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Rho kinase inhibitors: Filling a gap in glaucoma treatment


The glaucoma medication market is thriving today with newer medications that are increasingly efficacious with a new mechanism of action.

It is safe to say that the glaucoma medication market is thriving with therapies that can help the vast majority of patients achieve their target IOPs.

The good news is that the products that comprise all of the various glaucoma drug classes are so highly efficacious as solo or combination therapies prescribed alone or in conjunction with additional drugs, that the need for glaucoma surgeries has decreased.

Two new recently introduced anti-glaucoma drugs are adding to this success as a result of a new mechanism of action, high efficacy, a low treatment burden.

New kids on the block

Aerie Pharmaceuticals has developed two new drugs that have become commercially available recently. One is netarsudil ophthalmic solution 0.02% (Rhopressa), a rho kinase inhibitor, and the second is netarsudil and latanoprost ophthalmic solution 0.02%/0.005% [Xalatan ophthalmic solution 0.005%] (Rocklatan), a combination of a prostaglandin and a rho kinase inhibitor, according to Fiaz Zaman, MD, who is on the clinical faculty, University of Houston, and in private practice at Houston Eye Associates, Houston.

The FDA approval of Rhopressa in 2018 marked the first member of a new class of anti-glaucoma drugs to appear since 1996 when latanoprost ophthalmic solution 0.005% (Xalatan, latanoprost Pfizer), a prostaglandin, entered the marketplace.

The beauty of this new drug class of rho kinase inhibitors is its unique mechanism of action to treat glaucoma, according to Dr. Zaman.

Previous classes of glaucoma drugs work to lower IOP by impacting the aqueous humor outflow or production; in contrast, rho kinase inhibitors work directly in the angle of the eye on the trabecular meshwork, with 70% to 80% of aqueous drainage occurring there, and the rest in the alternative pathway, the uveo-scleral pathway.

“Rhopressa targets the part of the eye that does most of the heavy lifting regarding aqueous drainage,” he said.

No side effects

Other plusses of Rhopressa are the absence of systemic side effects, making it useful for any patient with any medical condition eliminates, and a low treatment burden of one drop once daily, which contributes to increased patient compliance, Dr. Zaman explained.

“Many patients with glaucoma have IOPs that are in the normal to slightly elevated normal range,” he said. “Another benefit is that studies have shown that the efficacy of Rhopressa is the same in patients with lower pressures as those with moderately elevated pressures. This is important, because with the other classes of glaucoma drugs, in patients with lower IOPs the efficacy is not as robust as in patients with moderate IOPs. Rhopressa works the same with these patients.”

Dr. Zaman uses Rhopressa primarily in already treated patients who may need an additional medication to achieve the target IOP, in his practice that is about 70% to 75% of patients; the other 25% are using Rhopressa alone. Any patient in whom the trabecular meshwork is visible is a candidate for this drug, such as in open-angle glaucoma, but not angle-closure glaucoma. he explained.

The other newbie, Rocklatan, the combination formulation of netarsudil and latanoprost, received FDA approval in April 2019. In 1996, when latanoprost was the first prostaglandin to be introduced, it was initially a tertiary drop, i.e., a last resort of sorts for physicians because of uncertainty about its effects.

However, latanoprost was a game changer and the prostaglandins are now what Dr. Zaman describes as the “foundational drug” for glaucoma, with most patients starting on a prostaglandin; these drugs are dosed once daily and are highly efficacious with a safe systemic profile; the prostaglandin class has the highest efficacy data of all glaucoma drugs on the market.

Latanoprost reduces IOP by its action on the uveoscleral pathway; with netarsudil added, the two drugs promote aqueous outflow in the most comprehensive way possible by targeting both outflow pathways. This approach appears to be more beneficial to the overall health of the eye compared with all over anti-glaucoma drugs that decrease aqueous production.

“The aqueous has a purpose in the eye, i.e., it carries nutrients to the eye, to the lens specifically, and removes waste products from the eye,” Dr. Zaman explained. “Alteration of aqueous production has been hypothesized to induce earlier cataract formation.”

