Investigators report findings from 2 noninferiority trials comparing once-daily netarsudil 0.02% (Rhopressa, Aerie) with twice-daily timolol 0.5% in patients with ocular hypertension or open-angle glaucoma.

Netarsudil is new class of glaucoma medication that inhibits Rho kinase and norepinephrine transporters. It lowers IOP by increasing trabecular outflow facility, decreasing production of aqueous humor and decreasing episcleral venous pressure.

Study design

After a wash-out phase, 1,167 patients in the ROCKET 1 and ROCKET 2 trials were randomized to once-daily netarsudil or twice-daily (BID) timolol. The ROCKET 2 trial had an additional nertasudil BID arm. Patients were followed through 3 months.

Outcomes

Netarsudil did not meet noninferiority criteria in the ROCKET 1 study (baseline washout IOP between 20 to 27 mm Hg). A post-hoc analysis revealed that netarsudil was noninferior to timolol for patients with a post-washout IOP lower than 25 mm Hg.

Each arm of the ROCKET-2 study included 122 patients with a baseline IOP lower than 25 mm Hg. The netarsudil arms (once-daily and twice-daily dosing) were both noninferior to once-daily timolol.

Conjunctival hyperemia was the most common adverse event in the netarsudil arms, and symptoms were usually mild. The high rate of conjunctival hyperemia (58.9%) with BID netarsudil among ROCKET-2 participants led to a 30% discontinuation rate, compared with a 10% to 12% drop-out rate with daily dosing.

Limitations

The study population was redefined for a post-hoc analysis after completion of the ROCKET-1 study. It is not immediately clear why the narrowed range (post-washout baseline IOP between 20 to 25 mm Hg) met noninferiority criteria, while the higher baseline IOP (up to 27 mm Hg) did not.

Although timolol is the standard comparative drop for many glaucoma studies, prostaglandin analogues are now the usual first-line treatment for monotherapy and might have provided a more clinically meaningful comparison. Finally, this report only follows patients through 3 months. A longer follow-up period is desirable.

Clinical significance

Netarsudil was approved by the FDA in December 2017. It is exciting to have a potential glaucoma medication with a different mechanism of action in the armamentarium of ocular hypertensive medications.

While it seems unlikely that netarsudil would supplant prostaglandins for first-line monotherapy treatment, this drug could be a useful addition to the treatment regimen for patients with uncontrolled glaucoma. It is surprising that netarsudil failed to meet noninferiority criteria in the initial ROCKET-1 study population. Further studies with expanded inclusion criteria (baseline IOP up to 35 mm Hg) are underway.