, 64.1% [50/78]; latanoprost,
62.5% [20/32]). Conjunctival hyperemia led to treatment discontinuation in 7.1%
(17/238) of patients randomized to netarsudil/latanoprost FDC, 4.9% (12/244) of those
randomized to netarsudil, and no patient randomized to latanoprost. On biomicroscopy,

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mean conjunctival hyperemia score across all study visits was <1 and remained
relatively unchanged from week 2 to month 3 in all treatment groups (Figure 4).
Other common ocular AEs included conjunctival hemorrhage and cornea
verticillata. Conjunctival hemorrhage was reported in 10.5% (25/238), 13.9% (34/244),
and 0.4% (1/236) of patients administered netarsudil/latanoprost FDC, netarsudil, and
latanoprost, respectively, and was reported as mild in all affected patients. Two patients,

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both in the netarsudil group, discontinued treatment due to conjunctival hemorrhage.
Cornea verticillata was reported in 5.0% (12/238) of netarsudil/latanoprost FDC-
treated patients, 4.1% (10/244) of netarsudil-treated patients, and no latanoprost-treated

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patient. All AEs of cornea verticillata were reported as mild, except in 1 netarsudil-
treated patient in whom the event was reported as moderate. Cases of cornea
verticillata were asymptomatic (ie, no apparent change in visual acuity among affected

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patients). One netarsudil/latanoprost FDC-treated patient was discontinued from study
treatment by the investigator due to cornea verticillata.
Other common AEs (>5% incidence) associated with netarsudil/latanoprost FDC

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were instillation site pain, eye pruritus, and increased lacrimation (Table 3). AEs other
than conjunctival hyperemia that resulted in treatment discontinuation in >1% of patients
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treated with netarsudil/latanoprost FDC were eye pruritus, allergic conjunctivitis,
increased lacrimation, and instillation site pain. There were no notable differences
between treatment groups for visual acuity, pupil diameter, ophthalmoscopy findings,
cup-to-disc ratio, visual field, eye drop comfort, vital signs, or clinical laboratory findings.
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DISCUSSION
In the primary efficacy analysis of this study of patients with open-angle
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glaucoma or ocular hypertension, once-daily (PM) netarsudil/latanoprost FDC produced

reductions in mean IOP that were statistically significantly superior to the IOP reductions
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achieved by either netarsudil or latanoprost across all 9 study time points, lowering IOP
by up to an additional 3 mmHg than its individual active components. According to
American Academy of Ophthalmology Preferred Practice Patterns, initial treatment of
patients should seek to reduce IOP by 20–30% relative to baseline.20 In a prespecified
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responder analysis, significantly more patients treated with netarsudil/latanoprost FDC

(64.5%) achieved ≥30% reduction in mean diurnal IOP compared with either netarsudil
(28.8%) or latanoprost (37.2%). These results confirm that netarsudil provides additional
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IOP-lowering when used in an FDC with latanoprost. This is notable, for prostaglandin
analogs are regarded as the most effective class of IOP-lowering agents, and no
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prostaglandin analogue-containing FDC is approved in the United States.20 The

significantly greater IOP reductions seen with netarsudil/latanoprost FDC are likely
attributable to the complementary mechanisms of action of its 2 active components, with
netarsudil primarily targeting trabecular outflow18 and latanoprost primarily targeting
uveoscleral outflow.20
In the Early Manifest Glaucoma Treatment Study, every 1-mmHg decline in IOP
was associated with a 10% decrease in the risk of glaucomatous disease progression.22
However, this study did not address at what level of IOP reduction the benefit of an
additional 1-mmHg reduction becomes diminished. In the Advanced Glaucoma

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Intervention Study (AGIS) VII report, patients with advanced disease who maintained
IOP <18 mmHg by medical or surgical intervention experienced a reduction in visual
field defect progression, and those who maintained IOP <14 mmHg experienced on
average no disease progression during the study period.1 In a prespecified responder
analysis of MERCURY-1, 82.0% of netarsudil/latanoprost FDC-treated patients
achieved mean diurnal IOP ≤18 mmHg at month 3 compared with 53.5% of netarsudil-
treated patients and 69.1% of latanoprost-treated patients. Furthermore, twice as many

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netarsudil/latanoprost FDC-treated patients (32.5%) achieved mean diurnal IOP ≤14
mmHg compared with either netarsudil-treated (13.6%) or latanoprost-treated (14.8%)
patients. These data suggest that netarsudil/latanoprost FDC has the potential to assist

