Clinical and Experimental Optometry

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New considerations for the clinical efficacy of old

and new topical glaucoma medications

Sarah MacIver, Nicole Stout & Olivia Ricci

To cite this article: Sarah MacIver, Nicole Stout & Olivia Ricci (2021) New considerations for the
clinical efficacy of old and new topical glaucoma medications, Clinical and Experimental Optometry,
104:3, 350-366, DOI: 10.1080/08164622.2021.1877529

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Published online: 16 Mar 2021.

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CLINICAL AND EXPERIMENTAL OPTOMETRY
2021, VOL. 104, NO. 3, 350–366
https://doi.org/10.1080/08164622.2021.1877529

INVITED REVIEW

New considerations for the clinical efficacy of old and new topical glaucoma
medications
Sarah MacIver , BSc, OD, FAAOa, Nicole Stout , BSc, OD, FAAOb and Olivia Ricci , BSc, OD, FAAOa
a
School of Optometry and Vision Science, University of Waterloo, Waterloo, Ontario, Canada; bOklahoma College of Optometry, Northeastern
State University, Tahlequah, OK, USA

ABSTRACT ARTICLE HISTORY

Glaucoma is the most common form of irreversible blindness in the world. Lowering intraocular Received 9 April 2020
pressure (IOP) remains the only clinically established method of treatment to slow the progression of Revised 13 July 2020
glaucoma. Primary open angle glaucoma is a disease of the optic nerve head and often is associated Accepted 15 July 2020
with changes to the trabecular meshwork that cause a reduction to aqueous humour outflow and an KEYWORDS
increase in intraocular pressure. Until recently, topical IOP lowering medication has been limited to Glaucoma; IOP-lowering
the mechanisms of action of decreasing aqueous production and/or redirecting outflow to the medication;
unconventional uveoscleral outflow pathway. Both of these mechanisms neglect to treat or act on latanoprostene-bunod;
tissue that becomes altered from glaucoma. Latanoprostene-bunod 0.024%, a nitric-oxide donating netarsudil; trabecular
prostanoid, netarsudil 0.02%, a potent Rho-associated protein kinase (ROCK) inhibitor and norepi­ meshwork outflow
nephrine transporter inhibitor, and a once daily dosed fixed combination medication with netarsudil
0.02% and latanoprost 0.005% have recently come on the market. This paper will discuss and review
the limitations to traditional IOP lowering glaucoma medications as well as the mechanism of actions
and clinical efficacy of the new glaucoma medications. It will also discuss how the new class of
glaucoma medications might help to overcome some known limitations in treatment and barriers to
patient adherence.

Glaucoma is the most common form of irreversible blindness Current treatment protocols support starting a first line
in the world, second only to cataracts among all causes of therapy of either a prostaglandin analogue or beta blocker
blindness.1,2 Glaucoma refers to a group of diseases that and aiming for an IOP reduction of 20-30%.13 If first line
manifest as a characteristic progressive optic neuropathy therapy is not successful at achieving target IOP or if progres­
and retinal ganglion cell loss that eventually leads to perma­ sion is noted, a second line therapy is usually added by
nent loss of vision.3 switching to another class of medication or switching to
Glaucoma is a growing public health concern as the popu­ a combination medication which means the individual
lation continues to grow and age. The global glaucoma pre­ requires multiple doses of drops per day.8,13 A new class of
valence has been shown to be 3.54% and the number of medication to add to the available treatment options is long
people living with glaucoma is estimated to be around overdue. Ideally, a new glaucoma medication should be
65 million. It is thought that the number of people living equally as effective at lowering IOP as a prostaglandin analo­
with glaucoma worldwide will increase to over 110 million gue and preferably have a different mechanism of action.
in the year 2040.4 This is a concern given that vision loss from Overcoming known barriers to adherence and minimal side
glaucoma still occurs in patients receiving adequate treat­ effects is also desired. Three new topical glaucoma medica­
ment. The percentage of at least unilateral vision loss in tions: latanoprostene bunod 0.024%, netarsudil 0.02% and
patients with glaucoma being managed over a lifetime with fixed concentration netarsudil 0.02%/latanoprost 0.005%
medical or surgical intervention varies in the literature have recently completed relevant clinical trials and all have
between 5-40%.5–7 the ability to improve trabecular meshwork outflow with
Lowering intraocular pressure (IOP) remains the only clini­ once daily dosing.14–16
cally established method of treatment to slow the progres­ This paper will review the mechanisms of action and clin­
sion of glaucomatous visual field loss.8 The current means to ical relevance of three new glaucoma medications.
lower IOP for glaucoma management include medications, A discussion on the limitations of traditional IOP lowering
laser therapy and surgical interventions. To date, glaucoma glaucoma medications and how the new medications might
medication in the form of drops remain the most commonly help overcome some of these will follow.
used therapy although there are promising advances in the
use of sustained release devices9,10 and the use of laser
Latanoprostene bunod (Vyzulta)
therapy as a first line treatment.11 Despite new advances in
glaucoma treatment becoming available, patients still prefer Latanoprostene bunod (LBN) is not an entirely new class of
drops over more invasive options.12 It is unlikely that there glaucoma medications since it is still considered in the pros­
will be a global shift away from using eye drops for glaucoma taglandin analogue family. LBN breaks down into two active
in the near future and therefore the development of a new components on the ocular surface, latanoprost and butanei­
glaucoma medication is long overdue. dol mononitrate, a nitric oxide (NO) donating agent.17,18 LBN

CONTACT Sarah MacIver [email protected] School of Optometry and Vision Science, University of Waterloo, Waterloo, Ontario, Canada
© 2021 Optometry Australia
 CLINICAL AND EXPERIMENTAL OPTOMETRY 351

