May 2020


Revolution in Glaucoma Medications
An overview of new glaucoma medications

by Chiles Samaniego Contributing Writer

Source: Bausch + Lomb

Source: Aerie Pharmaceuticals


Seemingly, the glaucoma stars have aligned,” said Daniel Lee, MD. “Three novel medications received FDA approval in a very short window.”
“Since November 2017, three new topical, IOP-lowering agents have been approved by the U.S. FDA,” said Janet Serle, MD. “Vyzulta [latanoprostene bunod, Bausch + Lomb] in November 2017, Rhopressa [netarsudil, Aerie Pharmaceuticals] in December 2017, and Rocklatan, the fixed-dose combination of netarsudil and latanoprost [Aerie Pharmaceuticals], in March 2019.”
“Those new medications represent the first approved novel agents in more than 2 decades when prostaglandins and alpha agonists were approved in 1996,” said Albert Khouri, MD. “Since then, we have only had different formulations and combinations of existing agents.”
EyeWorld spoke with Drs. Khouri, Lee, and Serle for a comprehensive overview of these three novel glaucoma medications.

Mechanism of action

“These new agents are thought to target the trabecular meshwork, which is the site of pathology leading to ocular hypertension in glaucoma,” Dr. Khouri said. “Because the new agents target the site of pathology, they seem to be effective at wide ranges of IOP.”
Netarsudil is a rho kinase inhibitor—it inhibits rho-associated protein kinase (ROCK) and norepinephrine transporter (NET). “ROCKs induce the formation of stress fibers and focal adhesions, which result in increased contractility,” Dr. Lee said. ROCK inhibition “leads to relaxation of the TM and reduction of episcleral venous pressure, improving outflow to the proximal and distal conventional outflow pathway. NET inhibition leads to reduced aqueous production.”
Netarsudil thus acts “directly at the cellular level,” Dr. Serle said, noting that episcleral venous pressure is the most distal resistance to trabecular outflow. “The primary mechanism is enhancing trabecular outflow and the secondary mechanism is lowering episcleral venous pressure.”
She added that a small reduction in aqueous humor flow rates was identified in preclinical nonhuman primate studies as a third mechanism.
Meanwhile, latanoprostene bunod is “currently the first and the only ocular hypotensive agent that is a nitric oxide donor,” Dr. Serle said. “Evidence for reduced levels of nitric oxide in the aqueous and plasma of glaucoma patients has been reported.”
“When applied topically to the eye, Vyzulta breaks down into two metabolites: latanoprost acid and butanediol mononitrate,” Dr. Lee said. Butanediol mononitrate is a nitric oxide-donating moiety.
“Nitric oxide is proposed to relax trabecular meshwork cells by working at the intracellular level (suggested mechanisms of action include inhibiting actin-myosin interaction and release of intracellular calcium, among others),” Dr. Khouri said. “For clinicians, the desired effect is lowering IOP with a well-tolerated side effect profile.”
Given this proposed mechanism, “Vyzulta is thought to lower IOP by increasing aqueous humor outflow through both the trabecular meshwork via nitric oxide, and the uveoscleral route via latanoprost,” Dr. Serle said.


