Glaucoma: Novel IOP-lowering drugs

Latanoprostene bunod and netarsudil could change the landscape of glaucoma therapy.

Glaucoma is one of the leading causes of irreversible blindness worldwide. Reduction of intraocular pressure (IOP), the only effective therapy for reducing glaucoma risk or progression, is achieved with medications, laser, and surgical therapies. Each treatment option has its own benefits and risks.

More than 50% of glaucoma patients require two or more medications for adequate IOP control.1 Six classes of topical medications to lower IOP are available: (1) prostaglandin analogs, (2) selective and non-selective β-adrenergic antagonists, (3) selective α2-adrenergic agonists, (4) carbonic anhydrase inhibitors, (5) cholinergic agonists, (6) non-selective α and β adrenergic agonists (Table 1). The first four classes are most commonly used clinically.

Table 1. Dosing regimen and ocular and systemic side effects of approved IOP-lowering medications.
1. Prostaglandins
Once daily
Hyperemia, increased iris pigmentation, eyelash growth, foreign body sensation, loss of orbital fat tissue, periocular hyperpigmentation, eye ache Headache, flu-like symptoms
2. Beta adrenergic antagonists
Once or twice daily
Dry eyes, hyperemia Decreased exercise tolerance, decreased pulse, bronchospasm, fatigue, depression, impotence
3. Selective alpha2 adrenergic agonists
Two or three times daily
Hyperemia, allergic conjunctivitis/dermatitis, follicular conjunctivitis Dry mouth and nose, hypotension, headache, fatigue, somnolence
4. Topical carbonic anhydrase inhibitors
Two or three times daily
Hyperemia, burning, blurred vision, allergic conjunctivitis, dermatitis Bitter taste, sulfa-related side effects
5. Non-selective α and β adrenergic agonists
Two times daily
Ocular allergy, irritation, hyperemia, tachyphylaxis Tachycardia, arrhythmia, headache, hypertension
6. Cholinergic agonists
Four times daily
Decreased vision, dermatitis, small pupil, increased myopia, cataract, retinal tears, eye pain Brow ache, headache, increased salivation, abdominal cramps
Adapted from the American Academy of Ophthalmology Preferred Practice Pattern, Primary Open-Angle Glaucoma Suspect, 2016; and Atlas of Glaucoma, Third Edition. CRC Press, 2014.

Despite these treatment options, some patients continue to have progressive glaucomatous vision loss and experience intolerable side effects. Thus, the following new and in-the-pipeline novel medications for glaucoma patients are welcome.

Latanoprostene bunod (LBN)

Approved in November 2017, LBN (Vyzulta, Bausch + Lomb) is the first novel topical IOP-lowering agent approved by the FDA since latanoprost in 1996 (Table 2). LBN 0.024% is metabolized into two components: latanoprost acid (the active acid of latanoprost) and butanediol mononitrate, which then releases nitric oxide (NO). Unavailable in other medications, NO increases aqueous outflow through the trabecular pathway. Also, NO is additive to latanoprost, which reduces IOP by enhancing uveoscleral outflow, providing a dual mechanism of IOP reduction.2 LBN is dosed once a day in the evening.

Table 2. Latanoprostene bunod (Vyzulta) clinical studies: Nitric oxide donating PGF2α agonist.
Date Pub Author Study Duration Number Completed Description
2014 Weinreb et al3 VOYAGER 28 days 396 patients dose response vs. latanoprost
2015 Araie et al4 (Japan) 14 days 24 volunteers 24 hour IOP
2016 Liu et al5 28 days 21 patients 24 hour IOP
2016 Weinreb et al6 APOLLO 3 months 387 patients vs. timolol b.i.d.
2016 Kawase et al7 JUPITER 1 year 121 patients open label “normal tension glaucoma”
2016 Medeiros et al8 LUNAR 3 months 387 patients vs. timolol b.i.d.

Six clinical trials evaluating LBN have been published (Table 2).3-8 VOYAGER, a phase-2, 28-day dose-ranging comparison study of patients with increased IOP demonstrated greater IOP reduction with LBN than with latanoprost 0.005% alone. Patients experienced a greater incidence of instillation site pain with LBN and otherwise similar ocular tolerability of the two drugs.2 In two pivotal phase-3 clinical trials that involved a total of 831 patients with open-angle glaucoma (APOLLO and LUNAR), once-daily LBN demonstrated greater IOP lowering than twice daily timolol 0.5%, with a consistent mean IOP reduction of 7.5 mm Hg to 9.1 mm Hg from baseline through three months of treatment. LBN and timolol had similar rates of reported ocular adverse events.6,8 In the JUPITER study, an open-label clinical trial, 130 Japanese patients with IOP in the normal range (mean baseline IOP <20 mm Hg) were enrolled.8 In these patients, LBN produced stable IOP reductions during a one-year treatment period.

