Until recently, glaucoma management has been at a standstill in terms of new treatment options. Fortunately, that has finally changed: We are now living in a glaucoma renaissance, with a variety of new medical therapies and surgical procedures being developed and introduced. This includes a new class of medical therapeutics poised to change the way we think about what might be possible with glaucoma pharmacology.

But this exciting news is also fraught with the potential for confusion around which therapies to select for which patients. Understanding each of these new medications, including their different mechanisms of action, safety and efficacy profiles and dosing, is not only essential to navigating this new landscape, it is also critical to ensure that we prescribe the right therapy for each of our patients — and ultimately, deliver the best possible outcomes.

FIRST, A BRIEF HISTORY

The aqueous outflow approach

For more than 20 years, the glaucoma therapy armamentarium consisted of four main drugs classes: prostaglandin analogs (PGAs), alpha-adrenergic receptor agonists (alpha agonists), beta-adrenergic receptor antagonists (beta-blockers) and carbonic anhydrase inhibitors (CAIs). These therapies help facilitate aqueous outflow via the uveoscleral pathway or decrease aqueous production at the ciliary body level.

Even though the trabecular meshwork (TM) is the site of highest resistance to aqueous outflow in glaucomatous eyes, we did not have drugs that specifically targeted the TM. What’s more, the reduction of aqueous humor is a less than ideal therapeutic approach. Aqueous is the waste removal system of the eye, and it contains nutrients and antioxidants that the TM needs to survive. Using an aqueous suppressant may lower IOP, but it also decreases the level of antioxidants, potentially leading to cellular damage, fibrosis and contraction and damage to the TM. So, even though we are treating IOP, we could be contributing to longer term glaucoma damage by promoting TM dysfunction.

No one wrestled with these challenges more than the late David Epstein, MD, former chair of ophthalmology at Duke University. In an editorial challenge published in the Archives of Ophthalmology (now JAMA Ophthalmology) in 1987, Dr. Epstein called on his colleagues to pursue a treatment that targets the underlying disease process — the depredation of the TM. He went on to establish a company in pursuit of this goal, but it would be nearly two decades before such a therapy would be made available.

However, another new agent preceded the fruit of Dr. Epstein’s vision to market.

Progress: A prostaglandin plus

In November 2017, the FDA approved Vyzulta (latanoprostene bunod ophthalmic solution) 0.024% (Bausch + Lomb), a prostaglandin analog indicated for the reduction of IOP in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT).¹ Latanoprostene bunod is a chemical entity that releases latanoprost acid and nitric oxide (NO) on administration (Figure 1).^2,3 Like previous-generation PGAs, Vyzulta is thought to lower IOP by increasing outflow of aqueous humor through the uveoscleral pathway. While preclinical evidence suggests that NO has an effect on the TM, currently no clinical evidence demonstrates this effect.³

NEW CLASSES OF MEDICATION

Rho kinase inhibition

In December 2017, the FDA approved Rhopressa (netarsudil ophthalmic solution) 0.02% (Aerie Pharmaceuticals), the first of an entirely new class of drugs for the reduction of IOP to be approved in the United States in more than 20 years.

Rhopressa is indicated for the reduction of elevated IOP in patients with OAG or OHT. Netarsudil, the active ingredient in Rhopressa, is a Rho kinase (ROCK) inhibitor. ROCK is a serine/threonine kinase that affects cell shape, adhesion and motility by regulating cell contraction. In the TM, inhibition of ROCK activity is thought to reduce resistance to aqueous humor outflow by disrupting actin-myosin contraction, decreasing extracellular matrix production and relaxing the tissue. Netarsudil also may have suppressive activity against the norepinephrine transporter (NET)⁴ and has been shown to lower episcleral venous pressure (EVP), a secondary mechanism for lowering IOP that may be particularly important at lower pressures.^5,6

Rhopressa not only represents the result of more than a decade of small molecule drug discovery and clinical development but also the fulfillment of Dr. Epstein’s quest for an agent that targets the pathological process in the disease: restoring outflow through the TM. A study published in Investigate Ophthalmology and Visual Science demonstrated expansion and relaxation of the TM tissue in donor eyes perfused with a ROCK inhibitor for 3 hours (Figure 2), allowing aqueous to easily flow through and reach Schlemm’s canal.⁷

Pooled efficacy data from two Phase 3 clinical studies demonstrated that once-daily Rhopressa was non-inferior to twice-daily timolol in patients with baseline IOP below 25 mm Hg, producing a mean reduction of IOP at peak of up to 5 mm Hg. This effect was consistent regardless of baseline IOP, with IOP reduction within 1 week of treatment initiation and no tachyphylaxis observed over the course of 12 months.⁴

