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The quest for a trabecular outflow drug


The advancement of AR-13324 into phase III represents a major step toward the goal of adding an effective and well-tolerated trabecular outflow drug to the glaucoma armamentarium.


The advancement of AR-13324 into phase III represents a major step toward the goal of adding an effective and well-tolerated trabecular outflow drug to the glaucoma armamentarium.


Dr. Serle

By Janet B. Serle, MD, and Casey C. Kopczynski, PhD, Special to Ophthalmology Times

It has been 20 years since a glaucoma drug with a new mechanism of action advanced to phase III clinical testing. That drug-latanoprost-went on to become the most widely prescribed treatment for glaucoma and ocular hypertension.

Enter a new class of drugs called ROCK/NET inhibitors that lower IOP through a dual mechanism of action, simultaneously inhibiting Rho kinase (ROCK) to increase fluid outflow through the trabecular meshwork and inhibiting the norepinephrine transporter (NET) to reduce fluid production.

The most commonly prescribed glaucoma medications do not address the physiologic cause of elevated IOP in glaucoma, the diseased trabecular outflow pathway.

The need for a trabecular outflow drug is what inspired Aerie’s founders, David Epstein, MD, chairman, Department of Ophthalmology, Duke University; Eric Toone, PhD, professor of chemistry at Duke; and Casey Kopczynski, PhD, Aerie’s chief scientific officer, to start the company in 2005. Aerie Pharmaceuticals’ novel glaucoma compound, AR-13324, is generating excitement in the eye-care community and on Wall Street. Aerie’s recent IPO raised $77 million to fund phase III development of AR-13324 and phase II testing of PG324, a fixed-dose combination of AR-13324 and latanoprost.

“Targeting the diseased tissue to restore normal function is a fundamental tenet of medicine, yet no available glaucoma therapies do this,” Dr. Epstein said. “We founded Aerie with the specific goal of bringing a safe and effective trabecular outflow drug to physicians and their patients.”

Dr. Kopczynski

 Twists and turns

“Innovation is rarely a linear process, especially in drug development,” said Dr. Kopczynski, a biotech start-up veteran. “In a start-up, you have to be focused, but more importantly you have to follow the data, even if it takes you in a different direction than originally planned.”

The first potential trabecular outflow drugs Aerie pursued were ethacrynic acid and ticrynafen-compounds that Dr. Epstein’s lab had studied for years. Since neither was a good drug candidate, Aerie’s chemists generated related compounds with the goal of improving efficacy, tolerability, and solubility-a considerable challenge given that the biological targets for these drugs were unknown. After 6 months and little progress, Aerie abandoned the effort.

Committed to developing a trabecular outflow drug, Aerie initiated a new drug discovery program focused on inhibitors of Rho kinase, an enzyme that promotes actomyosin contraction in trabecular meshwork cells. At the time, Rho kinase inhibitors had been shown to relax trabecular meshwork cells, increase trabecular outflow in preclinical models, and lower IOP in healthy volunteers in the clinic.

However, the first ROCK inhibitor to reach the clinic required twice-daily dosing and caused significant hyperemia due to transient vasodilation of conjunctival blood vessels. For Aerie, these problems were an opportunity.

“Vasodilation is a pharmacological effect of Rho kinase inhibitors, but it is a transient effect,” Dr. Kopczynski said. “Our strategy was to develop a more effective Rho kinase inhibitor that could be dosed once-daily with less hyperemia.”

Aerie coupled medicinal chemistry, kinase profiling and high-content cell-based screening to characterize more than 1,500 newly synthesized ROCK inhibitors. This extensive effort produced Aerie’s first clinical stage trabecular outflow drug, a highly-selective ROCK inhibitor with strong activity and a long duration of effect in preclinical models.

This agent also performed as designed in the clinic, providing the duration of action required to allow once-daily evening dosing. As a result, hyperemia during the day was minimal, similar to latanoprost in a phase IIb study. This observation confirmed that the transient hyperemia associated with ROCK inhibitors could be effectively managed with a once-daily dosing regimen.