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patients in achieving maximal IOP reductions, thereby delaying or preventing visual field
loss.
In this study, topical application of netarsudil/latanoprost FDC was associated

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with no treatment-related serious AEs, minimal treatment-related systemic AEs, and
tolerable ocular AEs. By month 3, 16.8% of patients in the netarsudil/latanoprost FDC
group, 14.3% of those in the netarsudil group, and no patient in the latanoprost group

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discontinued treatment due to AEs. Although discontinuation rates were higher for
netarsudil/latanoprost FDC than for latanoprost, this comparison may be influenced by
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the fact that patients with known hypersensitivity or contraindications to latanoprost
were excluded from enrollment. The safety profile of netarsudil/latanoprost FDC was
consistent with that of netarsudil monotherapy14,23,24 and latanoprost monotherapy,25
with no new AEs emerging with netarsudil/latanoprost FDC. Additionally, although the
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incidence of AEs was higher among netarsudil-latanoprost FDC-treated patients than

among those treated with either monotherapy, combination use of netarsudil and
latanoprost does not appear to be associated with an additive effect on AE incidence.
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The most frequent ocular AE among netarsudil/latanoprost FDC-treated and

netarsudil-treated patients was conjunctival hyperemia, which was generally mild in
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severity. This finding is consistent with prior clinical studies of single-agent

netarsudil23,26 and netarsudil/latanoprost FDC.27 The conjunctival hyperemia observed
in netarsudil/latanoprost FDC-treated and netarsudil-treated patients is possibly due to
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the vasodilatory effects of ROCK inhibition.28–31 Conjunctival hemorrhages were

observed intermittently via biomicroscopy in patients treated with netarsudil/latanoprost
FDC or single-agent netarsudil and generally resolved with continued dosing. Cornea
verticillata, which is a collection of lipid microdeposits localized to the corneal
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epithelium, was reported in ≤5% of netarsudil/latanoprost FDC-treated and netarsudil-

treated patients. Cornea verticillata forms through a process known as phospholipidosis,
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which occurs when cationic amphiphilic drugs like netarsudil bind to lysosomal
phospholipids.32–34 The development of cornea verticillata is associated with systemic
amiodarone and other United States Food and Drug Administration-approved drugs,
including subconjunctival gentamicin and tobramycin. It is typically asymptomatic, with
no apparent effect on visual function, and generally resolves following treatment
discontinuation.14,34,35
In conclusion, treatment with once-daily netarsudil/latanoprost FDC provided
clinically and statistically significantly greater IOP-lowering over 3 months than either of
its individual active components, with no treatment-related serious AEs, minimal

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treatment-related systemic AEs, and acceptable ocular safety. With once-daily dosing,
netarsudil/latanoprost FDC has the potential to reduce treatment burden, which may
improve adherence and clinical outcomes in patients with open-angle glaucoma or
ocular hypertension.

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Acknowledgments/disclosure
A. FUNDING/SUPPORT: The MERCURY-1 study was sponsored by Aerie
Pharmaceuticals, Inc., who participated in the design and conduct of the study; the
collection, management, analysis, and interpretation of data; and the preparation,
review, and approval of the manuscript.
B. FINANCIAL DISCLOSURE(S): Sanjay Asrani: consultant for Aerie Pharmaceuticals,

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Camras Vision, Regenex Bio, and Noveome Biotheraputics. Alan L. Robin:
consultant for Versant Health; financial support from National Institutes of Health,
and Glaucoma Research Foundation; honoraria from Aerie Pharmaceuticals, Inc.;
advisory board member for Aravind Eye Foundation; Executive Vice President of

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American Glaucoma Society. Janet B. Searle: advisory board member for Aerie
Pharmaceuticals, Inc.; consultant for Bausch & Lomb and Allergan; financial support
from National Institutes of Health, Allergan, and Ocular Therapeutix; Share-holder of

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Aerie Pharmaceuticals, Inc. Dale W. Usner: consultant for Aerie Pharmaceuticals,
Inc. Richard A. Lewis, Casey C. Kopczynski, and Theresa Heah are employees of
Aerie Pharmaceuticals, Inc.