Vyzulta and Rocklatan “have the additional punch of a prostaglandin. Rocklatan in MERCURY trials delivered 40% reduction in about a third of patients,” Dr. Khouri said. In particular, he noted how by netarsudil’s effect on episcleral venous pressure, “these agents work even when baseline pressures are lower. Such effects were observed in multiple studies with new agents including ROCKET, MERCURY, and JUPITER trials.”
“Phase 3 pivotal clinical trials, which led to the U.S. FDA approval of these drugs, confirmed the relative efficacy of these three new agents to topical medications commonly used to treat elevated IOP,” Dr. Serle said.
Pooled data from the APOLLO and LUNAR trials comparing once-daily latanoprostene bunod with twice-daily timolol 0.5% in 831 patients with open angle glaucoma demonstrated greater (p<0.001) IOP lowering with latanoprostene bunod at all nine measured time points, with mean IOP reductions of 7.5–9.1 mm Hg from baseline through 3 months of treatment.1 In VOYAGER, latanoprostene bunod was superior to latanoprost with mean IOP reductions of about 9 mm Hg at 4 weeks.2
The pooled data including 1,621 patients from ROCKET-1, -2, and -4 showed that IOP lowering with netarsudil 0.02% once daily (17.5–19.5 mm Hg) was comparable to that with timolol 0.5% twice daily (17.6–18.4 mm Hg) at nine time points through 3 months of treatment.3,4
The MERCURY trials had three arms testing the fixed-dosed combination of netarsudil 0.02%/latanoprost 0.005%, netarsudil alone, and latanoprost alone. IOP reductions with the fixed-dose combination ranged from 7.2–9.2 mm Hg (31–36%) from baseline—reductions up to 3 mm Hg greater than with the individual components. Furthermore, efficacy through 12 months of dosing were consistent with 3-month results.5
Real-world experience has also been reported. Dr. Serle cited a retrospective review of netarsudil in 172 eyes of 108 patients that confirmed that netarsudil is additive to other medications used to treat glaucoma.6 “This study suggests netarsudil is efficacious early in the disease when patients are presumably receiving fewer medications as well as later in the disease when patients tend to be on more medications to control intraocular pressure,” she said.
Meanwhile, a retrospective review of 95 eyes of 52 patients in which latanoprostene bunod was substituted for prostaglandin demonstrated that latanoprostene bunod was more efficacious than a prostaglandin that does not contain nitric oxide and found that latanoprostene bunod is additive in patients on multiple ocular hypotensive medications.7

Side effects

The doctors all agreed that latanoprostene bunod has a similar side effect profile to latanoprost and other prostaglandin analogues, including periocular side effects, occasional ocular irritation, pain on instillation, and hyperemia, Dr. Serle said.
Hyperemia was also the most commonly reported side effect with netarsudil-based products. Dr. Khouri said that it was mostly mild and not always present. He thinks this is partly due to how netarsudil works—the dilation of episcleral veins leading to reduction of episcleral venous pressure.
“Newer agents are very safe systemically with no cardiac or pulmonary side effects,” he added.
At Wills Eye, Dr. Lee said that a “small percentage of those receiving Rhopressa and Rocklatan experience unique side effects not seen in prior classes—subconjunctival hemorrhages and corneal verticillata”—also seen by Drs. Khouri and Serle. Fortunately, Dr. Lee said, none of the corneal verticillata seen in 5–9% of their patients were visually significant. The subconjunctival hemorrhages were generally mild, self-limited, and “mostly described as small and petechial hemorrhages,” he said.
Interactions between any of the three drugs and other medications have not been reported.

Challenges to prescribing

“From a strictly clinical standpoint, these medications check off all boxes for characteristics we look for in first-line treatments,” Dr. Lee said. However, all three doctors noted challenges to prescribing new medications.
In addition to the standard challenges of prescribing any medication—familiarity and comfort of the prescribing physician and the ability and acceptance of patients to incorporate new medications or changes into their routine, Dr. Serle said—all three doctors noted that the main challenge is insurance coverage limitations and prior authorization requirements. “Clinicians’ offices can be overburdened with prior authorization requests,” Dr. Khouri said.
Despite being seemingly ideal as first- or second-line treatment, Dr. Lee thinks the new agents are currently impractical, in many cases, due to cost and insurance coverage. Also, due to the significant drop in adherence with each additional medication, adding these medications onto an “already medically maximized patient certainly does not help from a compliance standpoint,” he said.
Dr. Khouri emphasized giving each patient more chair time as therapy is individualized and so patients are prepared for side effects.

