Article

Rho Kinase Inhibitors for Glaucoma

A novel class of drugs to lower intraocular pressure.

Increased resistance to outflow of aqueous humor through the conventional pathway is thought to be the underlying mechanism of intraocular pressure (IOP) elevation in most patients with primary open-angle glaucoma (POAG) and ocular hypertension (OHT). It is widely believed that the normal resistance to outflow of aqueous humor from the anterior chamber is provided by the juxtacanalicular connective tissue of the trabecular meshwork and the endothelial cells of the inner wall of Schlemm’s canal.1 There is evidence that the cells in Schlemm’s canal and trabecular meshwork are abnormally stiff in POAG and OHT.

Ocular hypotensive medications for long-term use to lower IOP work through a variety of mechanisms of action. Cholinergic agents such as pilocarpine increase outflow facility by inducing contraction of the longitudinal fibers of the ciliary muscle. As they contract, they mechanically deform the trabecular meshwork and open Schlemm’s canal. Beta-blockers (timolol, levobunolol, carteolol, and betaxolol, for example), carbonic anhydrase inhibitors (dorzolamide and brinzolamide topically and acetazolamide and methazolamide systemically) and alpha2–adrenergic agonists (brimonidine and apraclonidine) primarily lower IOP by reducing aqueous production (inflow).2 The alpha2–adrenergic agonists may also increase uveoscleral outflow; however, that is thought to be a minor contribution.3 The mainstay of glaucoma medical therapy, the prostaglandin analogs (latanoprost, bimatoprost, travoprost and tafluprost), increase uveoscleral outflow.4 Bimatoprost may also increase conventional outflow, but again, that represents a minor contribution to its overall IOP-lowering efficacy.5

The newest prostaglandin analog to be approved in the United States, latanoprostene bunod (LBN, Vyzulta; Bausch + Lomb), is similar to latanoprost but has a chemical moiety that ultimately, once in the eye, becomes free nitric oxide (chemical symbol NO, as opposed to nitrous oxide, chemical symbol N2O). Nitric oxide is important in biologic systems, especially in the cardiovascular system, serving as a signaling molecule that regulates vascular endothelial cells and promotes vasodilation.6 With respect to IOP regulation, nitric oxide is a messenger that triggers a cascade of intracellular events (Figure 1) that causes relaxation of the cytoskeleton in cells in the trabecular meshwork and Schlemm’s canal — this leads to an increase in conventional aqueous humor outflow.7 Although the evidence is limited, it seems LBN lowers IOP about 1 mmHg more than latanoprost in patients with OAG or OHT.8

Figure 1. Netarsudil and nitric oxide (NO) promote cytoskeletal relaxation through their influence in Rho signaling cascade. Myosin and actin are key components of the cytoskeleton of muscle and nonmuscle cells. Phosphorylated myosin interacts with actin, increasing cell stiffness. Phosphorylation of myosin is regulated by the activity of myosin light chain kinase and myosin light chain phosphatase (MLCP). Netarsudil inhibits Rho kinase and thereby interferes with its inhibitory effect on MLCP, an enzyme that dephosphorylates the regulatory light chain to induce relaxation. NO inactivates the Rho pathway upstream of Rho kinase. Binding of NO to soluble guanylate cyclase (sGC) results in increased conversion of guanosine triphosphate (GTP) to cyclic guanosine 3’5’-monophosphate (cGMP), which in turn activates cGMP-dependent protein kinase (PKG). Among the effects of activated PKG is the inhibition of the RhoA, a G-protein that activates Rho kinase. Diminished Rho kinase activation results in increased MLCP activity, thus contributing to cytoskeletal relaxation.
IMAGE COPYRIGHT ANGELO P. TANNA, MD; IMAGE CREATED USING BIORENDER.

Rho Kinase and Outflow Facility

The complex intracellular signaling pathway by which NO alters the cytoskeleton and intercellular spaces in the trabecular meshwork and Schlemm’s canal also includes Rho A, a G-protein that is active when bound to GTP, and Rho kinase, which is only active when bound to activated Rho A (Figure 1). Rho kinase has many potential targets in the Rho pathway. Importantly, it phosphorylates myosin light chain, resulting in interactions of myosin and actin, increased cell stiffness and increased intercellular adhesions. Rho kinase inhibitors reduce cell stiffness in the trabecular meshwork and Schlemm’s canal and reduce focal adhesions between endothelial cells of the inner wall of Schlemm’s canal and the juxtacanalicular connective tissue. Through these cellular processes, like nitric oxide which acts upstream in the same shared pathway, Rho kinase inhibitors increase outflow facility through the conventional pathway and thereby lower IOP.

