Apr 15, 2016
Take-home message: Netarsudil ophthalmic solution 0.02% q.d. maintained consistent IOP-lowering efficacy through 12 months for the Rocket 2 trial.
By Michelle Dalton, ELS; Reviewed by Richard A. Lewis, MD
Irvine, CA—Rocket 2—the second pivotal phase III registration trial for netarsudil ophthalmic solution 0.02% (Rhopressa), a novel once-daily eye drop being tested for its ability to lower IOP in patients with glaucoma or ocular hypertension—demonstrated safety results consistent with those observed for the 90-day efficacy period, according to developer Aerie Pharmaceuticals.
The study compared Rhopressa once a day with timolol twice a day, said Richard A. Lewis, MD, chief medical officer for Aerie.
“It was designed as a non-inferiority study to showed equivalence in efficacy at each time point,” Dr. Lewis said. “We’re happy with how it performed.
“In terms of other aspects, it seems to be exactly what we thought. Very similar to what we found in our phase II trials,” he said, adding full results after data lock are likely sometime in the late second quarter or early third quarter.
Aerie has designed Rocket 2 as the pivotal trial for U.S. registration, with Rocket 1 as supportive data, Dr. Lewis said. (Aerie is also conducting two additional studies on Rhopressa—Rocket 3 and 4—neither of which is necessary for U.S. regulatory filing.)
Rocket 2 details
The Rocket 2 study enrolled 756 patients, randomly assigned to Rhopressa once a day, Rhopressa twice a day, or timolol twice a day, with a 3-month interim efficacy and a 1-year safety endpoint.
The company’s primary efficacy endpoint for this study was the mean IOP at all time points through Day 90 (for maximum baseline IOP under 25 mm Hg). A total of 403 patients met entry criteria and were included in the Rocket 2 efficacy analysis.
Patient disposition in Rocket 2 showed a high level of patient retention through 3 months, with 133/155 patients in the once a day arm (85%) and 154/163 in the timolol arm (94%) completing the initial efficacy portion. The leading cause for discontinuation in the once a day arm was an adverse event, while in the timolol arm it was protocol violations.
There were 129 patients in the per-protocol once a day arm and 142 in the timolol arm with baseline IOPs under 25 mm Hg. Rocket 2 analyzed nine different time points, three each on Day 15, Day 43, and Day 90.
The mean diurnal IOP in the once a day arm was 21.4 mm Hg, which decreased to 17.4 mm Hg at Day 90; these changes were seen as early as week 2.
For the first 118 patients who reached the 12-month mark, Rhopressa once a day demonstrated a consistent level of IOP lowering at 8 am from day 90 through month 12, with a nominal variance of only 0.1 mmHg between day 90 and month 12, Aerie reported.
As in previous studies, the most common adverse event was conjunctival hyperemia, 83% of which was considered mild, and similar to the incidence reported in other studies with topical prostaglandins.
“Anybody who’s followed Rhopressa’s history would have not have been surprised by those reports,” Dr. Lewis said. “Like almost all of our glaucoma drugs, particularly those that are vaso-dilators, this drug causes some hyperemia. Timolol, which was the comparator drug, has a different mechanism of action. Timolol is a beta-blocker—so it won’t have the direct ocular vasodilation effect that the ROCK inhibitors do.”
At the time the Rocket 2 preliminary results were reported, the financial sector took issue with the rates of hyperemia, but somewhat “missed the boat” on the side effect profiles, Dr. Lewis said.
The systemic side effect profile of timolol is much more serious than the vasodilators—and can include slow/irregular heartbeat, muscle weakness, chest pain, slurred speech, or weakness on one side of the body.
Aerie “screened very nicely and excluded those at risk for systemic complications for the timolol part of the study, which is probably why we saw so few side effects,” Dr. Lewis said.
For instance, people with lung or heart conditions were excluded from the study to ensure safety, he said.
Because Rhopressa will be a new chemical entity for the topical treatment of glaucoma, there were “much more strict criteria” in evaluating the safety profile—and the side effect of hyperemia was transient.
There were no drug-related serious adverse events.
In Rocket 2, patients in the timolol arm had a statistically significant reduction in heart rate from baseline at all visits, even with the strict exclusion factors, Dr. Lewis said.
The other adverse events observed during the 12-month trial are consistent with those observed during the initial 90-day efficacy period, according to Aerie. They included conjunctival hemorrhages, corneal deposits, and blurry vision, ranging from 5% to 23% of the 118 patients.
Richard A. Lewis, MD
Dr. Lewis is the chief medical officer of Aerie Pharmaceuticals.