has three mechanisms of action: increasing aqueous humour using LBN treatment compared to timolol treatment and this
outflow through the conventional and uveoscleral outflow result was significant.28 Further investigation into whether
pathways as well as lowering episcleral venous pressure there is a difference in 24-h IOP lowering and ocular perfusion
(EVP).19 The NO donating agent is an endogenous signalling pressure increase between LBN and latanoprost 0.005% will be
mediator that induces cell relaxation in the trabecular mesh­ beneficial to compare the efficacy between these two
work by activating the NO–cyclic guanosine monophosphate medications.
signalling pathway. The NO–cyclic guanosine monopho­ The APOLLO and LUNAR study were phase 3 clinical studies
sphate signalling pathway is thought to have a role in widen­ that sought to confirm efficacy of LBN 0.024% compared to
ing the intercellular spaces in the trabecular meshwork, twice daily timolol 0.5% in subjects with open angle glaucoma
thereby increasing the conventional trabecular meshwork and ocular hypertension.29,30 The APOLLO study included 418
outflow.18,20,21 NO donors may also trigger the reduction of subjects with mean baseline IOP of 26.5 mmHg. Inclusion into
actomyosin contractility and disassembly of the actin cytos­ the study required baseline IOP to be greater than 22 mmHg,
keleton, as well as the cell adhesion system in the cells of the thereby excluding subjects with normal tension glaucoma.29
conventional outflow pathway. This causes cell shape Results of the study demonstrated that LBN 0.024% signifi­
changes and overall relaxation of the trabecular meshwork cantly lowered IOP compared to timolol 0.5% at all time points
and inner wall of the canal of Schlemm leading to a decrease over the three months efficacy study period with IOP reduc­
in resistance of aqueous humour outflow.22,23 In the episcleral tions of ≥ 25% in 35% of subjects compared to 19.5% of
circulation, NO likely causes vasodilation of arterioles and subjects in the timolol group.29 The LUNAR study included
arteriovenous anastomoses, thereby increasing blood flow 420 subjects with mean baseline IOP of 26.5 mmHg.30 The
to veins and subsequently lowering the EVP.18 This impact study again found that LBN 0.024% was superior to timolol
on EVP has primarily been demonstrated in animal studies 0.5% bid, with greater IOP lowering in the LBN group at all but
but the translation to clinical efficacy is still to be the earliest time point evaluated over three months.30
determined.21 An additional benefit of LBN over a single A pooled analysis of the APOLLO and LUNAR data showed
agent prostaglandin analogue is that NO has been shown to that LBN demonstrated a significant and sustained IOP low­
be faster acting and induce a more rapid IOP- lowering ering response throughout a 12-month period.14 Both studies
response.24 would have more applicability to clinical practice if they had
compared LBN to latanoprost or another prostaglandin, how­
ever, timolol 0.5% remains a standard choice for drug regis­
Clinical trials summary
tration trials which is likely why it was used in these studies.
The clinical trials evaluating LBN’s IOP lowering efficacy are The JUPITER study included subjects from Japan with
summarised in Table 1. The KRONUS study evaluated the 24-h a diagnosis of open angle glaucoma or ocular hypertension.31
IOP lowering impact of LBN 0.024% dosed once daily in It investigated the safety and efficacy of once daily LBN 0.024%
24 healthy Japanese men with normal (≤ 21 mmHg) IOP for one year. The mean baseline IOP was 19.6 mmHg and
and no glaucoma.25 After 14 days of use, there was a 27% therefore included subjects with normal tension glaucoma.
reduction of mean IOP from baseline and a significant reduc­ The baseline mean IOP was reduced by 22.0% in the study
tion of IOP from baseline at all time points over a 24-h eye and 19.5% in the treated fellow eye by week four and the
monitoring period.25 Results from this study demonstrate reductions were maintained throughout the 12-month study.31
the ability of LBN to effectively lower IOP when IOP is normal. The lower mean baseline IOP is likely the reason why the
The study suggests the potential superiority of LBN at mana­ reduction in IOP was less than the larger clinical studies.
ging normal tension glaucoma over other traditional IOP These large clinical trials were effective at proving that LBN
lowering medications that have demonstrated less IOP low­ 0.024% once daily at night-time is an effective IOP lowering
ering efficacy in individuals with lower baseline IOP values.26 agent that can be used as a first line therapy for individuals
The VOYAGER and CONSTELLATION studies were phase 2 with normal tension and ocular hypertension.14,31
clinical trials and compared LBN against the first line therapy of LBN 0.024% was very well tolerated in the safety analyses
latanoprost 0.005% to determine the ideal concentration27,28 of all the above studies, a summary can be found in Table 4a.
The VOYAGER study included 396 subjects with open angle Mild conjunctival hyperaemia was the most commonly
glaucoma or ocular hypertension; inclusion IOP range for the reported adverse event.25,28–31 Other less commonly reported
study was between 22 and 32 mmHg.27 The efficacies of four side effects included eye pain, eye irritation at the instillation
different concentrations of LBN, 0.006%, 0.012%, 0.024%, and site (3.6-11.5% occurrence) and punctate keratitis (1.10-
0.040% were investigated. The study concluded that both LBN 2.4%).25,28–31
0.024% and 0.040% reached successful primary endpoints of
lower diurnal IOP after 28 days compared to latanoprost and
Netarsudil (Rhopressa)
the other concentrations of LBN. LBN 0.024% was selected as
the optimal concentration because it had fewer side effects The Rho-associated protein kinase (ROCK) inhibitors are the
and fewer subject drop out than LBN 0.040%.27 The first, truly new, class of glaucoma medications since the pros­
CONSTELLATION study included 25 subjects with bilateral tanoid analogues were introduced in the late 1990s. ROCK is
early glaucoma or ocular hypertension and compared once present in the trabecular meshwork and canal of Schlemm and
daily LBN 0.024% with twice daily timolol 0.5%.28 The study helps cells drive actomyosin contraction, promote extracellular
measured IOP over a 24-hour period. A significant IOP reduc­ matrix production, and increase cell stiffness, thus contributing
tion was noted in subjects taking LBN 0.024% during diurnal to outflow resistance in glaucoma.32 In animal and human
and nocturnal sleep periods compared to baseline; the noctur­ models, ROCK inhibitors have been shown to increase trabe­
nal benefit was not related to supine positioning. Greater cular outflow facility and lower IOP.32–35 Earlier animal studies
nocturnal ocular perfusion pressure was measured in subjects even demonstrated a potential neuroprotective effect by
 352

Table 1. A summary of the large clinical trials investigating the clinical efficacy of latanoprostene bunod.
IOP am IOP pm
Medications Duration of Mean IOP Change from Change from
Study reference Study Design n Diagnosis of subjects compared Mean age study Mean IOP reduction Baseline baseline Baseline baseline Other notes
S. MACIVER ET AL.

KRONUS25 (Phase 1) single arm, single 24 24 healthy Japanese Latanoprostene 26.8 years 14 days 13.6 10 NR (−4.2 mmHg) 30% NR (−2.8 mmHg) 20% 3.6 mmHg or
centre open label clinical men bunod 27%
study 0.024% QD reduction
from
baseline
VOYAGER27 (Phase 2) randomised, 396 396 completed study; LBN 0.006%, 60.8–61.6 28 days LBN 0.006% Day 28: LBN NR Day 28: LBN NR Day 28: LBN LBN 0.024%
investigator-masked, OAG (including 0.012%, 26.12 mmHg; 0.006% 0.006% 0.006% had highest
parallel group, dose- pigmentary or 0.024% LBN 0.012% (−7.81 mmHg); (−8.45 mmHg); (−7.17 mmHg); proportion
ranging study pseudoexfoliation 0.040%) QD 26.25 mmHg; LBN 0.012% (- LBN 0.012% LBN 0.012% of subjects
syndrome) or OHT; vs LBN 0.024% 8.26 mmHg); (−8.83 mmHg; (−7.79 mmHg; with IOP <
IOP > 22- latanoprost 26.01 mmHg; LBN 0.024% LBN 0.024% LBN 0.024% 18 mmHg at
32 mmHg after 0.005% QD LBN 0.040% (−9.0 mmHg); (−9.59 mmHg; (−8.59 mmHg; all
28-day washout at 8pm 26.04 mmHg; LBN 0.040% LBN 0.040% LBN 0.040% timepoints
period latanoprost (−8.93 mmHg); (−9.64 mmHg; (−8.44 mmHg; especially
0.005% latanoprost latanoprost latanoprost compared to
26.15 mmHg 0.005% 0.005% 0.005% latanoprost
(−7.77 mmHg) (−8.64 mmHg) (−6.25 mmHg) group
CONSTELLATION28 (Phase 2) randomised cross- 25 25 subjects bilateral LBN 0.024% QD 60.3 ± 24 hours 23.2 mmHg NR Diurnal/wake LBN 0.024% Nocturnal/sleep LBN 0.024% OPP difference
over, clinical trial early glaucoma or 8pm vs 10.6 years (sitting) 17.6 mmHg; supine 23.2 mmHg; between
OHT. 4-week timolol 0.5% 21.6 mmHg timolol 25.7 mmHg timolol 0.5% LBN and
washout BID 8am and 18.9 mmHg 25.6 mmHg timolol
8pm p = 0.10
significance;
LBN better
at nocturnal
lowering
compared to
timolol
APOLLO29 (Phase 3) randomised, 418 Open angle LBN 0.024% QD 64.2 3 months LBN 0.024%: 8am 3 months: LBN 4pm 3 months: 17.8 LBN 0.024%:
controlled, multicenter, glaucoma or OHT vs timolol (active 26.7 mmHg; 0.024% LBN 0.024% 30% had >
double-masked, parallel (included 0.5% BID controlled) timolol 18.7 mmHg; 17.8 mmHg; 25 % CFB vs
group pigmentary and randomised then 26.5 mmHg timolol timolol 18.5% in
pseudoexfoliation in 2:1 ratio 9-month 19.7 mmHg 19.2 mmHg timolol
syndrome) safety (−1.0 diff (IOP diff of −1.3 group. 17%
extenstion p = 0.002) p < 0.001 had mean
significance) IOP <
18 mmHg
LBN, vs
11.1% in
timolol)
(Continued)
Table 1. (Continued).
IOP am IOP pm
Medications Duration of Mean IOP Change from Change from
Study reference Study Design n Diagnosis of subjects compared Mean age study Mean IOP reduction Baseline baseline Baseline baseline Other notes
LUNAR30 (Phase 3) randomised, 420 Open angle LBN 0.024A% 64.7 3 months LBN 0.024% 8am 3 months: LBN 4pm 3 months: LBN 30% had > 25
multicenter, double glaucoma or OHT qhs vs (active 26.6 mmHg; 0.024%; 0.024% % CFB in
masked, parallel group, (included timolol 0.5% controlled) timolol 18.7 mmHg; 17.7 mmHg; LBN group
clinical study pigmentary and BID in 2:1 then 26.4 mmHg timolol timolol vs 18.5% in
pseudoexfoliation ratio 3-month 19.6 mmHg 19.1 mmHg timolol
syndrome) safety (−0.9 p = 0.006) (−1.3 diff group. 17%
extenstion p < 0.01) had mean
IOP <
18 mmHg
LBN, 11.1%
in tim)
Pooled APOLLO Pooled analysis of two phase 3 840 Open angle LBN 0.024% qhs 64.5 3 months LBN 0.024% 32% for LBN vs 8am 3 months: LBN 4pm LBN 0.024% 71.9% vs 60.2%
and LUNAR14 randomised, multicenter, glaucoma or OHT vs timolol followed 26.7 mmHg; 27.6% for tim 0.024% 17.8 mmHg; IOP < 18, 60
double masked parallel (included 0.5% bid by 3- or timolol (p < 0.001%) 17.9 mmHg; timolol vs 41% IOP
group, non inferiority pigmentary and 9-month 26.5 mmHg timolol 19.1 mmHg ≤17; 46.4%
studies) pseudoexfoliation safety 19.2 mmHg (−1.3 p < 0.001) vs 33.55 for
syndrome) study (−1.3 p < 0.001) IOP ≤ 16, 31
vs 19% for
IOP ≤ 15,
19% vs 9%
for IOP ≤ 14
(p < 0.001
for all)
JUPITER31 Single arm, multicenter, open- 121 Open angle Safety and IOP 62.5 12 months 19.6 mmHg 22% reduction by Up to 50% had
label clinical study glaucoma or OHT efficacy for week 4, a change
LBN 0.024% 12 months: IOP from
only reduction 26.3 baseline of >
% (p < 0.001) 5 mmHg and
26% mean
IOP
reduction
after
12 months
in a mostly
normal
tension
glaucoma
population.
Abbreviations: IOP: intraocular pressure; LBN: latanoprostene bunod; NR: not recorded in study; OHT: ocular hypertension; POAG: primary open angle glaucoma; QD: once daily dosing.
CLINICAL AND EXPERIMENTAL OPTOMETRY
353
354 S. MACIVER ET AL.

