Reducing intraocular pressure (IOP) in a phase IIb trial and providing new hope for glaucoma patients, Aerie Pharmaceuticals Inc.'s quadruple-acting combination drug Roclatan nailed its primary endpoint by showing statistically significant superiority over each of its components.

The once-daily eye drop consists of the Bedminster, N.J.-based company's Rhopressa with the prostaglandin analogue Xalatan (latanoprost, Pfizer Inc.). Following the news, Aerie's shares (Nasdaq:AERI) shot up 28.3 percent, or $5.95, to close Wednesday at $26.98.

In the phase IIb trial, Roclatan hit its primary endpoint on day 29. Roclatan lowered mean diurnal IOPs from 25.1 mmHg at baseline to 16.5 mmHg, a 34 percent decrease and about 2 mmHg greater than Xalatan. Most physicians consider normal pressure to be 20-21 mmHg. The results were statistically significant at all time points – 8 a.m., 10 a.m., 4 p.m. on days eight, 15 and 29 – with "p" values less than 0.05. The 28-day trial included 297 patients.

An interesting finding was that on day 29, half of Roclatan patients experienced a 35 percent or greater decrease in mean diurnal IOP from baseline, compared to 28 percent of Xalatan patients. Reaching a mean diurnal IOP of 16 mmHg or less were 46 percent of Roclatan patients compared to 18 percent of Xalatan patients on day 29.

"This is a big deal," said Vicente Anido, Aerie's chairman and CEO, in a conference call. "The more that they decrease the pressures, [the more] they decrease the risk of further damage to the optic nerve."

In terms of adverse events, the most common was a mild form of eye redness, or hyperemia, in 40 percent of patients, resulting in six total discontinuations. With a vasodilator, it is unavoidable, Anido said. "It is purely cosmetic. It doesn't really hurt. It is not sight threatening. It does not cloud the vision in any way."

The company is preparing for a phase III program for Roclatan to start in summer 2015, following about nine months of additional preclinical work, and it is starting phase III trials for Rhopressa this July. Its strategy is to market its products through an internal sales force in North America, and license its products for commercialization elsewhere. Aerie's products have patent protection through 2030.

If approved, Roclatan would be the first product to lower IOP through four different mechanisms: by increasing fluid outflow through the trabecular meshwork and through the uveoscleral pathway, and by reducing fluid production in the eye and reducing episcleral venous pressure (EVP).

According to Tom Mitro, the company's president and chief operating officer, there hasn't been a new mechanism of action brought to the glaucoma marketplace in 20 years. His market research with 300 physicians showed tremendous interest in both Roclatan and Rhopressa. "They feel like they have walked through a desert and are ready to come out."

"They've never seen a drug that drops pressures this far," Anido said.

Rhopressa targets the eye's primary fluid drain, the trabecular meshwork, and also lowers EVP and reduces fluid production in the eye. It inhibits Rho kinase and norepinephrine transporter. It is expected to compete against prostaglandin analogue (PGA) products in patients with IOPs of 26 mmHg or below, the majority of patients with glaucoma and ocular hypertension, whereas Roclatan would address patients above that level. Rhopressa also could be used as an add-on therapy to PGAs, which target the secondary uveoscleral outflow mechanism.

Data from a phase IIb trial completed in June 2013 showed a strong and consistent IOP-lowering effect with Rhopressa, with mean reductions of 5.7 mmHg and 6.2 mmHg on days 28 and 14, respectively. Currently marketed PGAs and beta blockers have their highest effect at higher baseline IOPs, giving Rhopressa an advantage with its consistency. In the Roclatan phase IIb trial just completed, Rhopressa performed similarly to its earlier clinical results, lowering mean diurnal IOP on day 29 by 6.3 mmHg from baseline.

The Rhopressa phase III trials, two in the U.S. and one in Canada, are expected to enroll 1,300 patients and measure efficacy over three months and safety over 12 months, attempting to demonstrate noninferiority of IOP lowering compared to timolol, the leading second-line beta blocker that has historically performed about 1 mmHg worse than Xalatan. Based on Roclatan's phase IIb results, the company is moving forward with a 0.02 percent concentration of Rhopressa, as the 0.01 percent concentration was not as efficacious. The first efficacy data should come in mid-2015, and a new drug application filing is slated for mid-2016.

RBC Capital Markets analyst Adnan Butt estimates approval could come for Rhopressa in 2017, and for Roclatan a year later. He gave Aerie's stock an outperform ranking: "In our view, positive results significantly de-risk AERI shares and the combination program, establish Roclatan's potential as a drug that could have the best efficacy of any drug targeting glaucoma, making it a likely blockbuster drug and AERI a potential takeout target."

Anido agreed about Roclatan's potential as a blockbuster, considering Xalatan's annual sales have reached $1.7 billion worldwide. "Certainly that's something that we think is reachable for something that is better than latanoprost, better than Xalatan."

Aerie, which also has a corporate office in Newport Beach, Calif., and a research and development facility in Research Triangle Park, N.C., completed its $70 million initial public offering last year and had about $65 million remaining at the end of March, an amount that should take the company through the middle of 2016. (See BioWorld Today, Oct. 28, 2013.)

"For glaucoma medications," Anido said, "the drugs that have been successful in going through phase II studies, all of the prior 13 NCEs [new chemical entities] that made it through phase II successfully got approved, and so we're hoping that trend will continue for us."