The phase II clinical studies revealed an unexpected finding as well. Aerie’s ROCK inhibitor was apparently too selective for Rho kinase. Other clinical stage ROCK inhibitors with activity against other kinases were previously shown to maintain a stable IOP-lowering effect over 28 days of dosing.

Aerie found that its more selective ROCK inhibitor lost efficacy over 28 days and continued to do so out to 3 months. Aerie now believes that in addition to inhibiting Rho kinase, ROCK inhibitors also need activity against Protein Kinase C (PKC) to maintain IOP-lowering efficacy over time.

Fortunately, innovation at Aerie had continued even after its ROCK-selective inhibitor advanced to the clinic. These efforts were rewarded with the discovery of a new class of dual-action ROCK/NET inhibitors that ultimately gave rise to its current lead trabecular outflow drug, AR-13324.

The discovery was made when a newly synthesized ROCK inhibitor produced unprecedented drops in IOP that lasted 24 hours after a single dose in pre-clinical models. Aerie’s scientists suspected that the compound had activity against another target and screened it against a large panel of kinase and non-kinase proteins.

That first compound, and its subsequent derivatives, had significant activity against the norepinephrine transporter (NET) in addition to ROCK. Inhibition of NET is known to increase adrenergic signaling and appears to be responsible for the decrease in aqueous humor production observed in primates after AR-13324 application.

The “dual-action” of AR-13324 refers not only to its biochemical activity against ROCK and NET, but to the two known physiological mechanisms by which it lowers IOP-increasing trabecular outflow and decreasing aqueous inflow.

Making progress

AR-13324 has successfully completed phase II clinical testing and will be advanced into phase III registration trials in 2014.

In a recent 28-day phase IIb study in patients with glaucoma or ocular hypertension, AR-13324 dosed once-daily in the evening was highly effective at lowering IOP, reducing mean IOP by 5.7 to 6.2 mm Hg. AR-13324 maintained stable activity through 28 days of dosing, consistent with its secondary activity against PKC. It was also well tolerated, with no systemic side effects and a 24% incidence of mild-moderate hyperemia on Day 28.

AR-13324’s efficacy profile differed significantly from the comparator latanoprost in a prospective analysis of IOP-lowering efficacy versus baseline IOP.

As reported previously for a variety of glaucoma drugs, latanoprost was more effective in patients with baseline IOPs above 26 mm Hg and less effective in patients with moderately elevated IOPs of 22 to 26 mm Hg.

In contrast, AR-13324 produced the same IOP-lowering efficacy regardless of baseline IOP.

As a result, AR-13324 was less effective than latanoprost in high-baseline patients, but equally as effective as latanoprost in patients with moderately elevated IOPs. This may be significant in clinical practice since epidemiological studies have shown that about 80% of patients with glaucoma have low to moderately elevated IOP at the time of diagnosis.

The advancement of AR-13324 into phase III represents a major step toward the goal of adding an effective and well-tolerated trabecular outflow drug to the glaucoma armamentarium. The fact that it took 8 years to reach this milestone is a reminder of just how difficult it is to develop new drugs with novel mechanisms of action.

The next major milestones for AR-13324 are to complete phase III and win FDA clearance.

“If approval can be achieved, there will be an explosion of academic research on AR-13324 aimed at understanding the benefits of directly treating the diseased trabecular outflow pathway,” Dr. Epstein said. “My colleagues and I have been waiting a long time for this.”


Janet B. Serle, MD

E: janet.serle@mssm.edu

Dr. Serle is professor of ophthalmology and glaucoma clinical and research fellowships director, Mount Sinai School of Medicine, New York.

Casey C. Kopczynski, PhD

Dr. Kopczynski is chief scientific officer, Aerie Pharmaceuticals Inc.



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