In glaucoma patients, the highest IOP often occurs during the nocturnal period.9 Two recent studies showed that LBN provides IOP control during both the diurnal and nocturnal periods, which is important for managing glaucoma. In one study, Japanese volunteers dosed with LBN for 14 days had reduced IOP during both the diurnal and the nocturnal periods.4 In a U.S. study, patients dosed for 28 days with LBN had reduced IOP throughout 24 hours and greater IOP reductions than with timolol during the nocturnal period.5

These studies demonstrate LBN is efficacious and well tolerated in patients treated through one year. LBN can be used as monotherapy and is anticipated to be effective as adjunctive therapy in patients on other topical agents. LBN can be used as a substitute for a prostaglandin in patients requiring additional IOP reduction.


Approved by the FDA in December 2017, Netarsudil 0.02% (Rhopressa, Aerie Pharmaceuticals) is the first-in-class Rho kinase (ROCK) inhibitor for lowering IOP (Tables 3 and 4). Netarsudil lowers IOP primarily by increasing outflow through the trabecular pathway and in part by reducing episcleral venous pressure. Additionally, netarsudil is a norepinephrine (NET) transporter inhibitor; thus, it has a third potential mechanism: decreasing aqueous humor formation.10 The dosing regimen for netarsudil is once daily in the evening.

Table 3. Clinical trials: Netarsudil 0.02% (Rhopressa) ROCK/NET inhibitor.
Study Duration # of Patients Description Conclusion
Phase 2B11 28 days
152 patients
q.h.s. vs. latanoprost Similar to latanoprost @IOP <27*
Rocket 1
Phase 312
3 months
400 patients
q.h.s. vs. timolol
Similar to timolol @IOP < 25*
Rocket 2
Phase 311
3 month efficacy
12 month safety
460 patients
q.h.s. vs. timolol
b.i.d. vs. timolol
Similar to timolol @IOP < 25
through month 12
Rocket 3
Phase 3
12 month safety
240 patients
q.h.s. vs. timolol
Ongoing data analysis
Rocket 4
Phase 313
3 month efficacy
6 month safety
608 patients
q.h.s. vs. timolol
Similar to timolol @IOP < 25, <30*
90 day results
*secondary endpoint
Table 4. Clinical trials: Netarsudil .02%/latanoprost .005% (Roclatan) FDC ROCK/NET inhibitor/PGF2α agonist.
Study Duration # of Patients Description Conclusion
Mercury 1
Phase 315,16
3 month efficacy, 12 month safety
718 patients
FDC q.h.s. vs. timolol
b.i.d. vs. latanoprost
FDC more efficacious than components 1-3 mm Hg at all nine time points (p<.0001)
Mercury 2
Phase 316
3 month efficacy
750 patients
FDC q.h.s. vs. timolol
b.i.d. vs. latanoprost
FDC more efficacious than components 1-3 mm Hg at all nine time points (p<.0001)
Mercury 3
Phase 3
6 month efficacy & safety FDC q.h.s. vs. FDC bimatoprost/timolol

Clinical safety and efficacy trials with netarsudil include a phase-2 comparison with latanoprost,11 four phase-3 trials comparing netarsudil to timolol, and two phase-3 trials of the fixed dose combination of netarsudil and latanoprost. In a phase-2, 28-day comparison trial of netarsudil and latanoprost, efficacy was similar in patients with baseline IOP between 22 mm Hg and 26 mm Hg (-5.7 mm Hg, netarsudil; -6.0 mm Hg, latanoprost). In all enrolled patients (with a baseline IOP up to 36 mm Hg), netarsudil was 1 mm Hg less effective than latanoprost (-5.7 vs -6.8 mm Hg).

In three phase-3 clinical trials [Rocket 1 (three months), Rocket 2 (12 months), and Rocket 4 (6 months)], netarsudil once daily and timolol twice daily caused similar reductions in IOP in patients with baseline IOP <25 mm Hg and in Rocket 4 in patients with baseline IOP <30 mm Hg.12,13 In Rocket 2 and in Mercury 1 (discussed below) — the longest duration studies — IOP reductions with netarsudil were stable through 12 months of dosing.

