Aerie’s focus on therapies that address cause of vision loss

Existing glaucoma drugs work, but they all work using the same mechanism of action (MOA). Aerie Pharmaceuticals is developing the first novel mechanism of action for the treatment of glaucoma in over 20 years.

“Aerie Pharmaceuticals is focused on developing new medicines that speak to the root cause of vision loss in patients,” said Casey Kopczynski, PhD, chief scientific officer. “We have two products in development for the treatment of patients with glaucoma and ocular hypertension. One is an entirely new agent, netarsudil, the other is a combination of netarsudil plus latanoprost.”

Dr. Kopczynski discussed the mechanism of action of netarsudil for an Industry Spotlight during the New Horizons Forum, held in conjunction with the 2017 Glaucoma 360 meeting. Aerie has been a regular contributor to Glaucoma 360, providing annual updates on its molecular entity, called Rhopressa.

Now that the molecule has been submitted to the FDA for marketing approval, presentations describing the MOA and the latest clinical trial results use the generic name. The netarsudil/latanoprost combination is still being called Roclatan.

New drug in demand

The potential demand for a new ocular hypertensive drug is enormous. Aerie has put the potential market at between 16 million and 17 million prescriptions yearly in the United States alone. Drugs currently available to lower IOP are two to three decades old, require dosing two or more times daily, and can have serious systemic side effects. Aerie’s aim is to beat all three barriers with a single product.

Netarsudil is a once-daily eye drop that inhibits Rho kinase (ROCK), and norepinephrine transporter (NET). Both novel targets lower intraocular pressure (IOP) and combine three distinct MOAs.

ROCK inhibition increases fluid outflow through the trabecular meshwork (TM) and reduces episcleral venous pressure, while NET inhibition reduces the production of aqueous. The NET inhibition can make netarsudil helpful in patients with extremely high IOP.

For Aerie, the cause of elevated IOP in glaucoma is a dysfunctional TM. In a normal eye, Dr. Kopczynski continued, about 80% of the fluid in the anterior chamber drains through the TM. In the eye with elevated IOP, the TM contracts and secretes excess amounts of extracellular matrix. The combination creates resistance to outflow, which raises pressure within the eye.

The predominant MOA of netarsudil appears to increase outflow via the TM, he said. The agent relaxes and expands the TM tissue on the microscopic level as it reduces the production of extracellular matrix by TM cells. Both actions contribute to increasing fluid outflow via the TM.

Netarsudil on TM

Netarsudil on TM

Work in animal models and human donor eyes using fluorescent microbeads demonstrates the action of netarsudil on the TM. Compared with normal eyes, eyes treated with the agent show an increased accumulation of microbeads in the episcleral veins that are downstream of the TM. The increase in fluorescence in episcleral veins is also associated with a measurable increase in TM outflow facility.

“We have shown that netarsudil can increase trabecular outflow facility not only in preclinical models, such as the mouse and monkey, but also in human donor eyes and in healthy volunteers,” Dr. Kopczynski said. “This is important because preclinical models and tissue culture experiments can sometimes be misleading.”

Recent data form 24-hour IOP studies show a second advantage for netarsudil. The agent is able to reduce IOP effectively at night as it does during the daytime.

Many drugs to reduce IOP, including beta blockers and alpha agonists, lack the ability to reduce IOP at night, Dr. Kopczynski continued. Other ocular hypertensive agents tend to low IOP less at night than they do during the day.

Another potential benefit of this new MOA is that increased TM outflow is complementary to the uveoscleral outflow mechanism seen in prostaglandins. Because the two mechanisms are complementary, it should be possible to combine netarsudil and a prostaglandin to maximize IOP lowering.

“Roclatan, a combination of netarsudil and latanoprost, is the first to demonstrate superior IOP lowering compared to latanoprost in a phase III study at 9 different time points,” Dr. Kopczynski said. “David Epstein, one of the founders of Aerie Pharmaceuticals, was a passionate believer that a drug that targeted the diseased tissue responsible for elevated IOP would bring significant benefit to patients. We are hopeful that next year, we will be able to report that David’s vision has become reality.”