improving blood flow to the optic nerve after topical applica­ determined to be equivalent to timolol 0.5% twice a day.
tion in rabbit eyes.3 The mean reduction in IOP from baseline was clinically rele­
Netarsudil (formerly AR 13324) is the first ROCK inhibitor to vant and statistically significant in both groups. Unlike the
become available clinically for glaucoma. Preclinical trials ROCKET 1 and 2 studies, ROCKET 4 demonstrated that netar­
identified netarsudil as having 20+ fold greater potency sudil 0.02% was at least equivalent to twice daily timolol 0.5%
than other clinically studied ROCK inhibitors, and is one of in subjects with IOP < 30 mmHg and this was sustained after
the most potent ROCK inhibitors described to date.36 The six months of treatment.15,43
norepinephrine inhibition that is unique to netarsudil is While netarsudil 0.02% has not consistently demonstrated
thought to be the reason why netarsudil has shown the a potential to be a more effective first line therapy compared
ability to decrease aqueous humour production and to a prostaglandin analogue, it may be a preferred first line
decreased episcleral venoius pressure in addition to increased treatment choice for patients with normal tension glaucoma
trabecular outflow facility.33,36–38 or when a prostaglandin is contra-indicated or not desired by
In preclinical models, netarsudil has been shown to lower the patient. Netarsudil is at least equally as effective as timolol
IOP via three effects on aqueous humour dynamics: 1) 0.5% but with once a day dosing at nighttime and no risk of
increasing trabecular outflow facility, 2) decreasing produc­ systemic side effects.39,43 It may also be a more
tion of aqueous humour (shown in monkeys) and 3) decreas­ beneficial second line therapy because of its once a day dos­
ing episcleral venous pressure (shown in rabbits).38–41 ing, milder side effects and different mechanism of action
compared to other medications.
Netarsudil was well tolerated in the safety analyses of the
Clinical trials summary
above studies. Similar to LBN, the most common adverse event
A summary of the IOP lowering efficacy of netarsudil from was conjunctival hyperaemia, likely due to ROCK inhibition
clinical trials is shown in Table 2. The ideal concentration of leading to localised blood vessel dilation.15,42 The ROCKET 1
netarsudil was investigated in a double-masked, randomised, study noted that hyperaemia was more commonly reported
dose response study.42 224 subjects with primary open angle and identified by the investigators rather than the subjects.15
glaucoma or ocular hypertension were randomised to either Corneal verticillata, was another prevalent, yet mild, adverse
netarsudil 0.01%, 0.02% or latanoprost 0.005%, all dosed once event with incidence ranging from 4.4.15,41 The presence of
daily. The inclusion range of IOP was between 22 and corneal verticillata did not cause discontinuation of the med­
36 mmHg. The subjects taking netarsudil did not demon­ ication. A detailed description of the safety events reported in
strate superiority or equivalency to latanoprost 0.005% after the clinical trials of netarsudil is done in Table 4b.
28 days of use, but a significant reduction in IOP from base­
line was noted in subjects taking netarsudil (p < 0.001). Of
Fixed combination netarsudil 0.02% – latanoprost
importance, netarsudil did show similar efficacy to latano­
0.005% (Rocklatan)
prost in a subgroup analysis that excluded subjects with
baseline IOP > 26 mmHg suggesting that netarsudil may be Fixed combination medications help improve adherence to
more beneficial when used in individuals with lower baseline glaucoma medication by decreasing the number of medica­
IOP.42 tion bottles and dosing.44 The new fixed dose combination
ROCKET 1 and 2 were phase 3 clinical trials evaluating medication of netarsudil 0.02% combined with latanoprost
1,167 subjects with primary open angle glaucoma or ocular 0.005% (FCNL) has IOP lowering capabilities from both the
hypertension.15 The range of baseline IOPs included in the ROCK inhibitor and prostaglandin analogue and is dosed
studies was 17 and 27 mmHg which allowed for inclusion of once a day at nighttime. The four mechanisms of action
subjects with normal tension glaucoma. Subjects were ran­ include increased trabecular meshwork outflow, decreased
domised to netarsudil 0.02% once daily, timolol 0.5% twice aqueous humour production, decreased episcleral venous
daily or netarsudil 0.02% twice daily (ROCKET 2 study only). pressure and increased uveoscleral outflow facility.16,45
ROCKET 1 and 2 showed that after 3-months of treatment,
netarsudil 0.02% once daily showed clinically relevant and
Clinical trials summary
statistically significant reductions in IOP from baseline.
Netarsudil was at least equivalent to timolol when compared A summary of the main studies investigating the IOP lowering
to subjects with IOP < 25 mmHg.15 The ROCKET 2 data efficacy of FCNL is found in Table 3. Lewis et al. investigated
showed that netarsudil 0.02% was effective at consistently the IOP lowering efficacy of latanoprost 0.005% combined
lowering IOP over a 12-month period and that it was well with two netarsudil concentrations, 0.01% and 0.02%, relative
tolerated by the majority of subjects.39 ROCKET 2 also to the active components of latanoprost 0.005% and netarsu­
included a noninterventional corneal observation study for dil 0.02% individually.46 All topical medications were dosed
patients manifesting cornea verticillata (whorl keratopathy) once daily at nighttime. After 28 treatment days, FCNL 0.02%
and reported an incidence of 26%. The severity of corneal met the criteria of superiority against latanoprost 0.005% and
verticillata was mild and did not cause a reduction in visual netarsudil 0.02% and provided additional IOP lowering com­
acuity in any of the subjects. It was also only reported by the pared to the individual components.46
investigators and not the subjects.15,39 The MERCURY phase 3 clinical trials investigated the IOP
ROCKET 4 was a phase 3 clinical trial that included 708 lowering efficacy and safety of FCNL 0.02% compared to the
subjects with either primary open angle glaucoma or ocular individual components, latanoprost 0.005% and netarsudil
hypertension.43 Unmedicated IOP was between 20 and 0.02%.16,45 MERCURY 1 enrolled 718 subjects and reported
30 mmHg at 8:00am. Subjects were randomised to either three-month and 12-month primary endpoint data. Baseline
netarsudil 0.02% once daily or timolol maleate 0.5% twice IOP range was between 20 and 36 mmHg. A statistically sig­
daily. After three months of treatment, netarsudil was nificant reduction in IOP from baseline was noted in all three
Table 2. A summary of the large clinical trials investigating the clinical efficacy of netarsudil.
IOP am IOP pm
Medications Mean Duration
Study reference Study Design n Diagnosis of participants compared age of study Mean IOP Mean IOP reduction Baseline Change from baseline Baseline Change from baseline Other notes
Dose response Double-masked, 224 OAG or OHT with AR-13324 (now 65.1 28 days (Mean diurnal (Mean diurnal IOP) after 28 days: (0.01%)
study of AR- randomised unmedicated IOPs in netarsudil) IOP) 25.8 20.1 mmHg (0.02%) 20.0 mmHg
13324 versus study in 22 range of 22-36 mmHg 0.01% daily (PM), (0.01%), 25.6 (latanoprost 0.005% 18.7 mmHg. All
AR-13324 0.02%
latanoprost42 private practice (0.02%) and decreases from baseline were significant
(PM) or
ophthalmology latanoprost 25.5 (lat) (p < 0.001)
clinics 0.005% QD