In contrast, Dr. Zaman noted that aqueous outflow drugs do not alter aqueous production, just augment outflow.

Dr. Zaman said he uses Rocklatan with patients with an open-angle glaucoma and as a substitute for patients already on a prostaglandin who are not adequately controlled.

Treatment-naïve patients also can benefit to achieve aggressive control from the outset of therapy. A downside to these two new rho kinase inhibitors that is attributable to netarsudil is the potential development of conjunctival hyperemia, which in about 10% of patients can be moderate to severe and in about 30% to 50% mild and transient.

Glaucoma medication market overview

The prostaglandins currently have the highest share of the glaucoma market for all of the reasons listed previously, i.e., once daily dosing, high efficacy, safe systemic profile, and it is well tolerated by patients. The prostaglandins tick all of these boxes. Hyperemia also can be a side effect of the prostaglandins, as can lash growth and slight skin discoloration under the eyelid.

Rare side effects include changes in iris color and swelling of the retina. The prostaglandins that are available are latanoprost (Xalatan, Aerie Pharmaceuticals), bimatoprost (Lumigan, Allergan), travoprost (Travatan Z, Novartis), tafluprost (Zioptan, Akorn), and latanoprostene bunod (Vyzulta, Bausch & Lomb). In addition to the rho kinase inhibitors and prostaglandins the other classes of glaucoma drugs with a share of the market are the beta-blockers, alpha-agonists, and carbonic anhydrase inhibitors (CAIs).

These drugs are prescribed as single therapies as well as in combination with a drug from another class. The primary mechanism of action of these drugs is to decrease aqueous production. The beta-blockers include timolol maleate 0.5% (timolol maleate, Akorn Ophthalmics); timolol maleate ophthalmic gel forming solution 0.25%, 0.5% (Timoptic XE, Merck & Co.); timolol maleate (Istalol, ISTA Pharmaceuticals); timolol hemihydrate 0.25%, 0.5% (Betimol, Johnson & Johnson); betaxolol HCI 0.25%, 0.5% (Betoptic S, Alcon); metipranolol 0.3% (OptiPranolol, Bausch & Lomb); and levobunolol HCI ophthalmic solution 0.25%, 0.5% (Betagan, Allergan). The alpha-agonists include the most widely used brimonidine tartrate ophthalmic solution 0.1% or 0.15% (Alphagan P, Allergan); apraclonidine hydrochloride (Iopidine, Alcon, and Novartis); and generic apraclonidine (Sandoz, Falcon, and Akorn). The available CAIs are acetazolamide (Diamox Sequels, Duramed Inc.), brinzolamide ophthalmic suspension 1% (Azopt, Alcon); and dorzolamide HCI 2% Trusopt, Merck & Co.) and Neptazane (methazolamide, Perrigo Company).

Combination drugs

A number of combination drugs are on the market that combine drugs for a more encompassing effect. Combigan (Allergan) is one such drug that combines an alpha-agonist (brimonidine) with a beta-blocker (timolol); dosing is twice daily and it is highly efficacious. Dr. Zaman uses it as an additive drug. In some patients this drug can cross the blood-brain barrier resulting in sleepiness. Another combination drug is Cosopt (Merck & Co.), which is comprised of a beta-blocker (timolol) and a CAI (dorzolamide). This also is doses twice daily and lowers IOP well. Systemic side effects include, for example, low blood pressure and fatigue. Simbrinza (Alcon) combines a CAI (brinzolamide) and alpha-agonist (brimonidine). combination medication consisting of (alpha-agonist). Without a beta-blocker, this drug is indicated for patients with asthma and is dosed three times daily.

Shaking the bottle is mandatory because the active ingredient sinks to the bottom.

“The glaucoma medications have improved over time with increased efficacy,” Dr. Zaman concluded. “Patients are achieving lower pressures recently with a resultant fewer glaucoma surgeries.”


Fiaz Zaman, MD
E: fzaman@houstoneye.com
Dr. Zaman is a speaker for Aerie Pharmaceuticals and Allergan.

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