The most common ocular adverse event observed was conjunctival hyperemia, which was reported in 53% of patients (however, after a washout period and prior to starting treatment with Rhopressa, a baseline hyperemia rate of 20% was not factored out of this statistic). In nine out of 10 patients, hyperemia was either not reported or reported as mild. Other ocular adverse reactions (~20%) included cornea verticillata, instillation site pain and conjunctival hemorrhage. Conjunctival (petechial) hemorrhage was graded as mild in more than 90% of cases. Cornea verticillata, likely due to netarsudil-induced phospholipidosis, was seen only under biomicroscopy, resolved or improved by the end of a noninterventional follow-up study, and was not associated with any clinically meaningful impact on visual function.⁴

Dosed q.d., Rhopressa has no labeled systemic contraindications. Unlike beta-blockers and alpha agonists, it does not have any effect on blood pressure or heart rate.

Combining the best of both worlds

Less than two years later, in March 2019, the FDA approved Rocklatan (netarsudil and latanoprost ophthalmic solution) 0.02/0.005%, bringing together latanoprost, the most widely prescribed PGA, and netarsudil, the active ingredient in Rhopressa, in a fixed-dose combination, dosed q.d.

In two Phase 3 clinical trials comparing Rocklatan’s IOP-lowering effect to that of both latanoprost q.d. and Rhopressa q.d., Rocklatan’s was up to 3 mm Hg greater than both of its individual components.^8-10 These studies also demonstrated that nearly twice as many Rocklatan patients achieved a 30% IOP reduction compared to latanoprost patients¹¹ and nearly 60% of Rocklatan patients achieved an IOP of ≤ 16 mm Hg vs 37% of latanoprost patients.⁹ Rocklatan was statistically superior to latanoprost at every timepoint measured.^8,9

The Rocklatan side effect profile is similar to that of Rhopressa, with ocular adverse events including hyperemia, cornea verticillata, instillation site pain and conjunctival hemorrhage and no labeled systemic contraindications.¹¹

CLINICAL APPLICATIONS AND CONSIDERATIONS

Vyzulta

Each of these therapies has something to offer and fills a previously unmet need in my armamentarium. In some cases, I have even seen significant synergy between Vyzulta and Rhopressa, with consistent increased IOP reductions when both drops are used together compared to each drop used individually. I typically prescribe Vyzulta where I would have previously prescribed a prostaglandin. I also sometimes replace a prostaglandin with this new agent if a patient needs further reduction.

I applied this strategy recently with a 55-year-old male patient with mild pseudoexfoliation glaucoma in both eyes (OU). On latanoprost once daily at bedtime (q.h.s.) OU and timolol 0.5% twice daily OU, his IOP was 18 mm Hg OU with a cup-to-disk ratio (C/D) 0.65 OD and 0.55 OS and Humphrey visual field (HVF, Zeiss) of -6.17 in his right eye (OD) and 5.01 in his left (OS). To reach a goal IOP of 15 mm Hg OU, I switched him from latanoprost to Vyzulta instead of adding another agent/glaucoma medication. After 4 weeks of the new regimen, IOP was 14 mm Hg OU. I have employed the netarsudil line across all types of glaucoma (including POAG, chronic angle closure and pseudoexfoliative) and all disease severity levels (mild, moderate and severe), including patients who are on zero to one drops and those on MMT, with good effect.

Rhopressa

For Rhopressa, typical responses from my patients have been in line with what investigators found in the clinical studies (mean IOP reduction of up to 5 mm Hg). However, I do occasionally have “hyper responders” who experience significantly greater pressure drops.

One scenario in which I saw particularly exceptional results with Rhopressa was when I used it as a first-line therapy in low-tension glaucoma (LTG). We often need to achieve pressures of 10 to 12 mm Hg in LTG, and sometimes even single digits based on disease severity. I believe netarsudil can help us achieve these goals because of the drug’s promotion of outflow through the TM as well as its potential for decreasing EVP, which plays a more important role in determining IOP in lower pressures.

Recently, I saw a 65-year-old Caucasian female with newly diagnosed LTG who had an IOP of 17 mm Hg OU, a C/D of 0.90 OU and HVF of -18 OD and -20 OS. I prescribed Rhopressa q.h.s. Two weeks later, her IOP in both eyes dropped to 9 mm Hg.