ROCKET 115 Phase 3 study 411 Bilateral OAG or OHT. IOP Netarsudil 0.02% QD 65 3 months NR NR (8am) baseline in 8am: 3 months: (4pm) Baseline in (4pm) 3 months: Netarsudil had greater
describing between > 20 and < PM and timolol primary group (IOP Primary group primary group (IOP Primary group (IOP efficacy at 2 weeks,
ROCKET 1 and 27 (no pigment BID < 27 mmHg): (IOP < 27 mmHg): < 27 mmHg) < 27 mmHg) 6 weeks and 3 months
ROCKET 2 data. dispersion or PXE) netarsudil 0.02% QD netarsudil 0.02% netarsudil 0.02% QD netarsudil 0.02% when compared to
Double masked 23.42 mmHg; QD 19.81 mmHg, 21.78 mmHg, timolol QD 18.48 mmHg, timolol in post hoc
randomised, timolol 0.5% timolol 0.5% 0.5%BID timolol 0.5% BID analysis which used IOP
multicentre, 23.37 mmHg. 18.47 mmHg Post 21.45 mmHg. 17.74 mmHg. Post < 25 (as opposed to
parallel group Baseline in Post Hoc hoc group (IOP < Baselne in Post Hoc hoc group (IOP < main group which was
studies (IOP < 25 mmHg) 25 mmHg) (IOP < 25 mmHg) 25 mmHg) < 27 mmHg); The IOP
netarsudil 0.02% netarsudil 0.02% netarsudil 0.02% QD netarsudil 0.02% reduction with
22.39 mmHg, 18.22; timolol 20.62 mmHg; timolol 17.02 mmHg, netarsudil once daily
timolol 0.5% BID 0.5% 17.91 mmHg 0.5% BID timolol 0.5% was 15–22%
22.50 mmHg 20.52 mmHg 17.37 mmHg In comparison with
17–22% with timolol
39
ROCKET- 2 Phase 3 Double- 756 Bilateral OAG or OHT. Netarsudil 0.02% qd 64 12 month NR NR (8am) netarsudil 0.02%: (8am at 3 month) (4pm) netarsudil 0.02% (4pm at 3 months) Netarsudil 0.02% QD and
masked, PM or BID am/ 22.4 mmHg QD, netarsudil 0.02% 20.43 mmHg QD, netarsudil 0.02% BID was non inferior to
randomised, pm vs timolol 22.55 mmHg BID 18.24 mmHg QD, 20.56 mmHg BID, 17.13 mmHg QD, timolol 0.5% BID
multicentre, 0.5% bid and timolol 0.5% 17.58 mmHg BID, timolol 0.5% 16.51 mmHg BID,
parallel-group, 22.54 mmHg and timolol 0.5% 20.71 mmHg timolol 0.5%
noninferiority 17.47 mmHg; (8 16.95 mmHg
clinical study am 12 month)
netarsudil 0.02%
18.80 mmHg QD,
17.96 mmHg BID,
timolol 0.5%
17.55 mmHg
ROCKET 443 Double masked 708 POAG or OHT (IOP 17- Netarsudil 0.02% vs 64.1 3 months 20.7-22.4 mmHg (8am) baseline (Primary (8am) 3 months (4pm) baseline (Primary (4pm) 3 months Percent reductions in IOP
randomised, 30 mmHg. Primary timolol 0.5%bid group) netarsudil netarsudil 0.02% group) netarsudil netarsudil 0.02% Ranged from 18.7 to
phase 3 non- analysis only included 0.02% QD QD 17.86 mmHg; 0.02% 20.69 mmHg; 16.73 mmHg; 21.4% and 18.1 to
inferiority study subjects with IOP < 22.40 mmHg timolol 0.5% BID timolol 0.5% BID timolol 0.5% BID 22.9% for netarsudil
25, secondary timolol 0.5% BID 17.29 mmHg 20.69 mmHg 16.80 mmHg And timolol,
analyses were done 22.44 mmHg (non-inferiority respectively
with subjects with IOP criteria met)
< 27 mmHg and IOP <
30 mmHg
CLINICAL AND EXPERIMENTAL OPTOMETRY

Abbreviations: BID: twice daily dosing; IOP: intraocular pressure; NR: not recorded in study; OHT: ocular hypertension; POAG: primary open angle glaucoma; QD: once daily dosing.
355
 356

Table 3. A summary of the large clinical trials investigating the clinical efficacy of fixed concentration netarsudil and latanoprost.
IOP am IOP pm
Diagnosis of Medications Duration of
Study reference Study Design n subjects compared Mean age study Mean IOP Mean IOP reduction Baseline Change from baseline Baseline Change from baseline Other notes
FDC of AR-13324 Double masked 298 OHT or OAG Comparison of 64.9 28 days 25.1-26 mmHg Mean IOP reduction FCNL 0.02% met the criterion
and randomised netarsudil 0.01%/ at day 29: for statistical superiority
latanoprost45 parallel latanoprost 17.3 ± 2.8, relative to both latanoprost
comparison study 0.005% (PG 324 16.5 ± 2.6, and netarsudil 0.02%,
0.0.1%), netarsudil 18.4 ± 2.6 and (p < 0.0001), providing
0.02%/latanoprost 19.1 ± 3.2 mmHg additional IOP lowering of
S. MACIVER ET AL.

0.005% (PG 324 in PG 0.01%, PG 1.9 (90% CI 1.2 to 2.6) and

0.02%), 0.02%, Lat, AR 2.6 mm Hg (90% CI 1.8 to
latanoprost 13324 3.4), respectively. At Day 29
0.005% and AR 38% of patients had IOP ≤
13324 0.02% 15 in 0.02% group,
compared to 8% in
latanoprost and 10% in
netarsduil (p < 0.001)
MERCURY 116 Phase 3; 12 month, 718 Bilateral POAG FCNL qd vs netarsudil NR 3 month data 23.5-23.7 mmHg 3 months: FCNL 8 am baseline: FCNL: 8am 3 months: FCNL 4pm baseline: FCNL: 4pm 3 month FCNL 3 months reduction from
double masked- or OHT IOP 0.02% QD vs from 15.6 mmHg; 24.8 mmHg; netarsudil 16.2 mmHg; netarsudil 22.6 mmHg; netarsudil 15.4 mmHg; netarsudil baseline IOP:: FCNL 34%;
active controlled >20 and <36 latanoprost 12 month netarsudil 0.02% 0.02% 24.8 mmHg; 0.02% 18.2 mmHg; 0.02%: 22.6 mmHg 0.02% 18.1 mmHg; netarsudil: 22.6%;
parallel group, 0.005% QD 18.1 mmHg; latanoprost 0.005% latanoprost 0.005% latanoprost 0.005%: latanoprost: latanoprost: 29%.
randomised phase latanoprost 24.6 mmHg 17.3 mmHg (IOP 22.4 mmHg 17.1 mmHg. (IOP 82% had IOP ≤ 18 in FCNL;
3 trial 0.005% difference from baseline difference from baseline 53.5% ≤18 in net group and
17.1 mmHg in FCNL vs netarsudil in FCNL vs netarsudil 69.1% in latanoprost group.
0.02% and latanoprost 0.02% and latanoprost 32.5% lower than 14 in
0.005% is significant 0.005% is significant FCNL, 13.5% < 14 in net
(p < 0.001) (p < 0.001) group and 14.8 % < 14 in
latanoprost group
MERCURY 1 As above As above As above As above 12-month data 25.1-26 mmHg 12 months: FCNL: 8am baseline: FCNL: 8am 12 months: FCNL 4pm baseline: FCNL: 4pm 12-month FCNL 2-month extension study: FCNL
(continued)46 16.2 mmHg, 24.8 mmHg; netarsudil 16.9 mmHg; netarsudil 22.6 mmHg; netarsudil 15.8 mmHg; netarsudil and netarsudil
netarsudil: 17.9; 0.02% 24.8 mmHg; 0.02% 18.4 mmHg; 0.02%: 22.6 mmHg 0.02% 17.9 mmHg; demonstrated a durable
latanoprost latanoprost 0.005% latanoprost 0.005% latanoprost 0.005%: latanoprost: IOP-lowering effect, with
17.6 mmHg 24.6 mmHg 17.9 mmHg (IOP 22.4 mmHg 17.6 mmHg. (IOP fewer than
difference from baseline difference from baseline Half of patients in the
in FCNL vs netarsudil in FCNL vs netarsudil netarsudil (37.5%) and FCNL
0.02% and latanoprost 0.02% and latanoprost (46.2%) groups
0.005% is significant 0.005% is significant Returning to baseline IOP
(p < 0.001) (p < 0.001 after 2 months without
treatment
MERCURY 245 Phase 3 double 750 Bilateral POAG (1:1:1) randomisation NR 3 months 23.5-23.7 mmHg 3 months: FCNL 8am baseline: FCNL 8 am 3 months FCNL 4pm baseline FCNL 4pm 3 month: FCNL Percentage change in IOP from
masked, or OHT >20 of FCNL, netarsudil 15.9 mmHg; 24.7 mmHg; netarsudil 16.5 mmHg; netarsudil 22.4 mmHg; netarsudil 15.6 mmHg; netarsudil baseline (diurnal) 3 months:
randomised, to <36 0.02%: latanoprost netarsudil 0.02% 0.02% 24.6 mmHg; 0.02% 19.8; latanoprost 0.02%: 22.8 mmHg; 0.02% 17.9 mmHg; FCNL 32.5%; netarsudil
active-controlled, 0.005% all QD 18.6 mmHg; latanoprost 0.005% 0.005%: 18.0 mmHg latanoprost 22.6 mmHg latanoprost 0.005%: 20.5%; latanoprost 25.4%
multicenter site. dosing latanoprost 24.8 mmHg 17.1 mmHg lat.
0.005%: FCNL: 76.5 % had IOP ≤ 18
17.5 mmHg at 3 months compared to
46.1% in netarsudil and
66% in lat;
FCNL 32.1% IOP ≤ 14 vs
8.4% in netarsudil and 8.9%
latanoprost.
MERCURY 1 and 2 Phase 3 studies 1468 OHT or bilateral 1:1:1 randomisation 64.3-64.9 3 months 23.50-23.62 At 3 months: FCNL: 8am baseline FCNL 8am 3 month: FCNL 4pm baseline: FCNL 4pm Month 3: FCNL The proportion of patients who
pooled data16 combined POAG 15.80 mmHg, 24.76 mmHg; netarsudil 16.38 mmHg, netarsudil 22.48 mmHg; netarsudil: 15.57 mmHg; netarsudil achieved at least a 40%
(pooled netarsudil 0.02% 0.02% 24.73 mmHg, 19.39 mmHg, 22.69 mmHg; latanoprst 17.57 mmHg; reduction from baseline in
data) 18.38 mmHg, latanoprost 0.005% latanoprost 0.005% 22.51 latanoprost mean
latanoprost 24.67 mmHg 17.85 mmHg 16.93 mmHg Diurnal IOP was 30.9% with
0.005% FCNL compared with 5.9%
17.33 mmHg with
Netarsudil (p < 0.0001) and
8.5% with latanoprost
(p < 0.0001).

