Glaucoma has many risk factors, most of which are not modifiable. Intraocular pressure (IOP) is the main modifiable risk factor and is determined by the difference between aqueous humor production and outflow. Via the conventional pathway, most of the aqueous humor leaves the eye at the anterior-chamber angle through the trabecular meshwork, then passes into Schlemm’s canal (SC) and subsequently into collector channels, which feed into the episcleral venous system, where aqueous mixes with the venous circulation.

Episcleral Venous Pressure

The pressure in the episcleral veins is approximately 8 mmHg to 10 mmHg, and this episcleral venous pressure (EVP) forms a resistance to outflow and a lower limit to IOP.^1-4 The ability of medications to lower IOP is greatly dependent on the “floor” pressure determined by EVP.According to the modified Goldmann equation, aqueous outflow is dependent on the gradient between IOP and EVP: IOP = (F-U)/C + EVP, where F is the rate of aqueous humor formation, U is uveoscleral outflow, and C is the facility of outflow. This equation demonstrates that, for every mmHg rise in EVP, there is an equal increase in IOP, although it has been suggested that the magnitude of rise of IOP can be greater.⁴

The Link Between IOP and EVP

Until late 2017, the options to lower IOP were limited to drugs that focused on decreasing aqueous production or increasing aqueous outflow via either the trabecular or uveoscleral outflow pathways. It is clear that IOP alone cannot accurately, nor adequately, dictate a patient’s glaucoma treatment. Intraocular pressure, however, is also dependent on the level of EVP, and historically there have been few options to modify EVP. Given its role in determining IOP, it is imperative that clinicians pay attention to EVP in the management of patients with glaucoma.

Unfortunately, measuring EVP is very challenging, and currently only a few highly skilled clinical researchers are able to perform accurate EVP measurements. Despite the current limitations of measuring EVP in the office, a therapeutic agent that lowers EVP would provide a novel mechanism for IOP reduction.

In December 2017, the US Food and Drug Administration approved netarsudil ophthalmic solution 0.02%, (Rhopressa; Aerie Pharmaceuticals) for the lowering of IOP in patients with glaucoma or ocular hypertension. This novel, once-daily medication dosed in the evening is among a newer class of medications in the glaucoma space called Rho kinase (ROCK) inhibitors. Within the trabecular meshwork, Rho kinase enzymes promote actin-myosin contraction and increase actin stress fibers and focal adhesions to the extracellular matrix, thus increasing stiffness and causing resistance to aqueous outflow from the eye.⁵ ROCK inhibitors, such as netarsudil, work at the cellular level within the trabecular outflow pathway to disassemble the actin-myosin stress fibers and release these adhesions. This causes relaxation within the trabecular meshwork and the inner wall of SC, leading to increased trabecular outflow and decreased IOP. In addition, Rho kinase regulates cell morphology and smooth muscle contraction. ROCK inhibitors therefore cause smooth muscle to relax, resulting in vasodilation and decreased EVP.^6-7

Lowering EVP With Medications

Netarsudil is the first glaucoma medication shown to decrease EVP in humans. Clinical data from both healthy eyes and glaucomatous eyes have demonstrated an approximately 10% decrease in EVP with netarsudil 0.02%. In a phase 1 trial of 11 healthy eyes dosed once daily with netarsudil 0.02% in one eye and control vehicle in the other eye for 7 days, diurnal EVP decreased 10% from baseline (P=.01); however the difference compared to controls was not significant.⁸ Sit et al performed a similar study in 20 patients with either ocular hypertension or primary open angle glaucoma. Patients were washed out of current medications or were treatment naïve; baseline IOPs ranged between 21 mmHg and 29 mmHg. Netarsudil 0.02% dosed once daily in one eye and vehicle in the contralateral eye resulted in a 9.5% decrease in EVP compared to baseline (P=.0113) and a 12.6% decrease compared to placebo (P=.0003). Netarsudil has therefore been proven to lower EVP in clinical studies.⁹