Approved Rho Kinase Inhibitors

There are several Rho kinase inhibitors that have been studied in the laboratory and in clinical trials. Worldwide, however, there are only 2 Rho kinase inhibitors approved for clinical use – ripasudil (Glanatec; Kowa Company Ltd., approved in Japan in 2014) and netarsudil (Rhopressa; Aerie Pharmaceuticals, approved by the US FDA in December 2017, first available for clinical use in March 2018).

Clinical Use of Netarsudil

Netarsudil is a Rho kinase inhibitor and norepinephrine transporter inhibitor. It is thought to increase conventional outflow, and there is limited evidence that it may also reduce aqueous humor production and episcleral venous pressure.9 Netarsudil 0.02% can be used as first-line therapy or as adjunctive therapy with any other ocular hypotensive agent. Netarsudil is dosed once daily, in the evening, preferably at bedtime because Rho kinase inhibitors frequently cause conjunctival hyperemia that peaks after instillation and tends to diminish with time. Like latanoprost, bottles must be refrigerated; however, once used, the open bottle can be kept at room temperature for 6 weeks. There are no known contraindications, drug interactions or systemic side effects. There are, however, important frequent local side effects including conjunctival hyperemia, small perilimbal conjunctival hemorrhages, pain, pruritus, cornea verticillata, and increased lacrimation.

Clinical Trials

Ripasudil

Briefly, the clinical trial data for ripasudil (approved in Japan in 2014 but not approved in the United States) demonstrate modest IOP-lowering efficacy and the frequent occurrence of local adverse events such as conjunctival hyperemia, allergic conjunctivitis, and blepharitis.10-16 Ripasudil lowers IOP when used alone or when combined with other ocular hypotensive medications. Ripasudil was shown in 2 retrospective studies to be safe in patients with uveitis, suggesting the same may be true of netarsudil.

Netarsudil

Netarsudil vs latanoprost

A 28-day study comparing netarsudil 0.02% QD with latanoprost 0.005% QD in patients with POAG or OHT with baseline IOP between 24 mmHg and 36 mmHg demonstrated netarsudil lowered IOP about 22% below baseline but was not as effective as latanoprost.17-20 In the subgroup of patients with baseline IOP ≤26 mmHg, netarsudil was noninferior to latanoprost, which was interpreted to suggest that netarsudil was more effective in patients with lower baseline IOP.

Netarsudil-latanoprost fixed combination

The fixed combination of 0.02% netarsudil and 0.005% latanoprost, not yet approved by the FDA, goes by the trade name Roclatan (Aerie Pharmaceuticals). The results of 2 phase 3 clinical trials, Mercury 1 and 2, are available on the Aerie Pharmaceuticals website.21,22 Patients were randomized to the fixed combination or its individual components. Treatment with the fixed combination resulted in mean diurnal IOP lowering 1.9 mmHg more than latanoprost alone and 2.6 mmHg more than netarsudil alone.

Netarsudil vs timolol

ROCKET-1 and ROCKET-2 were double-masked, randomized, parallel-group 3-month clinical trials that compared netarsudil 0.02% QD (ROCKET-1 and ROCKET-2) or BID (ROCKET-2) to timolol 0.5% BID in patients with POAG or OHT with baseline IOP between 20 mmHg and 27 mmHg.20 The earlier results in the subgroup of patients with lower baseline IOP in the study that compared netarsudil to latanoprost prompted the FDA and Aerie Pharmaceuticals to focus on patients with lower baseline IOP in the ROCKET clinical trials. Netarsudil was found to be noninferior to timolol (the upper limit of the 2-sided confidence intervals of the difference between groups was within 1.5 mmHg at all time points and within 1.0 mmHg at the majority of time points) in both studies among the subgroup of subjects with maximum baseline IOP <25 mmHg. In the entire cohort in ROCKET-1, however, netarsudil did not meet the noninferiority criteria. Overall, the results suggest that netarsudil is slightly less effective than timolol when used as monotherapy.