Abbreviations: BID: twice daily dosing; FCNL: fixed concentration netarsudil 0.02%/latanoprost 0.005%; IOP: intraocular pressure; NR: not recorded in study; OHT: ocular hypertension; POAG: primary open angle glaucoma; QD: once daily dosing.
Table 4. Safety comparison of latanoprostene bunod, netarsudil, fixed concentration netarsudil/latanoprost based on large clinical trials.
Study Adverse reactions recorded
Severe
effects
related to
Abnormal Instillation or possibly
Conjunctival Ocular Punctate sensation Corneal Blurry Eye Subonjunctival Pain on site related to
hyperaemia hyperaemia Irritation keratitis in eye verticillata Pain Vision Prutitis Tearing haemorrhage instillation erythema drop Others
a. LBN Clinical Trials
KRONUS25 LBN 0.024% (28 50% 54.20% 4.20% None
eyes)
Treated fellow 50% 50% 4.20% None
eye (27 eyes)
27
VOYAGER 1) LBN 0.006% 1.20% 1.20% 1.20% 1.20% 2.40% 14.60% None 1 headache (possibly related), 1 gastric ulcer/GI
haemorrhage (likely unrelated)
2) LBN 0.012% 3.60% 6% 2.4.% 1.20% 0.00% 16.70% None 1 headache
3) LBN 0.024% 4.80% 2.40% 3.60% 2.40% 0.00% 12% None 1 headache
4) LBN 0.040% 3.70% 4.90% 6.20% 2.50% 0.00% 17.30% None
5) Latanoprost 0% 8.50% 0.00% 1.20% 0.00% 6.10% None 1 gastric ulcer haemorrhage, 1 acute MI (likely
0.005% unrelated)
28
CONSTELLATION 1) LBN 0.024% 1 (0.02%)—on 0% 1 (0.02%) None 1 nausea, 1 hyperhidrosis
instillation
2) timolol 0% 1 (0.02%) 3 (0.07% None 1 dizziness, 1 dyspnoea, 1 nausea, 1 dec BP, 2
maleate 0.5% - on dec HR (significant bradycardia – withdrew
instillation from study)
APOLLO29 1) LBN 0.024%, 2.80% 3.90% FBS 1.1% 1.40% 1.10% None *2 headaches, one fatigue, one sinus
study eye congestion, one hair colour change/hair
disorder
2) LBN 0.024% 3.60% 3.60% FBS 1.8% 2.50% 0.70% None 1 mild conj oedema
fellow eye
3) timolol 1.50% 2.20% 0% 2.20% 1.50% None *5 timolol subjectsd/c d/t lid oedema (likely
maleate 0.5% related), eye irritation (likely related),
allergic conjunctivitis, elevated IOP
4) timolol 2.20% 2.20% 0% 0.70% 2.20% None **timolol: 1 bradycardia, 1 procedural
maleate 0.5% headache, 1 rhinorrhoea
fellow eye
LUNAR30 1) LBN 0.024% 9% 2.50% 7.20% 1.10% FBS— 5.80% 1.80% 1.40% 1.40% None Corneal stain 1.1% (3 pt’s), 1 madarosis, 1 chest
1.1% discomfort, 1 dysgeusia, 1 headache, 1
insomnia, 1 dyspnoea
2) timolol 0.70% 0.70% 4.40% 0% FBS 0% 3.70% 2.20% 0.70% 0% None 2 headaches, 1 dizziness, 1 somnolence
maleate 0.5%
Pooled APOLLO and 1) LBN 0.024% 5.90% 2.00% 4.60% 3.60% 2.00% 1 blepharospasm, 1 conj hyperaemia, 1 allergic
LUNAR14 conjunctivitis, 1 RVO, 1 IOP increase, 1 lid
tumour, 5 headaches, 1 dysgeusia (only
definitely related ADR to tx)
2) timolol 1.10% 0.70% 2.60% 2.20% 1.80% 1— instillation site pain
maleate 0.5%
5 headaches
JUPITER30 1) LBN 0.024% 17.70% 11.50% 2.30% FBS 1.5% 10.0% 2.30% 1.50% None Eyelash growth 16.2%, iris hyperpigmentation
3.8%, blepharal pigmentation 3.1%,
CLINICAL AND EXPERIMENTAL OPTOMETRY

blepharitis 2.3%, trichiasis 2.3%, cataract

0.8%, hordeolum 0.8%, visual impairment
0.8%, floaters 0.8%
(Continued)
357
 358

Table 4. (Continued).
Study Adverse reactions recorded
Severe
effects
related to
Abnormal Instillation or possibly
Conjunctival Ocular Punctate sensation Corneal Blurry Eye Subonjunctival Pain on site related to
hyperaemia hyperaemia Irritation keratitis in eye verticillata Pain Vision Prutitis Tearing haemorrhage instillation erythema drop Others
S. MACIVER ET AL.

