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Aerie recently reported the results of its second phase III registration trial in the United States named Rocket 2, where the primary efficacy endpoint was to demonstrate non-inferiority of IOP lowering for Rhopressa compared with timolol.
Take-home message: Aerie recently reported the results of its second phase III registration trial in the United States named Rocket 2, where the primary efficacy endpoint was to demonstrate non-inferiority of IOP lowering for Rhopressa compared with timolol.
By Michelle Dalton, ELS
Las Vegas-The “big three” market-United States, Europe, and Japan-accounts for almost $4.7 billion and 100 million prescriptions in the glaucoma market, said Aerie president and COO Tom Mitro here during the 2015 meeting of the American Academy of Ophthalmology.
The United States alone accounts for more than $2.2 billion and 33 million prescriptions-the majority of initial therapy treatments today are prostaglandins. Latanaprost owns about one-third of the overall U.S. glaucoma market, with non-prostaglandin fixed combination agents a distant second at 15%.
Aerie’s triple-action, once-daily eye drop (Rhopressa) inhibits Rho Kinase (ROCK) and the norepinephrine transporter (NET), both novel biochemical targets for lowering of IOP, would mark the first new class of glaucoma medication in more than 2 decades. Rhopressa’s mechanisms of action relaxes the trabecular meshwork to increase outflow, its NET component inhibits fluid production, and it lowers episcleral venous pressure. Aerie’s second glaucoma medication (Roclatan) combines Rhopressa with latanoprost to also increase uveoscleral outflow.
Rhopressa will be “the future drug of choice as an adjunctive therapy to prostaglandin agonists when additional IOP lowering is desired,” Mitro said, declaring it “ideal” for patients with low-pressure or normal-tension glaucoma.
Roclatan will be a “future drug of choice for patients who require the maximal IOP lowering,” he added, and anticipates the “ideal” patient as someone who is already using two or more topical therapies, or treatment-naïve patients with high or very high IOP.
Simply put, “Roclatan is the most potent boat in the harbor,” Mitro said.
The company plans on filing the New Drug Application “with Rocket 2 as our pivotal and Rocket 1 data as supportive and the FDA was comfortable with us doing that,” said Vicente Anido Jr., PhD, Aerie’s chief executive officer, earlier during an investor conference call. “We did agree to file with only the QD form as part of the dosing schedule as opposed to both the QD and the BID.”
Aerie continues to move forward with both its Rocket 3 and 4 studies, but neither is required for FDA filing.
“We’ve always believed that those would be nice to have as a good backups and insurance policies for us,” Dr. Anido said. “Rocket 2 did have a tail for safety on the back of the 90-day efficacy trial and so, we do expect to file with 100 patients” in the active arm although well over 100 are expected to complete the trial; patients should have completed those studies by the end of 2015/early 2016.
Rocket 4 is the company’s fourth phase III trial for Rhopressa “that is designed to provide adequate information on safety for 6 months, which we do believe will support the European filing,” Dr. Anido said. “We’re getting the typical 90-day efficacy data out of Rocket 1 and 2 and also we built in a 6-month efficacy data point into Rocket 4.”
The 90-day data is expected roughly at mid-year around 2016 with the 6-month efficacy data available towards the end of 2016.
During the AAO briefing, Mitro said Rhopressa “is expected to be the only QD adjunctive therapy with no systemic side effects.”
The Rocket 2 study enrolled 756 patients, randomly assigned to Rhopressa QD, Rhopressa BID, or timolol BID, with a 3-month interim efficacy and a 1-year safety endpoint, said Theresa Heah, MD, vice president, clinical research and medical affairs. 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).
After a revision of baseline IOP, Dr. Heah said 403 patients met the per protocol criteria.
“Of the 477 subjects with a baseline IOP of under 25 mmHg, 74 had a major protocol deviation which was deemed likely to affect the primary efficacy outcome. For example, investigators enrolled ineligible patients,” she said.
All patients were included in the intent-to-treat population and were used to summarize a subset of efficacy variables, she said. Goldmann applanation tonometry was used to measure the IOP.
Patient disposition in Rocket 2 showed a high level of patient retention through 3 months, with 133/155 patients in the QD arm (85%) and 154/163 in the timolol arm (94%) completing the initial efficacy portion. The leading cause for discontinuation in the QD arm was an adverse event, while in the timolol arm it was protocol violations. Dr. Heah noted the discontinuation rates in Rocket 1 (about 15%) and Rocket 2 were similar to those in other glaucoma drug studies.
There were 129 patients in the per-protocol QD arm and 142 in the timolol arm with baseline IOPs under 25 mm Hg (as the BID formulation is not being submitted to the FDA, Dr. Heah presentation here concentrated on the QD results). Rocket 2 analyzed nine different time points, three each on Day 15, Day 43, and Day 90.
“At all time points, Rhopressa QD met the criteria for demonstrating non-inferiority to timolol,” Dr. Heah said. “The results from Rocket 2 replicated those we found in Rocket 1.”
The mean diurnal IOP in the QD 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.
An in-depth analysis at the upper limit 95% confidence intervals (CI) of ≤1.5 mmHg indicated patients with baseline IOPs of <27 mm Hg missed two time points by 0.4 mmHg to be non-inferior to timolol, and those with baseline IOPs of <26 mm Hg missed one time point by 0.2 mm Hg to be non-inferior to timolol; the registration trial parameters noted the 95% CI within 1.5 mmHg had to be met at all time points to be considered non-inferior.
“Prior prostaglandin use produced an enhanced IOP lowering with Rhopressa in both Rocket 1 and Rocket 2 compared with those who had not used prostaglandins previously,” Dr. Heah said. A retrospective analysis of phase 2b trial results showed prior prostaglandin use enhanced the IOP-lowering by 1 mm Hg (p = 0.007) at weeks 2 and 4 with Rhopressa relative to subjects not previously on a prostaglandin, she said.
As in previous studies, the most common adverse event was conjunctival hyperemia, 83% of which was considered mild. The mean rates of hyperemia in Rocket 1 and Rocket 2 were toward the lower end of the incidence reported in a head-to-head-to-head study of latanoprost, bimatoprost, and travoprost, Dr. Heah said. 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.
Mercury 1 is the company’s first phase 3 study on Roclatan that includes a 90-day efficacy read out as well as a 12-month safety trial designed to demonstrate the superiority of the combination Roclatan over each of the individual components of Rhopressa and latanoprost. Currently, the 90-day efficacy top-line results are expected in September 2016.
Mercury 2 is expected to begin sometime next quarter and is designed to evaluate Roclatan against each of the components and will be a 90-day efficacy trial only, Dr. Anido said. Presuming top-line data replicates what the company has found in its earlier phase II studies, Dr. Anido expects a U.S. NDA filing in the latter half of 2017.
Mercury 3 will be a non-inferiority trial comparing Roclatan to a combination products marketed in Europe.
“That will be used in Europe not only to support the filing in Europe, but also obviously, for price comparisons would become very, very critical” in Europe, Dr. Anido said. At present, Aerie does not have a timetable for Mercury 3.