July 2018


Pharmaceutical focus
An inside look at outflow drugs for glaucoma

by Maxine Lipner EyeWorld Senior Contributing Writer

In glaucomatous eyes, new outflow medications help to effectively manage IOP using different mechanisms than traditional agents.
Source: Janet Serle, MD

How these new agents are successfully lowering IOP

Two new medications for lowering IOP are gaining traction in the glaucoma sector, drugs that can increase the outflow of aqueous through the drainage tissue. These unique medications, latanoprostene bunod (Vyzulta, Bausch + Lomb, Bridgewater, New Jersey), which became available in late 2017, and netarsudil (Rhopressa, Aerie Pharmaceuticals, Irvine, California), which emerged in early 2018, offer new options for practitioners, according to Janet Serle, MD, professor of ophthalmology, glaucoma fellowship director, Icahn School of Medicine at Mount Sinai, New York. Here’s a closer look at these new outflow drugs.
In patients with glaucoma, the trabecular pathway is the site of the diseased tissue,1 Dr. Serle explained. “The changes in this tissue lead to elevated IOP,” she said. “Medications that act directly on this critical tissue to enhance outflow are very important as it is possible that instituting therapy early in the disease and protecting these tissues from chronic changes may reduce the long-term severity of glaucoma.”

Eyeing the agents

The first of these drugs to emerge was latanoprostene bunod. “The chemical entity consists of the well-known and commonly used medication latanoprost and a nitric oxide donating moiety called butanediol mononitrate,” Dr. Serle said, adding that this compound is broken into the active latanoprost acid and butanediol mononitrate by corneal esterases. The butanediol mononitrate is then further broken down into the active nitric oxide and an inactive metabolite. Both of these components independently have the ability to increase outflow, Dr. Serle noted.2
Jason Bacharach, MD, founding partner and medical director, Northbay Eye Associates, Sonoma, California, described the latanoprostene bunod as one drug with two different mechanisms of action. “The latanoprost component improves uveoscleral outflow by widening the spacing in the uveal tissue that restricts outflow,” Dr. Bacharach said, adding that the nitric oxide component targets and relaxes the trabecular meshwork tissue. He stressed the fact that there may be a need for nitric oxide here, which is bolstered by evidence that reduced levels of this have been found in glaucoma patients’ eyes.2
Dr. Serle pointed out that the latanoprostene bunod administered once a day has been shown in clinical trials to be slightly more effective than timolol 0.5% given twice daily. “In these trials, IOP reductions were 1 to 2 mm Hg greater with latanoprostene bunod than with timolol,” she said.3 Likewise, a 28-day dose ranging comparison study indicated that latanoprostene bunod 0.024% was more efficacious than latanoprost, lowering IOP an additional 1.23 mm Hg, Dr. Serle said.4 Two studies have confirmed that latanoprostene bunod remained efficacious at the 1-year mark.3,5 “Tolerability and reported side effects are similar to prostaglandins, with site instillation discomfort reported slightly more often with latanoprostene bunod than with latanoprost,” Dr. Serle said. “During the clinical trials, latanoprostene was well tolerated with a low discontinuation rate.”
The second drug, netarsudil, is part of a new class that targets the trabecular outflow pathway, rho kinase inhibitors, Dr. Bacharach noted. Rho kinase increases contraction in smooth muscle-like cells such as those in the trabecular meshwork. This medication improves outflow by relaxing contracted trabecular meshwork tissue, he explained.6
Dr. Serle pointed out that in addition to increasing outflow through the trabecular pathway, netarsudil reduces episcleral venous pressure. Also, because netarsudil is a norepinephrine transporter inhibitor, it has a third potential mechanism, decreasing aqueous humor formation.7
Four Phase 3 clinical trials of netarsudil have been completed. The Rocket 1, 2, 3, and 4 trials, which compared netarsudil dosed once daily in the evening with timolol dosed twice daily, showed that the IOP lowering of these drugs was comparable, Dr. Serle reported. “IOP reductions with netarsudil were stable through 12 months of dosing,” she said.8
A fixed combination of netarsudil 0.02% and latanoprost 0.005%, known as Roclatan (Aerie Pharmaceuticals), was submitted to the U.S. FDA for approval in May 2018. “This fixed dose combination was compared with the individual components in two Phase 3 clinical trials, Mercury 1, a 12-month study, and Mercury 2, a 3-month study,” Dr. Serle said. “In Mercury 1 and 2, IOP reductions were 1 to 3 mm Hg greater with the fixed-dose combination of netarsudil and latanoprost than with the individual components at all measurements.”9
Dr. Serle views these findings as confirming the additivity of netarsudil and latanoprost and bolstering the consistent efficacy that the fixed-dose combination maintained through 12 months. “Additionally, in patients with baseline IOP below 25 mm Hg, netarsudil IOP lowering remained constant and similar to latanoprost through month 12,” Dr. Serle said.
Both netarsudil and Roclatan were well tolerated with the most frequent side effect being conjunctival hyperemia, which Dr. Serle noted is attributed to the drug’s vasodilatory effect. “This side effect observed in 50–60% of patients is mild, sporadic, and occurred at every visit in only 10% of patients during the clinical trials,” she said.8