2) treated fellow 16.70% 11.90% 1.60% FBS 0.8% 10.3% 2.40% 2.40% None Eyelash growth 16.7 %, iris hyperpigmentation
eye 4.0%, blepharal pigmentation 3.2%,
blepharitis 2.4%, 1.6%, cataract 2.4%,
hordeolum 2.4%, visual impairment 1.6%,
floaters 1.6%, chalazion 1.6%
b. Netarsudil Clinical Trials
Dose response study 1) AR-13324 52% FBS 0% a 5% None *Unable to access full table with ADRs online
of AR-13324 versus 0.01% QHS
latanoprost42
2) AR-13324 57% FBS 7% 7% 6% None *Unable to access full table with ADRs online
0.02% QHS
3) latanoprost 16% None All unrelated serious adverse events (1
0.005% QHS pneumonia, 1 flu and syncope, 1 leukaemia
death)
ROCKET 115 1) Netarsudil 53.20% 3.90% deposits 5.40% 3.90% 13.30% 14.80% 11.80% None Eyelid erythema (12) 5.9%, reduced VA (8)
0.02% 5.4% 3.9%, conjunctival vascular disorder (8)
3.9%, allergic conjunctivitis (6) 3%, corneal
vital dye stain (17) 8.4%, infections/
infestations (14) 6.9%, nervous system
disorders (6) 3%, GI disorders (7) 3.4%,
respiratory/thoracic/mediastinal disorders
(6) 3%
2) Timolol 0.5% 8.20% 0.50% 0% 0.50% 0% 0.50% 20.20% 1.90% None Eyelid erythema 0%, reduced VA (3) 1.4%,
conjunctival vascular disorder (1) 0.5%, vital
dye stain cornea (19) 9.1%, infections/
infestations (14) 6.7%, nervous system
disorders (8) 3.8%, GI disorders (4) 1.9%,
respiratory/thoracic/mediastinal disorders
(3) 1.4%
ROCKET 239 1) Netarsudil 61.00% 4.40% 4.80% FBS 2.8% 8.80% 4.00% 1.80% 5.60% 7.60% 19.50% 17.90% 5.60% None Reduced VA 8.8%, conjunctival oedema 3.2%,
0.02% QD lid erythema 5.6%, lid oedema 4.4%, allergic
conjunctivitis 2.4%, blepharitis 1.6%,
corneal opacity 0.4%, discharge 1.6%,
conjunctivitis 2.4%, URT infection 2%,vital
dye corneal stain 5.6%, nervous system
disorders 6.4%, headache 2.4%, skin/
cutaneous disorders 5.2%, injury/poisoning/
procedural complications 5.2%,
metabolism/nutrition disorders 2.8%,
respiratory/thoracic/mediastinal 4%,
muscoskeletal/CT 4.8%, GI disorders 0.8%,
cardiac disorders 3.6%
(Continued)
Table 4. (Continued).
Study Adverse reactions recorded
Severe
effects
related to
Abnormal Instillation or possibly
Conjunctival Ocular Punctate sensation Corneal Blurry Eye Subonjunctival Pain on site related to
hyperaemia hyperaemia Irritation keratitis in eye verticillata Pain Vision Prutitis Tearing haemorrhage instillation erythema drop Others
2) Netarsudil 66.40% 5.10% 4.70% FBS 5.5% 14.60% 4.30% 17.40% 7.90% 9.90% 19.40% 17.80% 12.60% None Reduced VA 8.7%, conj oedema 7.5%, lid
0.02% BID erythema 4.7, lid oedema 4.7%, allergic
conjunctivitis 4.3%, blepharitis 3.2%,
corneal opacity 4.3%, discharge 3.2%,
conjunctivitis 3.2%, URT infection3.6%, vital
dye corneal stain 6.7%, nervous system
disorders 7.1%, headache 4%, skin/
subcutaneous tissue disorders 5.9%, injury/
poisoning/procedural complications 2.4%,
metabolism/nutrition disorders 3.6%,
respiratory/thoracic/mediastinal disorders
2.4%, muscoskeletal/CT disorders 1.2%, GI
disorders 4%, cardiac disorders 0.8%
3) Timolol 0.5% 13.90% 3.20% 2.00% FBS 0.4% 0.80% 3.20% 2.80% 1.20% 0% 0.80% 16.30% 2.00% None Reduced VA 2.4%, lid erythema 0.8%, lid
BID oedema 1.2%, allergic conjunctiviits 0.4%,
blepharitis 0.4%, dischrage 1.2%,
conjunctivitis 1.2%, URT infection 2.8%, vital
dye cornea stain 5.6%, nervous system
disorder 6.8%, headache 3.6%, skin/
subcutaneous tissue disorders 2.8%, injury/
pooisoning/procedural complications 4.4%,
metabolism/nutrition disorders 4.4%,
respiratory/thoracic/mediastinal disorders
5.6%, muscoskeletal/CT disorders 6.8%, GI
disorders 3.6%, cardiac disorders 2.8%
ROCKET 443 1) Netarsudil 47.90% 24.50% 6.30% 7.40% 16.00% 23.60% 10.30% None Eyelid erythema 7.4%. Corneal vital dye stain
0.02% QD 9.7%
2) Timolol 0.5% 9.20% 0% 1.10% 1.40% 3.10% 25.80% 1.10% None *Statistically sifnificant (p < 0.01) reductions in
BID mean HR up to 3 BPM across all on-
treatment study visits
c. FCNL Combo
FDC of AR-13324 1) PG423 0.01% 64.40% 2.70% 1.40% 1.40% 6.80% 16.40% None Infections/infestations (4) 5.5%
and latanoprost46
2) PG324 0.02% 75.30% 5.50% 5.50% 6.80% 11.00% 19.20% None Infections/infestations (2) 2.7%
3) Latanoprost 32.90% 2.70% 1.40% 0% 2.70% 1.40% None Infections/infestations (4) 4.5%
0.005%
4) AR-13324 76.90% 2.60% 6.40% 6.40% 5.10% 21.80% None Infections/infestations (4) 5.1%
0.02%
All patients 62.60% 3.40% 3.70% 3.70% 6.40% 14.80% None Infections/infestations (14) 4.7%
16
MERCURY 1 3 month 1) Netardusil/ 53.40% 5.00% 7.60% 5.90% 10.50% 19.30% None
latanoprost
FDC
CLINICAL AND EXPERIMENTAL OPTOMETRY

2) Netarsudil 41% 4.10% 7.00% 6.10% 13.90% 20.90% None

0.02%
3) Latanoprost 14.00% 0% 1.30% 0.40% 0.40% 6.40% None
0.005%
359

(Continued)
 360
S. MACIVER ET AL.

Table 4. (Continued).
Study Adverse reactions recorded
Severe
effects
related to
Abnormal Instillation or possibly
Conjunctival Ocular Punctate sensation Corneal Blurry Eye Subonjunctival Pain on site related to
hyperaemia hyperaemia Irritation keratitis in eye verticillata Pain Vision Prutitis Tearing haemorrhage instillation erythema drop Others
MERCURY 147 1) Netardusil/ 53.8% (mild); (moderate); 5% 17.6% 10% 8.8% 7.1% 13% 23.1%
latanoprost 8.4% 0.8% (severe)
FDC
2) Netarsudil 43.6% (mild); (moderate); 7.4% 13.2% 8.6% 7.8% 7.8% 18.1% 24.7 %
0.02% 7.4% 0.4% severe
3) Latanoprost 21.1% (mild); (moderate) 4.2% 0% 3.8% 3% 0.4% 1.3% 7.6%
0.005% 0.8% 0% (severe)
MERCURY 245 1) Netardusil/ 54.40% 4.10% 13.10% 8.60% 17.20%
latanoprost
FDC
Netarsudil 42.70% 5.50% 9.80% 11.00% 9.00%
Latanoprost 56.00% 2.80% 0% 80.00% 6.00%
16
MERCURY 1&2 1) Netarsudil/ 58.70% 3.50% 15.40% 7.70% 5.20% 10.80% 20.10% None Reduced VA 5.2%, instillation site discomfort
latanoprost 5.2%, nasopharyngitis (8), 1.7%
FDC
2) Netarsudil 47.00% 5.40% 11.60% 4.60% 5.60% 14.50% 16.70% None Reduced VA 4.2%, instillation site discomfort
4.6%, headache (9) 1.8%
3) Latanoprost 22.10% 2.90% 0% 1.00% 0.20% 1% 6.80% None Red uced VA 1.8%, instillation site discomfort
1.0%
 CLINICAL AND EXPERIMENTAL OPTOMETRY 361