Utilization, existing treatment, transition to surgery

While agents are “well-positioned as first-line medications,” Dr. Khouri said, they can also be integrated into the glaucoma treatment algorithm “as add-on medications in patients not sufficiently controlled,” Dr. Serle said.
Dr. Khouri sees these newer agents, dosed once a day, as an opportunity to simplify treatment regimens. “Maximal therapy can be as simple as two bottles now,” he said.
In compliant patients who reliably administer their medications and achieve target IOP, Dr. Serle said that numerous topical ocular hypotensive medications are “acceptable and beneficial. If target IOP is not achieved in a compliant patient, substitution or addition of newer medications can be considered.” Real- world studies have shown both latanoprostene bunod and netarsudil to provide additional IOP reductions in patients already taking three or more medications. While there is currently no real-world data for the additive effect of the more recently approved, fixed-dose combination, the experience with each component alone makes this the anticipated result.
Both Dr. Khouri and Dr. Serle see surgery as “the next discussion” for progressing patients not meeting target IOP on medications. Surgical intervention, Dr. Lee said, is now “a much more reasonable option in many cases,” given the improved safety profile of microinvasive techniques and devices. “On the other hand, a MIGS procedure in the wrong patient can potentially backfire with visually significant IOP spikes or large hyphemas,” he said. “The decision to add more medications vs. surgery should be made on a case-by-case basis.”
In patients already on a prostaglandin analogue, side effect profile and desired IOP reduction play a major role in deciding whether to switch to latanoprostene bunod or the fixed combination. “Both medications in this scenario would be a fine choice,” Dr. Lee said. “In eyes where I’m seeking to reduce IOP by more than 2 mm Hg, I am more likely to try Rocklatan first as it had a slight edge over Vyzulta compared to latanoprost alone in the MERCURY and VOYAGER trials, respectively. In eyes where I am concerned about significant hyperemia, I am more likely to try Vyzulta first due to its comparatively favorable side effect profile.”
In any case, Dr. Serle reminded clinicians that potential side effects of all treatment options need to be discussed with each patient. The actual impact on disease progression also remains an uncertainty and patients should be informed as such. “Studies need to be conducted to determine if the disease may progress at a slower rate, particularly if these agents are added early in the course of glaucoma,” she said.

At a glance
• The three recently approved agents for the treatment of glaucoma excluding sustained- release drugs are:
–Latanoprostene bunod (Vyzulta, Bausch + Lomb)
–Netarsudil (Rhopressa, Aerie Pharmaceuticals)
–Fixed-combination netarsudil and latanoprost (Rocklatan, Aerie Pharmaceuticals)
• Believed to target the site of pathology, these medications appear to be effective at a wide range of IOPs, including lower baseline IOPs.
• FDA studies and limited real-world experience show these agents to be comparable to existing glaucoma medications at once-daily dosing with minimal, typically mild and self-limited side effects.
• While challenges remain in terms of cost and insurance, clinically these drugs appear suitable for use as first-/second-line treatments or adjuncts to existing treatment.

About the doctors

Albert Khouri, MD
Associate professor
of ophthalmology
Rutgers New Jersey
Medical school
Newark, New Jersey

Daniel Lee, MD
Clinical instructor
of ophthalmology
Wills Eye Hospital
Philadelphia, Pennsylvania

Janet Serle, MD
Professor emeritus
of ophthalmology
Icahn School of Medicine
at Mount Sinai New York, New York


1. 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.
2. Weinreb RN, et al. A randomized, 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.
3. Fechtner RD, et al. Pooled efficacy analysis of once-daily netarsudil ophthalmic solution 0.02% in patients with ocular hypertension or open-angle glaucoma. 2018 ASCRS ASOA Annual Meeting.
4. Khouri AS, et al. Once-daily netarsudil versus twice-daily timolol in patients with elevated intraocular pressure: The randomized Phase 3 ROCKET-4 study. Am J Ophthalmol. 2019;204:97–104.
5. Asrani SG, et al. A 3-month interim report of a prospective, double-masked, randomized, multi-center, active-controlled, parallel-group 12-month study assessing the safety and ocular hypotensive efficacy of PG324 ophthalmic solution. 2017 American Glaucoma Society Annual Meeting.
6. Ustaoglu M, et al. The efficacy and safety profile of netarsudil 0.02% in glaucoma treatment: Real-world outcomes. 2019 Association for Research in Vision and Ophthalmology Annual Meeting.
7. Radell JE, et al. Incorporation of the first nitric oxide donating prostaglandin, latanoprostene bunod, into clinical practice. 2020 American Glaucoma Society Annual Meeting.

Relevant disclosures

: Glaukos, Optovue, Allergan, New Jersey Health Foundation, Aerie, Bausch + Lomb
Lee: Allergan, Optovue, Glaukos
Serle: Aerie Pharmaceuticals, Allergan, Bausch + Lomb, Qlaris Bio



An overview of new glaucoma medications An overview of new glaucoma medications
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