A study evaluated the 24-hour IOP effects of netarsudil in volunteers. IOP reductions were similar with netarsudil during both the diurnal and nocturnal periods. This is beneficial, because nocturnal IOP elevations in patients with glaucoma may be a cause of glaucoma progression.14


Patient compliance with medications improves by minimizing the number of required daily applications of drops. One solution to enhance patient compliance is fixed-dose combination (FDC) therapy, which is more than one medication in a single bottle. Roclatan is a novel FDC of netarsudil 0.02% and latanoprost 0.005%.

This FDC was compared with the individual components in two phase-3 studies: Mercury 1 (12 months) and Mercury 2 (three months).15,16 In these studies, IOP reductions were 1 mm Hg to 3 mm Hg greater (P < .0001) with the FDC of netarsudil and latanoprost than with the individual components at all measurements, which confirmed the additivity of netarsudil and latanoprost. In Mercury 1 consistent efficacy of the FDC was maintained through 12 months. Additionally, at baseline IOPs below 25 mmHg, netarsudil IOP lowering was similar to latanoprost at month 12.

In both Mercury 1 and Mercury 2, greater percentage IOP reductions and lower IOPs were achieved in substantially more patients treated with the FDC than those treated with the individual components. IOP reductions of at least 30%, a recommended target, were achieved in 59% of patients treated with the FDC versus less than 37% of those treated with the individual components.

For most glaucoma patients, the suggested target IOP is low- to mid-teens. The majority of patients treated with the FDC netarsudil/latanoprost (56%) achieved an IOP of 16 mm Hg or less, and 32% of patients achieved an IOP of 14 mm Hg or less. Among the patients treated with the individual components, fewer patients achieved IOP of ≤16 mm Hg and ≤14 mm Hg (39% and 15%, respectively). The majority of patients treated with the FDC achieved the low target pressures that glaucoma patients typically require.

Mercury 3 (six months), currently ongoing in Europe, is a third study comparing the FDC netarsudil/latanoprost with the FDC timolol/bimatoprost.

The dosing regimen with FDC netarsudil/latanoprost will be once daily in the evening. Submission of FDC netarsudil/latanoprost to the US FDA for approval is anticipated in 2018.

Side effects

In clinical trials, both netarsudil and FDC netarsudil/latanoprost were well tolerated. The most frequent side effect, conjunctival hyperemia, is caused by the drug’s vasodilatory effect. This side effect was observed in 50% to 60% of patients, typically mild, sporadic, and occurring at every visit in 10% of patients. Other ocular adverse events, reported in 5% to 25% of patients, included small conjunctival hemorrhages and cornea verticillata. Cornea verticillata are microdeposits of intracellular phospholipids and are observed in almost all patients taking systemic amiodarone.17 The verticillata are typically asymptomatic and do not reduce visual function.

Few systemic side effects were reported — this can be explained by the systemic absorption of netarsudil, which is below the lower limit of quantification.18

Thus, netarsudil will be an effective first-line agent for lowering IOP, providing similar efficacy to a topical beta blocker without the systemic side effects, and similar efficacy to latanoprost in patients with baseline IOP < 25 mm Hg. As demonstrated in the FDC studies netarsudil is an effective addition to a prostaglandin in the evening. Netarsudil is anticipated to be additive to other classes of IOP lowering compounds.


These novel medications, latanoprostene bunod, netarsudil, and the fixed dose combination netarsudil/latanoprost effectively lower IOP and are well tolerated. Once-daily dosing with these drugs addresses the important issue of compliance. These drugs are new classes of compounds, and additivity to the agents in current clinical use is anticipated.

These treatment options for glaucoma patients will hopefully lead to reduced rates of vision loss, visual disability, and blindness. OP