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C. OTHER ACKNOWLEDGMENTS: Editorial assistance for this manuscript was
provided by Jamie Weaver, PhD, of CodonMedical, an Ashfield Company, part of
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UDG Healthcare plc, and was funded by Aerie Pharmaceuticals, Inc.
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33. Hollander DA, Aldave AJ. Drug-induced corneal complications. Curr Opin
Ophthalmol 2004;15(6):541–548.
34. Raizman MB, Hamrah P, Holland EJ, et al. Drug-induced corneal epithelial
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FIGURE CAPTIONS
FIGURE 1. Patient disposition. FDC = fixed-dose combination.
FIGURE 2. Mean intraocular pressure (intent-to-treat population). *P < .001 vs
netarsudil and latanoprost. Two-sided P-values. Markov Chain Monte Carlo used to
impute missing data. CI = confidence interval; FDC = fixed-dose combination; IOP =
intraocular pressure.

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FIGURE 3. Percentages of patients with (top) diurnal intraocular pressure reduced to
≤18 mmHg at month 3 and (bottom) ≥20% reduction in intraocular pressure between
baseline and month 3 (observed data only). aP < .0001 vs netarsudil and latanoprost. bP

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< .0001 vs netarsudil and P < .05 vs latanoprost. Fisher’s exact test. FDC = fixed-dose
combination; IOP = intraocular pressure.

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FIGURE 4. Mean conjunctival hyperemia score via biomicroscopy (8:00 AM).
Biomicroscopic grading of conjunctival hyperemia was performed on a standardized,
four-point scale (0 = none [normal; appears white with a small number of conjunctival
blood vessels easily observed]; 1 = mild [prominent pinkish-red color of both the bulbar

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and palpebral conjunctiva]; 2 = moderate [bright, scarlet red color of the bulbar and
palpebral conjunctiva]; 3 = severe [“beefy red” with petechiae; dark red bulbar and
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palpebral conjunctiva with evidence of subconjunctival hemorrhage]). Error bars indicate
SD of the observations. FDC = fixed-dose combination; SD = standard deviation.
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TABLE 1. Baseline Demographics

Netarsudil/ Latanopro
Netarsudil
Latanoprost st
0.02%
FDC 0.005%
N = 244
N = 238 N = 236
Sex, n (%)
Female 134 (56.3) 136 (55.7) 136 (57.6)

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Male 104 (43.7) 108 (44.3) 100 (42.4)
Race, n (%)
White 162 (68.1) 167 (68.4) 157 (66.5)

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Black/African American 69 (29.0) 70 (28.7) 67 (28.4)
Asian 7 (2.9) 6 (2.5) 10 (4.2)

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Multiple 0 1 (0.4) 2 (0.8)
Age, n (%)
<65 years 109 (45.8) 107 (43.9) 95 (40.3)
≥65 years 129 (54.2) 137 (56.1) 141 (59.7)

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Iris color, n (%)
Brown/black 141 (59.2) 137 (56.1) 154 (65.3)
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Blue/gray/green 68 (28.6) 73 (29.9) 62 (26.3)
Hazel 29 (12.2) 34 (13.9) 20 (8.5)
Study eye diagnosis, n (%)
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Open-angle glaucoma 174 (73.1) 186 (76.2) 180 (76.3)

Ocular hypertension 64 (26.9) 58 (23.8) 56 (23.7)
403.0 337.6 336.5
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Mean time since diagnosis, weeks (SD)

(451.7) (350.2) (356.6)
Received prior therapy, n (%)
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Combination therapy 31 (13.0) 29 (11.9) 23 (9.7)

Prostaglandin monotherapy 132 (55.5) 142 (58.2) 123 (52.1)
Other monotherapy 19 (8.0) 12 (4.9) 19 (8.1)
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None 56 (23.5) 61 (25.0) 71 (30.1)

Mean time on current hypotensive therapy, 180.9 176.8 186.1
weeks (SD) (240.7) (196.2) (227.8)
FDC = fixed-dose combination; SD = standard deviation.
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TABLE 2. Mean (95% CI) Percentage Change in Intraocular Pressure From Baseline
(Intent-to-Treat Population, Observed Data)
Netarsudil/Latanopro
Netarsudil 0.02% Latanoprost 0.005%
st FDC
N = 244 N = 236
N = 238
Week 2