groups after three-months of treatment and the IOP reduc­ The new glaucoma medications have a new mechanism of
tion in the FNCL group was superior to the individual compo­ action, demonstrate the ability to lower IOP at both high and
nents netarsudil 0.02% and latanoprost 0.005% separately.16 low baseline IOP levels. They provide a superior alternative to
82% of subjects using FCNL 0.02% had IOP ≤ 18 mmHg current second line therapy options because they are dosed
compared to 53.5% and 69.1% of subjects using netarsudil once daily, cause less side effects and have improved 24-h IOP
0.02% and latanoprost 0.005% respectively.16 The 12-month lowering efficacy. A summary of the IOP lowering efficacy,
primary endpoint data from the MERCURY 1 study showed mechanism of action and side effects of the new medications
that the superior efficacy of FCNL noted after 3-months was compared to the existing armamentarium of medications is
sustained over a 12-month period in subjects with both low found in Table 5.
and high baseline IOPs.47 The MERCURY 2 study included 750 Traditional ocular hypotensive medications work by either
participants.45 The mean baseline IOP was 23.5-23.6 mmHg. suppressing aqueous fluid production or diverting aqueous
After three months of treatment, FCNL demonstrated a statis­ humour flow away from the conventional trabecular mesh­
tically significant reduction in IOP from baseline that was work outflow and towards the uveoscleral outflow pathway.8
superior to both netarsudil 0.02% and latanoprost 0.005% Figure 1 helps illustrate the pathways of aqueous humour
individually.45 The pooled analysis from the MERCURY 1 and production and outflow. Aqueous humour helps to form and
2 studies reported that the proportion of subjects that nourish the eye and can be thought of as a ‘blood surrogate’
achieved at least a 40% reduction from baseline in mean to the avascular and transparent structures of the cornea and
diurnal IOP was 30.9% in the FCNL group compared to 5.9% lens. It provides nourishment, removes excretory products
and 8.5% achieved in the netarsudil and latanoprost groups, from metabolism, transports neurotransmitters, and contri­
respectively.16 An extension study was added to MERCURY 1 butes to the regulation of the homoeostasis in the ocular
that followed patients for two months after discontinuing all tissue. In addition, it helps deliver drugs to ocular
treatments. The extension study found that the IOP lowering structures.49,50
response was sustained longer in subjects taking netarsudil Outflow facility is impaired in individuals with glaucoma.50
and FCNL compared to subjects taking latanoprost.47 The decrease in outflow facility is from changes to and
Overall, FCNL is a new medication with great promise, increases in the extracellular material found in the juxtacana­
especially when a first line treatment alone is not sufficient licular portion of the trabecular meshwork as described in
to lower IOP. It is a fixed combination medication that is Figure 1(inset), as well as, a decrease in the size of the canal of
dosed once daily at nighttime without the side effects of Schlemm.53 It has been suggested that improving outflow
a beta blocker. FCNL has demonstrated significant IOP low­ facility could provide greater IOP lowering and control com­
ering efficacy with over 30% of individuals measuring at least pared to decreasing aqueous production. It is suggested that
a 40% IOP reduction from baseline at three months and over medications that decrease aqueous humour production
60% of individuals measuring more than 30% IOP reduction might be less efficacious at controlling IOP than medications
from baseline in the pooled MERCURY 1 and 2 data analysis.16 that improve trabecular meshwork outflow facility. Further,
The most commonly noted side effect from FCNL was studies suggest that diverting aqueous humour perfusion
conjunctival hyperaemia and this was noted in approximately from the trabecular meshwork could be detrimental if main­
50% of the MERCURY 1 and 2 participants.16,45 Corneal verti­ tained over a long a period of time.50,53–55 Studies demon­
cillata was commonly reported by investigators but not strate that an under-perfusion of aqueous could alter the
subjects.16,45 Conjunctival haemorrhages were noted in sub­ trabecular meshwork by stimulating cells to produce more
jects in the netarsudil clinical trials, as well as the clinical trials extracellular material which further decreases trabecular out­
for FCNL.15,16,39,42,43,45–47 The conjunctival haemorrhages flow facility.55 This has the potential to create a vicious circle
were described as pinpoint and were more often reported leading to further outflow impairment and further worsening
by the investigator than the patient. The 12-month data of glaucoma.53,55 In addition, the concomitant use of drugs
published from MERCURY 1 showed a higher dropout rate that divert aqueous away from the trabecular meshwork and
in the netarsudil and FCNL group compared to latanoprost into the uveoscleral pathway may compound this effect and
and this was attributed to adverse events.47 The most com­ create further impairment of trabecular meshwork outflow.53
mon adverse ocular event leading to discontinuation was A 2004 study by Kiland showed that when prostaglandins
hyperaemia despite this being reported as mild in most were topically applied to monkey eyes receiving topical aqu­
cases. Overall, the medication is considered to be well toler­ eous suppressant medications, an overall decrease in IOP
ated since there were no significant or systemic side effects lowering efficacy was noted after months of use.53 Studies
and most side effects were graded as mild when present. have shown that pharmacologically targeting the trabecular
A detailed summary is found in Table 4c. meshwork outflow may lead to a more rapid IOP reduction
compared to reducing aqueous production and may cause
fewer peaks/fluctuations of IOP throughout the day.50,53
Discussion
These results support a need for a new class of glaucoma
Glaucoma is a chronic disease that requires lifelong treatment medications that target trabecular meshwork outflow.50,54
and adherence to medication use. There are widely accepted The new medications, LBN, netarsudil 0.02% and FCNL, all
problems with the current glaucoma medication options work to directly improve trabecular meshwork outflow
available including limited mechanisms of action, differences facility.56 Netarsusil and FCNL have demonstrated the poten­
in 24-h IOP lowering efficacy at high and low IOP levels, tial possibility of causing remodelling and structural repairs to
dosing frequency, comfort, side effects, and potential for the trabecular meshwork. This possibility was suggested in
systemic co-morbidities.8,13,48 Results from the clinical trials the reports from the MERCURY 1 study that found
of the new glaucoma medications are promising and demon­ a prolonged IOP lowering effect after subjects stopped
strate improvements to some of the problems listed above. using netarsudil.47 This possibility is further supported by
362 S. MACIVER ET AL.

Table 5. Comparison of the new medications to existing medications. Most common side effects listed in the new medications are in order of occurrence as per the
major clinical trials. The most common side effects listed for the existing medication are the most common reported and the systemic effects that need to be
considered.
IOP reduc­
Medication tion (%) Dosing Mechanisms of action Most common side effects
Latanoprostene bunod14,25,27–31 29-34 Once daily in the evening Increase uveoscleral outflow Conjunctival hyperaemia
Increase trabecular meshwork Eye irritation
outflow Systemic effects: minimal
Decrease episcleral venous
pressure
Netarsudil 0.02%15,16,39,42,43,45,46 15-22 Once daily in the evening Increase trabecular meshwork Conjunctival hyperaemia
outflow Corneal verticillata
Decrease aqueous humour Subconjunctival haemorrhage
production Tearing
Decrease episcleral venous Systemic effects: minimal
pressure
Netarsudil 0.02%-Latanoprost fixed 30-37 Once daily in the evening Increase uveoscleral outflow Conjunctiva hyperaemia
concentration16,45,46 Increase trabecular meshwork Corneal verticillata
outflow Subconjunctival haemorrhage
Decrease aqueous humour Tearing
production Systemic effects: minimal
Decrease episcleral venous
pressure
Comparison to existing Glaucoma Medication
Prostaglandin analogues13,76 25-33 Once daily in the evening Increase uveoscleral outflow Conjunctival hyperaemia
Iris colour changes
Periocular skin pigmentation
Eye lash growth
Prostaglandin associated
periorbitopathy
Macular oedema
Systemic effects: minimal
Beta blockers13,76 20–25 Usually twice daily (am and pm); Reduce aqueous humour Burning of eyes
gel form once in the morning production Ocular irritation
Systemic effects: cardiovascular,
pulmonary, CNS, etc
Contraindicated: asthma, chronic
pulmonary obstructive
disease and bradycardia
Alpha-2 agonists13,76 20–25 Two or three times daily for first Increase uveoscleral outflow Allergic conjunctivitis
line (twice daily as second line) Decrease aqueous humour Dry eye
production Burning sensation with drops
Systemic effects: dry mouth
Central nervous system effects:
drowsiness, caution in cerebral
or coronary insufficiency,
postural hypotension, renal or
hepatic failure
Topical carbonic anhydrase 15–20 Two or three times daily for first Decrease aqueous humour Blurred vision
inhibitors13,76 line (twice daily as second line) production Ocular irritation
Conjunctival hyperaemia
Systemic effects: headache
Cholinergic agonists13,76 20–25 Usually 4x/day Increase in trabecular meshwork Ocular irritation
outflow (indirect) Induced myopia and decreased
vision due to ciliary spasm
Systemic effects: headaches

the ability of netarsudil to induce structural change in the prior literature.57–59 Latanoprost and brinzolamide lower IOP
trabecular meshwork, however, this requires further a similar amount during both daytime and nocturnal hours
investigation.41 while timolol and brimonidine demonstrate greater IOP low­
LBN, netarsudil and FCNL all lower IOP through multiple ering efficacy during daytime hours.57–59 For glaucoma man­
mechanisms of action compared to other glaucoma medica­ agement, lowering nocturnal IOP is important since IOP is
tions that have one or two mechanisms.56 Multiple mechan­ highest at night and research suggests that the greatest risk
isms for lowering IOP may be the reason that the new for glaucoma progression could be highest during the noc­
medications were demonstrated to work more effectively turnal hours.60 Effective nocturnal IOP lowering may be of
over a wider range of baseline IOPs and work better at even greater importance in the management of normal ten­
nocturnal IOP lowering compared to older medications.56 sion glaucoma and low systemic blood pressure given the
Figure 2 illustrates the four main mechanisms of action uti­ likelihood of reduced ocular perfusion pressure causing wor­
lized by the new glaucoma medications compared to the sening of the disease.61 The Constellation study demon­
mechanisms of action used in conventional glaucoma strated that LBN provided a significantly superior nocturnal
medication. IOP lowering profile compared to timolol, as well as
The 24-h IOP lowering profiles of latanoprost, timolol, a potential to improve ocular perfusion pressure.28 These
brinzolamide and brimonidine have all been documented in results were similar to reported observations for other
 CLINICAL AND EXPERIMENTAL OPTOMETRY 363