  1. Kobelt-Nguyen G, Gerdtham UG, Alm A. Costs of treating primary open-angle glaucoma and ocular hypertension: a retrospective, observational two-year chart review of newly diagnosed patients in Sweden and the United States. J Glaucoma 1998; 7:95-104.
  2. Cavet ME, Vittitow JL, Impagnatiello F, Ongini E, Bastia E. Nitric oxide (NO): an emerging target for the treatment of glaucoma. Invest Ophthalmol Vis Sci. 2014;55:5005-5015.
  3. Weinreb RN, Ong T, Baldo SS, et al. A randomised, controlled comparison of latanoprostene bunod and latanoprost 0.005% in the treatment of ocular hypertension and open angle glaucoma: the VOYAGER study. Br J Ophthalmol. 2015; 99:738-745.
  4. Araie M, Baldo SS, Vittitow JL, Weinreb RN. Evaluation of the effect of latanoprostene bunod ophthalmic solution 0.024% in lowering intraocular pressure over 24 h in healthy Japanese subjects. Adv Ther. 2015; 32:1128-1139.
  5. Liu JHK, Slight JR, Vittitow JL, Baldo SS, Weinreb RN. Efficacy of latanoprostene bunod 0.024% compared with timolol 0.5% in lowering intraocular pressure over 24 hours. Am J Ophthalmol. 2016;169:249-257.
  6. Weinreb RN, Baldo SS, Vittitow J, et al. Latanoprostene bunod 0.024% versus timolol maleate 0.5% in subjects with open-angle glaucoma or ocular hypertension: The APOLLO study. Ophthalmology. 2016;123:965-973.
  7. Kawase K, Vittitow JL, Weinreb RN, Araie M, JUPITER Study Group. Long-term safety and efficacy of latanoprostene bunod 0.024% in Japanese subjects with open-angle glaucoma or ocular hypertension: The JUPITER study. Adv. Ther. 2016;33:1612-27.
  8. Medeiros FA, Martin KR, Peace J, et al. Comparison of latanoprostene bunod 0.024% and timolol maleate 0.5% in open-angle glaucoma or ocular hypertension: the LUNAR study. Am J Ophthalmol. 2016;168: 250-259.
  9. Mansouri K, Weinreb RN, Medeiros FA. Is 24-hour Intraocular Pressure Monitoring Necessary in Glaucoma? Semin Ophthalmol. 2013 May: 28(3): 157-164.
  10. Lin CW, Sherman B, Moore LA, et al. Discovery and Preclinical Development of Netarsudil, a Novel Ocular Hypotensive Agent for the Treatment of Glaucoma. J Ocul Pharmacol Ther. 2017 Jun 13. doi: 10.1089/jop.2017.0023. [Epub ahead of print].
  11. Bacharach J, Dubiner HB, Levy B, Kopczynski CC, Novack GD for the AR-13324-CS202 Study Group. Double-masked, randomized, dose-response study of AR-13324 versus latanoprost in patients with elevated intraocular pressure. Ophthalmology. 2015;122:302-307.
  12. Bacharach J, Heah T, Ramirez N, Kopczynski CC, Novack GD. AR-13324 ophthalmic solution 0.02%: topline results of two phase 3 clinical studies in patients with open angle glaucoma and ocular hypertension. Presented at: American Glaucoma Society Annual Meeting. March 3-6, 2016, Fort Lauderdale, Florida.
  13. Khouri AS, Heah T, Kopczynski CK, Novack GD, and the ROCKET-4 Investigator Group. A double-masked, randomized, parallel study of Netarsudil Ophthalmic Solution, 0.02% QD compared to timolol maleate ophthalmic solution, 0.5% BID in patients with elevated intraocular pressure (ROCKET-4). Paper presented at: the ARVO meeting May 9, 2017, Baltimore, MD. IOVS. 58:2461.
  14. Peace JH, Kopczynski, CK, Heah T. Ocular hypotensive efficacy of netarsudil ophthalmic solution 0.02% over a 24-hour period: a pilot study. Paper presented at: the ARVO meeting May 9, 2017, Baltimore, MD. IOVS. 58:2460.
  15. Asrani S, Kopczynski CC, Heah T. A 3-month interim report of a prospective, double-masked, randomized, multicenter, active-controlled, parallel-group, 12-month study assessing the safety and ocular hypotensive efficacy of PG324 ophthalmic solution compared to netarsudil ophthalmic solution, 0.02%, and latanoprost ophthalmic solution, 0.005%, in subjects with elevated intraocular pressure. Paper presented at: The 27th Annual AGS Meeting; March 3, 2017; Coronado, CA.
  16. Serle JB, Lewis RA, Kopczynski CC, Heah T. 3-month interim report of a prospective 12-month safety and efficacy study of topical PG324 (fixed combination of netarsudil 0.02% and latanoprost 0.005%) compared to the individual components in subjects with elevated intraocular pressure. Paper presented at the ARVO meeting May 9, 2017, Baltimore, MD. IOVS. 58:2462.
  17. Raizman MB, Hamrah P, Holland EJ, et al. Drug-induced corneal epithelial changes. Surv. of Ophthalmol. 2017; 62:286-301.
  18. Levy B, Ramirez N, Novack GD, Kopczynski C. Ocular hypotensive safety and systemic absorption of AR-13324 ophthalmic solution in normal volunteers. Am J Ophthalmol. 2015;159:980-985.