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8:00 AM −36.7 (−38.4, −34.9) −24.9 (−26.5, −23.3) −27.7 (−29.3, −26.1)
10:00 AM −36.5 (−38.3, −34.7) −24.0 (−25.8, −22.2) −25.5 (−27.2, −23.7)
4:00 PM −33.6 (−35.3, −31.9) −23.3 (−25.1, −21.5) −23.3 (−24.9, −21.7)

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Diurnal −35.8 (−37.4, −34.3) −24.3 (−25.8, −22.8) −25.7 (−27.1, −24.2)
Week 6
8:00 AM −35.4 (−37.0, −33.8) −23.0 (−25.0, −21.0) −28.6 (−30.1, −27.1)

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10:00 AM −35.0 (−36.7, −33.2) −23.0 (−24.9, −21.2) −26.8 (−28.5, −25.1)
4:00 PM −31.3 (−33.1, −29.5) −21.8 (−23.7, −19.9) −23.9 (−25.7, −22.2)
Diurnal −34.3 (−35.8, −32.8) −23.0 (−24.6, −21.4) −26.7 (−28.2, −25.3)

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Month 3
8:00 AM −34.5 (−36.3, −32.7) −22.6 (−24.5, −20.6) −28.8 (−30.3, −27.3)
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10:00 AM −34.8 (−36.7, −33.0) −21.9 (−23.9, −19.9) −27.9 (−29.5, −26.2)
4:00 PM −30.9 (−32.9, −29.0) −22.8 (−24.7, −20.8) −25.3 (−26.9, −23.7)
Diurnal −33.7 (−35.4, −32.1) −22.8 (−24.5, −21.2) −27.6 (−28.9, −26.2)
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CI = confidence interval; FDC = fixed-dose combination.

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TABLE 3. Adverse Events Occurring in ≥5% of Patients in Any Treatment Group

Netarsudil/
Netarsudil 0.02% Latanoprost 0.005%
Latanoprost FDC
N = 244 N = 236
N = 238
Eye disorders, n (%)
Conjunctival
127 (53.4) 100 (41.0) 33 (14.0)

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hyperemia
Conjunctival
25 (10.5) 34 (13.9) 1 (0.4)
hemorrhage
Eye pruritus 18 (7.6) 17 (7.0) 3 (1.3)

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Increased lacrimation 14 (5.9) 15 (6.1) 1 (0.4)
Cornea verticillata 12 (5.0) 10 (4.1) 0
Administration site conditions, n (%)

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Instillation site pain 46 (19.3) 51 (20.9) 15 (6.4)
FDC = fixed-dose combination.

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Assessed for Eligibility

(N = 951)

Randomized
(N = 718)

Netarsudil/Latanoprost FDC Netarsudil 0.02% Latanoprost 0.005%

(n = 238) (n = 244) (n = 236)

Received Intervention Received Intervention Received Intervention

(n = 238) (n = 244) (n = 236)

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Discontinued Prior to Month 3 37 (15.5%) Discontinued Prior to Month 3 43 (17.6%) Discontinued Prior to Month 3 13 (5.5%)
Adverse Event 25 (10.5%) Adverse Event 23 (9.4%) Adverse Event 0
Withdrawal of Consent 4 (1.7%) Withdrawal of Consent 4 (1.6%) Withdrawal of Consent 4 (1.7%)
Non-compliant 0 Non-compliant 1 (0.4%) Non-compliant 1 (0.4%)
Lost to Follow-up 1 (0.4%) Lost to Follow-up 3 (1.2%) Lost to Follow-up 1 (0.4%)
Lack of Efficacy 0 Lack of Efficacy 5 (2.0%) Lack of Efficacy 1 (0.4%)
Disallowed Concurrent Medication 1 (0.4%) Disallowed Concurrent Medication 4 (1.6%) Disallowed Concurrent Medication 1 (0.4%)
Investigator Decision 2 (0.8%) Investigator Decision 0 Investigator Decision 0

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Protocol Violation 4 (1.7%) Protocol Violation 1 (0.4%) Protocol Violation 5 (2.1%)
Other 0 Other 2 (0.8%) Other 0

Completed Month 3
Completed Month 3 Completed Month 3
n = 201 (84.5%)
n = 201 (82.4%) N = 223 (94.5%)

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26
Netarsudil/Latanoprost FDC (n = 238)
25
Netarsudil 0.02% (n = 244)
24
Latanoprost 0.005% (n = 236)
23
Mean (SEM) IOP (mmHg) 22
21
20