Netarsudil Side Effects

The adverse events observed with netarsudil 0.02% QD were similar across the different clinical trials conducted to date. The incidence of the adverse events observed in a clinical trial comparing netarsudil 0.02% QD, latanoprost 0.005% QD and the fixed combination of netarsudil and latanoprost are summarized in Table 1.

Table 1. Adverse Events Reported in the 12-Month Mercury 1 Clinical Trial Comparing Rocaltan (Netarsudil-Latanoprost Fixed Combination), Netarsudil, and Latanoprost
Adverse Events (≥5.0% in any group) Roclatan n=238 Rhopressa n=243 Latanoprost n=237
Discontinuation Due to Adverse Event 47 (19.7%) 53 (21.7%) 4 (1.7%)
Eye Disorders
Conjunctival hyperemia 150 (63.0%) 125 (51.4%) 52 (21.9%)
Conjunctival hemorrhage 31 (12.0%) 44 (18.1%) 3 (1.3%)
Cornea verticillata 42 (17.6%) 33 (13.6%) 0
Eye pruritus 27 (11.3%) 22 (9.1%) 3 (1.3%)
Punctate keratitis 12 (5.0%) 18 (7.4%) 10 (4.2%)
Lacrimation increased 17 (7.1%) 20 (8.2%) 1 (0.4%)
Visual acuity reduced 13 (5.5%) 13 (5.3%) 6 (2.5%)
Vision blurred 11 (4.6%) 15 (6.2%) 3 (1.3%)
Blepharitis 14 (5.9%) 8 (3.3%) 5 (2.1%)
Administration Site Conditions
Instillation site pain 55 (23.1%) 60 (24.7%) 18 (7.6%)
Note: Patients with known contraindications or hypersensitivity to latanoprost were excluded from participation in the clinical trial; therefore, the incidence of discontinuation and adverse events observed in the latanoprost and fixed-combination groups may be lower than expected to occur if those medications were used by patients without a prior history of treatment with latanoprost. Data obtained from Mercury 1 phase 3 topline results, available at http://investors.aeriepharma.com/static-files/29defd23-b47b-4319-ba01-5a7ac53e2108 .

Cornea verticillata, similar in appearance to that observed in patients on amiodarone, occurred in about 15% of patients using netarsudil 0.02% QD. There were no changes in vision and there was resolution after cessation of the drug. The key to dealing with the local side effects is to prepare the patient in advance. Inform patients of the common side effects listed above, taking the time to do this thoroughly. Even if the patient experiences one or more of these side effects, advance knowledge often helps patients tolerate them and continue with the medication. The ophthalmologist can then determine the IOP-lowering efficacy and make a decision, along with the patient, about the value in continuing the medication. Importantly, even if the side effects are not tolerable, the informed patient will not lose confidence in his or her physician. In fact, the opposite is often true — the patient may say, “You told me this could happen and you were right.”

Neuroprotection and Blood Flow

In POAG, the initial site of neuronal injury is the retinal ganglion cell axon at the level of the lamina cribrosa. Rho kinase signaling is critical in the regulation of axonal development, maintenance, and regeneration.23 Lower ocular blood flow and perfusion pressure are associated with glaucoma. Rho kinase inhibitors have been shown in laboratory models to have neuroprotective activity, to promote axonogenesis, to increase blood flow, and to prevent vasoconstriction. There are no studies that evaluate the effects of Rho kinase inhibitors on ocular blood flow in humans, nor are there any clinical trials that evaluate their potential neuroprotective activity. It is unknown whether adequate concentrations of the drug are achieved in the retina and optic nerve with topical therapy for these favorable effects to be realized in patients.

Conclusion

The Rho kinase inhibitor netarsudil is now approved and available for use in the United States. Clinicians can expect about 15% to 22% mean diurnal IOP lowering when used alone and about 1.5 mmHg to 2 mmHg additional mean diurnal IOP lowering when used with latanoprost. Based on the clinical trials, local side effects may represent a challenge in the use of this drug. On the other hand, if the investigators involved in the clinical trials were very meticulous in capturing adverse events such as mild conjunctival hyperemia, the drug may be better tolerated by patients than a review of the clinical trial results indicates. Now that the drug is available commercially, clinicians will soon learn first-hand about the utility of this novel agent in the real world. GP

References

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