Netarsudil Lowers IOP, but When Should It Be Given?

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)

Serle JB, Katz LJ, McLaurin E, et al; ROCKET-1 and ROCKET-2 Study Groups
Am J Ophthalmol. 2018;186:116-127

Study Summary

The double-masked ROCKET-1 and ROCKET-2 trials evaluated the efficacy and ocular and systemic safety of netarsudil 0.02% ophthalmic solution, a newly available rho-kinase inhibitor and norepinephrine transporter inhibitor. These large-scale studies enrolling 1167 total patients primarily sought to establish noninferiority of netarsudil to timolol.

Eligible patients with either open-angle glaucoma or ocular hypertension underwent a washout period of all prestudy ocular hypotensive medications, during which their intraocular pressure (IOP) had to be > 17 mm Hg but < 27 mm Hg.

Patients were then randomly assigned to receive netarsudil 0.02% once daily, timolol 0.5% twice a day, or (ROCKET-2 only) netarsudil 0.02% twice daily. Diurnal IOP, as well as side effects including degree of hyperemia, were recorded at day 1, week 2, week 6, and month 3. Each study population had a mean age in the mid-60s, was predominantly female, and approximately 75% white and 25% black.

All three treatment groups produced statistically significant mean reductions from baseline IOP at all nine treatment time points over the 3-month efficacy assessment. Mean IOP ranged from 16.7 mm Hg to 18.2 mm Hg in the netarsudil once-daily group, 15.7 mm Hg to 17.6 mm Hg in the netarsudil twice-daily group, and 16.6 mm Hg to 17.7 mm Hg in the timolol twice-daily group. The mean decreases from baseline IOP ranged from 3.3 mm Hg to 4.6 mm Hg and 4.1 mm Hg to 5.4 mm Hg for the netarsudil once-daily and twice-daily groups, respectively, and from 3.7 mm Hg to 5.1 mm Hg for the timolol twice daily group.

Overall, treatment with the once-daily dosing of netarsudil produced clinically and statistically significant reductions from baseline IOP (P < .001), and was noninferior to timolol. It was well tolerated, with no vision-threatening adverse events. There was a significantly higher percentage of conjunctival hyperemia compared with timolol. This was the most frequent adverse event, with an incidence up to 59% with twice-daily dosing compared with around 10% with timolol.

Viewpoint

In December 2017, the US Food and Drug Administration approved netarsudil 0.02% for lowering IOP in patients with glaucoma. This new medication is thought to lower IOP by increasing aqueous humor outflow through the trabecular meshwork and reducing episcleral venous pressure.^[1,2] The ROCKET trials demonstrated efficacy of this agent in lowering IOP.

An interesting finding with netarsudil is that IOP is reduced to the same degree regardless of its baseline levels.^[3] The question therefore remains where netarsudil will fall in the treatment algorithm. Although this study showed that netarsudil was noninferior to timolol, it did not show that it reduces IOP to a greater degree. Thus, it still may not be the first choice for patients who need only one agent to control IOP, especially as the adverse reaction of conjunctival hyperemia is significantly higher with the use of netarsudil compared with timolol.

Many ophthalmologists choose a prostaglandin analog (PGA) as monotherapy owing to its once-a-day dosing and efficacy with low side effects. Early studies of netarsudil showed it to be slightly inferior to latanoprost, resulting in 1 mm Hg less reduction in IOP in comparison.^[4] Thus, it is unclear whether netarsudil will replace PGA as a first-line agent.

Furthermore, it remains to be established whether there is further lowering of IOP with the addition of netarsudil in patients who are already on IOP-lowering treatment. We don't yet know if, for a patient who is already on timolol and latanoprost, whether the addition of netarsudil further reduces IOP or whether its mechanism of action is inhibited or reduced when used in combination with these agents. Conversely, it may act synergistically with another agent and thereby lower IOP more than either can do individually. One study with the combination of latanoprost and netarsudil did find that they worked synergistically,^[5] but further studies in different combinations of available agents will help determine where in the treatment algorithm netarsudil will fall and be most efficacious.

It is also possible that netarsudil has some neuroprotective effects separate from its IOP-lowering properties.^[6] Clinical studies involving visual field parameters, as well as cellular- and molecular-level studies, will help us fully understand the potential of this new agent.

Although further information is needed to optimize the use of netarsudil, thus far the evidence from studies is promising, showing consistent decrease in IOP and adding another agent to the array of currently available treatments. In some patients, this treatment could potentially obviate the need for more invasive treatment and prove vision-saving.

Abstract: http://www.medscape.com/medline/abstract/29199013

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