Figure 1. The blue arrows represent the direction of aqueous humour once it is produced from the ciliary body. Aqueous humour production occurs through three
different mechanisms, diffusion, ultrafiltration and active secretion. Diffusion and ultrafiltration are passive and therefore are unable to be modified by drug
molecules. The aqueous humour follows a temperature gradient and leaves the eye by passive flow via the anterior chamber angle.49 The conventional trabecular
meshwork outflow route (yellow arrows) follows a pressure gradient between the trabecular meshwork into Schlemm’s canal and through the inner wall of
Schlemm's canal and is a passive pressure-dependent trans-cellular mechanism along with associated giant vacuoles and pores acting as one-way valves. The non-
conventional, uveoscleral outflow (green arrows), route takes the remainder of the fluid through the uveal meshwork and into the ciliary muscle through the
suprachoroidal space and out through the sclera.49,55 The anatomical course of this pathway begins at the trabecular meshwork and ciliary body band. It does not
contain any channels or vessels. The fluid seeps through the anterior face of ciliary muscle and other tissues in and around the uvea. The fluid then leaves the eye
either by diffusing through the sclera or by diffusing through the scleral emissaria of the vortex veins. Inset: Anatomically, the TM is comprised of a spongy
connective tissue containing collagen and elastin fibres surrounded by endothelial-like trabecular cells, or trabeculocytes, which rest on a basement membrane.
The trabecular meshwork consists of three regions that differ in structure: 1) one to three layers of trabecular beams make up the inner uveal meshwork, 2) the
deeper corneoscleral meshwork forms 8–15 layers that are thicker than the uveal meshwork and originate from the scleral spur and 3) the juxtacanalicular tissue or
cribriform region that is localised directly adjacent to the inner wall endothelium of Schlemm’s canal and is the smallest part of the trabecular meshwork with
a thickness of only 2–20 µm. The juxtacanalicular tissue does not form trabecular lamellae or connective tissue beams, but rather represents a typical loose
connective tissue with 2–5 layers of loosely arranged cells that are embedded in a thinly distributed fibrillar extracellular matrix. These layers support the inner wall
of Schlemm’s canal. Experimental evidence and theoretical predictions indicate that normal aqueous humour outflow resistance resides in the inner wall region of
Schlemm’s canal.51,52 Medical illustration by Alyssa Mars.

prostaglandins.28 A comparison study investigating the ocu­ tension glaucoma since normal tension glaucoma is thought
lar perfusion pressure effect between latanoprost and LBN to be less driven by eye pressure and more driven by factors
would be helpful to investigate the potential added benefit of such as blood perfusion to the nerve.64
NO in the ocular tissues and the impact on ocular perfusion It is known that an inverse relationship exists between
pressure. number of glaucoma drops used and adherence to
Most glaucoma medications are less effective at lowering treatment.43,48 CAI inhibitors and alpha agonists are com­
IOP when IOP is already low (IOP < 20 mmHg) thus decreasing monly used for second line therapy, but both require twice
the efficacy of glaucoma drops in individuals with normal a day dosing. This is problematic for individuals that exhibit
tension glaucoma.62,63 The results from the large clinical trials glaucomatous progression and require further treatment
of both LBN and netarsudil are promising in that they both because the increase in drops will likely cause a decline in
demonstrated the ability to provide superior IOP lowering adherence.65,66 The mean adherence rate to once daily glau­
when IOP is already low.14,15,25,28 Unfortunately, the clinical coma dosing has been shown to be only 71% in onestudy,
trials of LBN compared LBN to timolol and not to despite the patient knowing that they are being monitored.48
a prostaglandin. However, improved efficacy was seen in In real life, adherence rates for glaucoma treatment are
individuals who had normotensive IOPs compared to what thought to be closer to 50%.59,66 Generally speaking, we can
has been noted in the literature for prostaglandins suggest­ assume that adherence with medication is an ongoing con­
ing an added value of the NO donating agent.26,28 Animal cern, however, ease of dosing and a less frequent drop sche­
studies have demonstrated a potential neuroprotective effect dule, like the ones in LBN, netarsudil and FCNL, will be
from netarsudil which would also be a benefit in normal beneficial.10,66
364 S. MACIVER ET AL.

Figure 2. Mechanism of action for glaucoma medications used to lower IOP. 1) Aqueous suppression—traditional medication suppresses aqueous humour
production to lower IOP. 2) Increase uveoscleral outflow—medications help widen the spaces in the uveoscleral route which help improve outflow facility. 3)
Increase in trabecular meshwork outflow—new mechanism of action for IOP lowering medication. The new medications act to decrease trabecular meshwork
resistance by remodelling the structural resistance in the TM that develops from glaucoma. 4) Decrease in episcleral venous pressure—new mechanism of action
for IOP lowering medication. The clinical efficacy of this mechanism of action is still not fully understood. “Medical illustration by Alyssa Mars“

Prostaglandins have a superior safety profile to the other practice.67–69 The hyperaemia noted in the clinical trials for the
classes of medications and are often selected for first line ROCK inhibitors and LBN were mild and side effects such as
treatment.8 Systemic side effects and drug interactions are subconjunctival haemorrhages and corneal verticillata were
a concern with the classes of medications typically selected also reported as mild, and therefore whether these side effects
as second line therapies including the beta-blocker class, adre­ become an issue to the patient in clinical practice will require
nergic agonists class and carbonic anhydrase inhibitors class.8 further investigation.
The new glaucoma medications, LBN and netarsudil were well Although preservative-free formulations are available, the
tolerated and manifested only minimal side effects including majority of eye drops currently in clinical use contain the
very minimal to no systemic side effect risk. Despite the low preservative benzalkonium chloride (BAK) that can be toxic
side effect risk, LBN and netarsudil 0.02% did have higher to the ocular surface and lead to patient discomfort.70,71 The
dropout rates of subjects compared to individuals using timo­ amount of total BAK getting into the eye can cause corneal
lol or latanoprost in the clinical trials, however, the dropout and conjunctival damage at low levels of 0.001% of BAK.
rates were similar to other glaucoma medication registration Studies suggest that the toxic effect of the medications are
trials.14–16,47 In addition, enrolment criteria allowed patients to cumulative and therefore the BAK will be more damaging
have been on either timolol or prostaglandins prior to the when more than one glaucoma drop is used each day.71,72
study and therefore the patients may have already built up A large percentage of individuals with glaucoma are also
tolerance to the side effects of these medications.56 A better known to have concurrent dry eye disease and up to 30% of
understanding of how these side effects will impact adherence these are reportedly severe.70 All three new medications in
and dropout rates will be gained when they are used more their commercial form in the United States, Vyzulta, Bausch
widely in clinical practice. The impact of new side effects is an and Lomb (latanoprostene bunod 0.024%), Rhopressa, Aerie
important consideration because despite the superior safety Pharmaceutical (netarsudil 0.02%) and Rocklatan®, Aerie
profile of the prostaglandin analogue, they are known to cause Pharmaceutical (0.02% netarusdil/0.005% latanoprost) are
cosmetic and localised side effects that can be bothersome to preserved with BAK and therefore individuals with severe
the patient. One study showed that these side effects may be dry eye may have some issues with these medications.
cause for discontinuation of a prostaglandin analogue in up to Vyzulta®, (latanoprostene bunod 0.024%), and Rocklatan®
30% of patients.67 It is still unknown as to whether the other (0.02% netarusdil/0.005% latanoprost) both have 0.02% BAK
commonly reported cosmetic side effects from prostaglandins and Rhopressa® (netarsudil 0.02%) has 0.015% BAK.73–75
including eyelash changes, skin and iris discolouration, and Importantly, since the new medications are only dosed once
orbital fat displacement, will also occur in individuals using daily they may still be safer to the ocular surface than the
LBN and FCNL but it could be assumed that the side effects traditional, more frequently dosed medications. Alternatives
will be similar and may cause similar dropout rates in clinical to topical medications such as SLT, or in the future, sustained
 CLINICAL AND EXPERIMENTAL OPTOMETRY 365

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