The IOP-lowering effect of netarsudil 0.02% was well studied in the ROCKET 1, 2, and 4 trials, which demonstrated up to a 5-mmHg reduction in IOP with once-daily nighttime dosing. This lowering was consistent despite the level of baseline IOP, which is not typical of most glaucoma medications.^10,11 The MOST study simulated real-world usage of netarsudil in clinical practice. This 12-week, prospective, multicenter, noncomparative, open-label trial evaluated the IOP-lowering efficacy of netarsudil 0.02% when used as monotherapy or when used concomitantly with other IOP-lowering agents in subjects with elevated IOP due to open-angle glaucoma or ocular hypertension. Of the 260 patients recruited, 161 were administered netarsudil as adjunctive therapy in addition to a prostaglandin (PGA) or other multidrop therapies. The primary endpoint was the percentage change from baseline in mean IOP after 12 weeks.¹²

This study truly simulated real-world experience. Patients were allowed to participate even if they had prior ocular medical treatments, including any number of IOP-lowering medications, or if they had undergone glaucoma laser treatment, minimally invasive glaucoma procedures, or prior cataract surgery. Because the treatment regimens were highly variable, there were varying sample sizes between groups, and it was not feasible to run statistical power calculations.¹²

The MOST results demonstrated that, regardless of the baseline regimen, the addition of netarsudil 0.02% yielded approximately an additional 4-mmHg or 20% reduction from baseline mean IOP. This was consistent whether netarsudil 0.02% was added to a PGA alone or to 2 or more medications. The group on 2 or more medications included patients on PGAs, beta blockers, topical carbonic anhydrase inhibitors, and/or alpha agonists, as well as fixed-dose combination medications.¹² Despite being added to regimens that included aqueous suppressants and uveoscleral outflow enhancers, the result was the same: netarsudil 0.02% resulted in consistent additional IOP lowering of 4 mmHg.¹²

Despite the varied mechanisms of action of the concomitant medications, the addition of netarsudil consistently lowered IOP, suggesting that netarsudil lowers IOP by a unique mechanism. This supports the data demonstrating that netarsudil has a two-fold, novel mechanism of action to decrease IOP: improving aqueous humor outflow through the trabecular meshwork as well as decreasing EVP.^8,9

Other medications may also lower EVP. Intracameral administration of bimatoprost (Durysta; Allergan) lowers IOP more than topical administration, and it has been postulated that decreased EVP is the mechanism for this additional IOP lowering.¹³ Similarly, nitric oxide release from latanoprostene bunod (Vyzulta; Bausch + Lomb) has also been hypothesized to lower EVP. The IOP lowering from latanoprostene bunod is greater than that achieved at the top of the dose-response curve for latanoprost, suggesting an additional mechanism. Clinical studies in humans are needed to fully elucidate these findings.

Conclusion

Reducing EVP is an additional mechanism to lower IOP. Clinical studies have shown that netarsudil decreases EVP, which contributes to netarsudil’s IOP lowering effect. In addition, the MOST study and its simulation of a real-world clinical scenario showed that IOP can be lowered even in patients on multiple other drops, further confirming the novel mechanism of action of netarsudil. Netarsudil is a welcome addition to our glaucoma armamentarium to help our patients reach their IOP goal and, ultimately, stabilize their disease. GP

Monisha M. Vora, MD, is a comprehensive ophthalmologist and glaucoma specialist at Northern Ophthalmic Associates in Jenkintown, Pennsylvania, and a clinical instructor on the glaucoma service at Wills Eye Hospital in Philadelphia, Pennsylvania. She reports consultancy to Sight Sciences, Aerie Pharmaceuticals, and Allergan. Reach her at mandalmv@gmail.com.

Jody R. Piltz-Seymour, MD, is the director of the Glaucoma Care Center at Valley Eye Professionals, LLC, in Huntingdon Valley, Pennsylvania. She is an attending surgeon on the Wills Eye Hospital Glaucoma Service and a clinical professor at the University of Pennsylvania in Philadelphia. She reports consultancy to and speaker’s fees from Aerie Pharmaceuticals. Reach her at jseymour@valleyeyepros.com.

References

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