Novel ocular hypotensive drug meets endpoints

January 1, 2017

Netarsudil ophthalmic solution 0.02% met its primary and secondary efficacy endpoints in a third phase III trial investigating its non-inferiority to timolol maleate 0.05% for IOP lowering.

Reviewed by Jason Bacharach, MD 

Topline results from data collected after 90 days in the 6-month Rocket 4 phase III clinical trial confirm that netarsudil ophthalmic solution 0.02% (formerly AR-13324; Rhopressa, Aerie Pharmaceuticals) safely and effectively lowers elevated IOP in eyes with ocular hypertension or open-angle glaucoma, said Jason Bacharach, MD.

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Rocket 4 randomly assigned about 700 patients 1:1 to once-daily netarsudil or twice-daily timolol maleate 0.5%. Netarsudil met the primary efficacy endpoint, achieving non-inferiority to timolol for lowering IOP in eyes with baseline IOP ranging from >20 to <25 mm Hg.

Netarsudil also met the secondary efficacy endpoints by demonstrating non-inferiority to timolol for lowering IOP in eyes with baseline IOPs ranging from >20 to <27 mm Hg and from >20 to <28 mm Hg.

“The 90-day topline efficacy results from Rocket 4 reiterated the positive findings of Rocket 1 and Rocket 2, the two phase III registration trials. Collectively, the phase III clinical trial program for netarsudil includes a robust number of treated patients, with nearly 2,000 patients dosed,” said Dr. Bacharach, who was an investigator in the Rocket 2 and Rocket 4 trials and a glaucoma specialist in private practice in Sonoma County, CA.

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“Approval of this rho kinase/norepinephrine transporter inhibitor would be an exciting and welcome development considering that it would be the first new class of IOP-lowering agents to become available in over 20 years,” he said. “Based on the clinical trial experience, I expect netarsudil will be an important part of our armamentarium, and I am looking forward to using it in the clinical practice.”

Dr. Bacharach observed that in Rocket 4, netarsudil performed better for lowering IOP in eyes with the higher baseline levels than it did in the Rocket 1 and Rocket 2 trials.

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In addition, its activity for reducing IOP in eyes with lower starting IOPs distinguishes it from available ocular hypotensive agents. Netarsudil’s broad efficacy is probably explained by its multimodal mechanism of action that involves increased trabecular outflow facility and likely also reduction of episcleral venous pressure, he said.

Clinical role

 

Clinical role

Dr. Bacharach foresees that if netarsudil is approved, it likely will be first adopted for use as an add-on to a prostaglandin analog in patients needing combination therapy.

“The fact that about 50% of patients with glaucoma are on two IOP-lowering medications clearly speaks to the need for having multiple therapeutic options with different mechanisms of action that can be used in combination therapy,” Dr. Bacharach said.

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Results from a phase II study of netarsudil and the phase III Mercury 1 trial investigating the fixed combination of netarsudil and latanoprost (Rhopressa, Aerie Pharmaceuticals) show that netarsudil is additive to latanoprost, he noted.

“In addition, there is evidence of additivity when ripasudil, a rho kinase inhibitor that is commercially available in Japan, is combined with other glaucoma medications,” he said.

As ophthalmologists become more familiar with the medication, they will probably begin to consider using netarsudil as a standalone agent, Dr. Bacharach said.

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In the Mercury 1 trial, netarsudil demonstrated non-inferiority to latanoprost in eyes with baseline IOP ranging from >20 to <25 mm Hg.

Well tolerated

The Rocket 4 study, which is still under way, was designed to provide safety data for registration filing with European regulatory authorities. Data collected so far in Rocket 4 and other clinical trials show that netarsudil has an acceptable safety profile in clinical trials.

So far, adverse events related to the medication have been limited to the eye. Erythema, mostly mild, has been the most common adverse event associated with netarsudil.

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In addition, verticillata has developed in some eyes, but these corneal deposits have not interfered with vision and resolve when treatment is discontinued, as does the erythema

“Most side effects in patients using netarsudil during clinical trials were well-tolerated and did not lead to treatment termination, and no side effects were permanent in patients who stopped the medication,” Dr. Bacharach said.

 

Jason Bacharach, MD

E: jbacharach@northbayeye.com

Dr. Bacharach is a consultant to Aerie Pharmaceuticals and to other companies that market and are developing medications for treatment of glaucoma.