For patients already on a PGA but in need of additional lowering, I add Rhopressa and monitor their progress. If they do well, I usually switch them to Rocklatan, which combines netarsudil with the PGA in one drop to achieve the same efficacy results with a simpler dosing regimen.

Rocklatan

Rocklatan patients are two to three times more likely to achieve IOPs in the low teens compared to Rhopressa or a PGA alone¹⁰ because it works on three pathways: promoting outflow through TM and decreasing EVP (netarsudil), and increasing outflow through uveoscleral pathway (latanoprost). As a result, I often not only reach target pressures but also achieve IOPs lower than target goals. This allows me to discontinue other agents and still maintain target IOP with the compliance benefit of one drop.

One example is a 55-year-old with pigmentary glaucoma OD>OS. He had a Tmax of 32 OD and IOP 22 mm Hg OD, 21 mm Hg OS on latanoprost q.h.s. OU and timolol b.i.d. OU. His C/D was 0.85 OD, 0.75 OS and HVF with MD -13.45 OD, 11.45 OS. We set a target IOP of mid-to-high teens for both eyes and switched the latanoprost to Rocklatan q.h.s. OU, maintaining the timolol b.i.d. OU. Two weeks later, his IOP was 13 mm Hg OU. Because this pressure exceeded our goal, we discontinued the timolol. Two weeks later, his IOP was 15 mm Hg OU.

More on side effects

Hyperemia is a potential side effect of both Rhopressa and Rocklatan. While most patients experience mild hyperemia, it’s important to discuss this potential side effect up front so that patients are not taken by surprise if it happens. I typically tell patients that hyperemia can happen but explain that is usually mild, does not progress over time and does not affect vision. When I counsel patients on the risk of hyperemia in this way, the incidence of discontinuation goes down because they are better informed. I have also seen corneal verticillata associated with long-term use, but it is mild, reversible and does not impact visual acuity.

A NEW DAY IN GLAUCOMA

After 20 years of stagnation in the category, it’s exciting to have new, effective treatments available that offer efficacy, favorable side effect profiles and q.d. dosing to foster greater compliance. These benefits address some the most significant challenges we’ve faced with previous therapeutic options.

I encourage you to try the drugs in scenarios like those I have described to gain a better understanding of the molecules and their efficacy. I believe you’ll find that we are in a position to offer our patients a new level of care in glaucoma and, ultimately, preserve sight. OM

REFERENCES

1. Center for Drug Evaluation and Research Summary Review: Application Number 207795Orig1s000.
2. Krauss AH, Impagnatiello F, Toris CB, et al. Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating prostaglandin F2α agonist, in preclinical models. Exp Eye Res. 2011;93:250-255.
3. 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;33:1612-1627.
4. Serle, JB, Katz LJ, McLaurin E, 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.
5. Kiel JW, Kopczynski CC. Effect of AR-13324 on episcleral venous pressure in Dutch belted rabbits. J Ocul Pharmacol Ther. 2015;31:146-151.
6. Kazemi A, McLaren JW, Kopczynski C, et al. The Effects of Netarsudil Ophthalmic Solution on Aqueous Humor Dynamics in a Randomized Study in Humans. J of Ocul Pharmacol Ther. 2018;34:380-386.
7. Ren R, Li G, Le TD, et al. Netarsudil increases outflow facility in human eyes through multiple mechanisms. Invest Ophthalmol Vis Sci. 2016;57:6197-6209.
8. Rocklatan (netarsudil and latanoprost ophthalmic solution) 0.02%/0.005% Prescribing Information, Aerie Pharmaceuticals, Inc., Irvine, Calif. 2019.
9. Asrani S, McKee H, Scott B, et al. Pooled phase 3 efficacy analysis of a once-daily fixed dose combination of netarsudil 0.02% and latanoprost 0.005% in ocular hypertension and open-angle glaucoma. Presented at: 13th Biennial Meeting of the European Glaucoma Society, March 2018.
10. Brubaker J, Teymoorian S, Lewis R, et al. Once-daily fixed-dose combination of netarsudil 0.02% and latanoprost 0.005% in ocular hypertension/open-angle glaucoma: 12-month data from MERCURY-1. Presented at: 28th Meeting of the American Glaucoma Society, March 2018.
11. Data on file, Aerie Pharmaceuticals

About the Author

Gagan Sawhney, MD, is in practice at Georgia Eye Partners, Atlanta. He specializes in cataract surgery as well as the medical and surgical management of glaucoma from early to advanced disease.

Financial disclosures: Dr. Sawhney is a speaker for Aerie Pharmaceuticals, Allergan and New World Medical.