Integrating outflow medications

From a clinical perspective, Dr. Bacharach pointed out that having these new agents available can improve the clinician’s ability to offer novel treatments for patients who need additional pressure reduction. “Approximately half of all treated glaucoma patients need at least two medications to control their IOP, and we have had no new options other than fixed combinations of commonly utilized classes over the past two decades,” Dr. Bacharach said, adding it’s possible that these outflow drugs can serve as first-line agents as well as having a possible adjunctive role.
Such agents may also be beneficial in the long run for maintaining and improving the health of the diseased tissue. “This could also be advantageous for a patient who in the future may undergo a trabecular-based MIGS procedure,” Dr. Bacharach said. “Similar to keeping flow going through a sink drain, it may theoretically potentiate the effects of a physical stent or scaffold placed into Schlemm’s canal at a later point in time.”
Dr. Serle noted how such agents could increase the value of MIGS, which themselves only influence a small area of the trabecular meshwork. “Maintaining the health and function of the trabecular outflow pathways may allow the addition of MIGS procedures to result in better IOP control,” Dr. Serle said, adding that with these medications improving outflow throughout the meshwork, this could enhance the reach of the MIGS procedure and make additional IOP reductions possible.
Dr. Bacharach thinks that practitioners who want to incorporate these new agents can do so confidently. “These agents have excellent systemic safety profiles and no restrictions on when to prescribe; whether this be first-line or adjunctive, there are minimal limitations to a prescribing physician interested in implementing these into their armamentarium,” Dr. Bacharach said. “The biggest hurdle we will encounter here is navigating the formulary restrictions that burden our practices and hamper patients’ access to these novel options.” This may make cost an issue for many, However, manufacturers are aware of such possible hurdles and have implemented multiple techniques to make these drugs easier to prescribe, Dr. Bacharach said.
Even with such barriers, as well as the fact that there are several glaucoma agents generically available on the market, Dr. Serle is optimistic that these agents will find a place in practice. “The once-daily dosing of these agents makes them extremely attractive for patients and physicians,” she said, adding that the fact that efficacy is in the range of timolol and latanoprost, two of the most effective agents, is something to contemplate as well.
While neither of the agents have the systemic issues of the beta blockers, practitioners need to be aware of other potential side effects in prescribing these and should discuss them with patients, Dr. Serle stressed. “The side effect profile of the latanoprostene bunod is similar to prostaglandins,” she said. It includes ocular and periocular pigment and orbital changes. The side effect profile of netarsudil is different and includes typically mild ocular side effects that are reversible once the drug is discontinued.
Dr. Serle has found that in practice latanoprostene bunod is an excellent substitute in some patients for latanoprost and other prostaglandins in those who need additional IOP control. Netarsudil has also been very effective in some patients in her practice. She views netarsudil as a new medication that can be offered as a first-line agent as it is similar in efficacy to timolol and latanoprost. “Both can be used as adjunctive therapy to the other classes of compounds available, with different mechanisms of IOP reduction,” Dr. Serle said.
Overall, these outflow agents represent a breakthrough, Dr. Serle stressed. “More than 20 years of research has gone into discovering two new classes of medications for lowering IOP,” she said. “These drugs will benefit our patients by reducing the rate of progression and vision loss from glaucoma.” Exciting research in the management of glaucoma continues, which hopefully will lead to additional treatments, she concluded.


1. Stamer WD, Acott TS. Current understanding of conventional outflow dysfunction in glaucoma. Curr Opin Ophthalmol. 2013;23:135–43.
2. Cavet ME, DeCory HH. The role of nitric oxide in the intraocular pressure lowering efficacy of latanoprostene bunod: review of nonclinical studies. J Ocul Pharmacol Ther. 2018;34:52–60.
3. Weinreb RN, et al. Latanoprostene bunod 0.024% in subjects with open-angle glaucoma or ocular hypertension: pooled phase 3 study findings. J Glaucoma. 2018;27:7–15.
4. Weinreb RN, 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;99:738–45.
5. Kawase K, et al. 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.
6. Lin CW, et al. Discovery and preclinical development of netarsudil, a novel ocular hypotensive agent for the treatment of glaucoma. J Ocul Pharmacol Ther. 2018;34:40–51.
7. Kazemi A, et al. The effects of netarsudil ophthalmic solution on aqueous humor dynamics in a randomized study in humans. J Ocul Pharmacol Ther. 2018. Epub ahead of print.
8. Serle JB, et al. Two phase 3 clinical trials comparing the safety and efficacy of netarsudil to timolol in patients with elevated intraocular pressure: Rho Kinase Elevated IOP Treatment Trial 1 and 2 (ROCKET-1 and ROCKET-2). Am J Ophthalmol. 2018;186:116–127.
9. Serle J. 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 (MERCURY 1). Paper presented at the 2017 Association for Research in Vision and Ophthalmology annual meeting.

Editors’ note: Dr. Bacharach has financial interests with Bausch + Lomb and Aerie Pharmaceuticals (Durham, North, Carolina). Dr. Serle has related financial interests with Aerie Pharmaceuticals, Allergan (Dublin, Ireland), Bausch + Lomb, and Ocular Therapeutix (Bedford, Massachusetts).

Contact information

: jbacharach@northbayeye.com
Serle: janet.serle@mssm.edu

An inside look at outflow drugs for glaucoma An inside look at outflow drugs for glaucoma
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