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19
18
17
* *
16 *
*

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* * *
* *
15
14
8 AM 10 AM 4 PM 8 AM 10 AM 4 PM 8 AM 10 AM 4 PM 8 AM 10 AM 4 PM
Baseline Week 2 Week 6 Month 3

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Mean Mean Mean Mean
8:00 AM 10:00 AM 4:00 PM 8:00 AM 10:00 AM 4:00 PM 8:00 AM 10:00 AM 4:00 PM 8:00 AM 10:00 AM 4:00 PM
Diurnal Diurnal Diurnal Diurnal
Netarsudil/
Latanoprost FDC 24.8 23.7 22.6 23.7 15.6 14.9 14.8 15.1 16.0 15.3 15.3 15.5 16.2 15.3 15.4 15.6
(n = 238)
Mean IOP,

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Netarsudil
mmHg 24.8 23.5 22.6 23.6 18.6 17.8 17.2 17.9 19.0 18.0 17.5 18.2 18.9 18.2 17.2 18.1
(n = 244)
Latanoprost
24.6 23.4 22.4 23.5 17.8 17.4 17.2 17.5 17.7 17.1 17.0 17.3 17.6 16.9 16.7 17.1
(n = 236)

Difference From
Netarsudil/
Latanoprost FDC
(95% CI)
Netarsudil
(n = 244)
Latanoprost
(n = 236)
–

–
–

–
–

–
–

–
-3.0

-2.2
AN -2.9

-2.5
-2.4

-2.3
-2.8

-2.4
-3.0

-1.7
-2.7

-1.9
-2.2

-1.7
-2.7

-1.8
-2.7

-1.5
-2.9

-1.6
-1.8

-1.3
-2.5
(-3.6, -2.5) (-3.5, -2.3) (-2.9, -1.9) (-3.3, -2.3) (-3.6, -2.4) (-3.3, -2.2) (-2.7, -1.6) (-3.1, -2.2) (-3.4, -2.1) (-3.5, -2.3) (-2.4, -1.2) (-3.0, -2.0)
-1.5
(-2.8, -1.7) (-3.1, -1.9) (-2.9, -1.8) (-2.9, -1.9) (-2.3, -1.1) (-2.5, -1.3) (-2.2, -1.1) (-2.3, -1.3) (-2.1, -0.9) (-2.2, -1.0) (-2.0, -0.7) (-2.0, -1.0)
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100.0
Netarsudil/Latanoprost FDC (n = 200)

Netarsudil 0.02% (n = 198)

82.0b
80.0
Latanoprost 0.005% (n = 223)
71.0b
69.1

a
61.0
Percent of Patients

60.0

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54.3 53.5

43.5a 42.4
40.0 38.6

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24.7
22.7
20.0
13.6 14.8

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0.0
≤14 mmHg ≤15 mmHg ≤16 mmHg ≤17 mmHg ≤18 mmHg

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Mean Diurnal IOP

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100.0
Netarsudil/Latanoprost FDC (n = 200)
87.5b
Netarsudil 0.02% (n = 198)

80.0 77.0b 78.0

Latanoprost 0.005% (n = 223)

64.5a
61.0
Percent of Patients

60.0 56.1

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45.5a
42.9
40.0 37.2
35.0a

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28.8

20.6
20.0 17.7

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9.4
7.1

0.0
≥40 ≥35 ≥30 ≥25 ≥20

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Percentage Change from Baseline in Mean Diurnal IOP

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3.0
Netarsudil/Latanoprost FDC
Netarsudil 0.02%
Latanoprost 0.005%
2.5
Mean (SD) Conjunctival Hyperemia Score

2.0

1.5

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1.0

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0.5

0.0

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Baseline Week 2 Week 6 Month 3
Number
assessed: 238 243 235 227 235 230 216 217 223 236 238 233

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Table-of-Contents statement:

In the phase 3 MERCURY-1 study, once-daily netarsudil/latanoprost fixed-dose combination provided

clinically and statistically significantly greater intraocular-lowering over 3 months than either of its
individual active components, with no treatment-related serious adverse events, minimal treatment-

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related systemic adverse events, and acceptable ocular safety. With once-daily dosing,
netarsudil/latanoprost fixed-dose combination has the potential to reduce treatment burden, which may
improve adherence and clinical outcomes in patients with open-angle glaucoma or ocular hypertension.

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