In So Many Words is a timely talk with an ophthalmic industry thought leader.

Aerie Pharmaceuticals was founded 12 years ago on a single premise: to find the right molecule that targets fibrosis in the trabecular meshwork. “When the meshwork becomes fibrotic, it gets stiff and very little fluid gets through, which increases IOP,” says Vicente Anido, PhD, Aerie’s chairman of the board and CEO. His ophthalmology career began with Allergan in 1993.

Dr. Anido thinks Aerie is closing in on its long quest. “We’ve dosed over 2,000 patients at this point, so we know [netarsudil] is a very effective glaucoma and ocular hypertension medication.”

Ophthalmology Management: Can you speak about your background, and discovery of the molecule.

Dr. Anido: Aerie was founded by glaucoma specialist David Epstein, who at the time was the chair of ophthalmology at Duke University. He believed it would be best for glaucoma and ocular hypertension patients to have a drug that treated the eye’s primary drain, the trabecular meshwork. When it becomes fibrotic, it gets stiff and very little fluid gets through, which backs up the pressure.

The only options for lowering pressure were drugs such as prostaglandins, alpha- and beta-blockers, but these also decreased the fluid received by the meshwork. So, fibrosis was still an issue.

Aerie developed biological models to test various chemical structures to find one that worked on the meshwork. Aerie decided on RHO-kinase inhibition. Researchers created about 3,000 molecules.

OM: How long did this take?

Dr. Anido: About seven years; the investment was about $75 million. This is not unusual: It’s normal to see a 10- to 12-year lag from starting a company to getting clinical trial results.

We eventually found that a pure RHO-kinase molecule, designated AR13286, worked exquisitely in decreasing pressure, but its efficacy lasted about 20 days. Eventually, the body realizes this one pathway is blocked, so it activates alternative pathways, and pressure starts rising again.

We also were working on an RHO-kinase inhibitor that blocked other kinases. This molecule, netarsudil, worked so well we moved it into the clinic.

OM: How did you join Aerie?

Dr. Anido: I joined in spring 2013. I’ve been in the ophthalmology space since 1993. I was president of the Americas for Allergan a few years, then started or ran other companies, including Ista. After 10 years, we sold to Bausch + Lomb. I also was on other boards, so investors on the Aerie board asked me to join.

I became CEO about August 2013. We went public a few months later. During that time, we kept moving our primary product, netarsudil, through the clinic. We conducted a few phase 3 trials. We also simultaneously moved forward with Roclatan, a fixed-dose combination of netarsudil and latanoprost. It completed its first phase 3 trial in 2016, and we announced the results in September. Now we have two products, we’re re-filing the new drug application for netarsudil probably very soon, and we’ve got one more trial to complete for Roclatan; that should be done next year. We’ll file the NDA for Roclatan soon after.

We’ve raised a lot of money since we went public. That’s why we say our intent is to build the next major ophthalmic pharmaceutical company.

OM: Let’s discuss netarsudil’s failed phase 3 trial.

Dr. Anido: We had two trials running simultaneously, ROCKET 1 and ROCKET 2. The primary endpoint for both was noninferiority to Timolol for efficacy. ROCKET 1 was purely for efficacy and short-term safety; ROCKET 2 was efficacy, short-term efficacy and long-term safety.

When we read ROCKET 1, the results didn’t make sense relative to the work we’d already done. The primary endpoint was the treatment of patients below 27 mm Hg, and we knew from prior studies the drug worked very well in those pressures.

We investigated and realized many patients were outliers. One day their pressure was below 27 mm Hg; the next it was in the 30s. On any given day, pressure can have quite a bit of variability.

Capping the upper end at below 27 mm Hg was a design flaw, because many patients have higher pressures. So we approached the agency.

The FDA agreed to change the primary endpoint of the second trial, which was still enrolling, to below 25 mm Hg.

It also suggested we keep the ROCKET 1 data since it achieved its secondary endpoint and could be used as supportive information for the NDA filing.

But, as an insurance policy, we started another trial. We were in the process of running a trial in Canada for safety only, so we started an efficacy trial in the U.S., ROCKET 4. Here we increased the range. Instead of above 20 and below 27 mm Hg, we went above 20 to below 30 mm Hg to see if the cap from the prior protocols was the problem. ROCKET 4 showed we hit the endpoint, and the drug was noninferior to Timolol to below 29 mm Hg. We barely missed below 30 mm Hg. We think there are fewer patients above 30 than above 27 mm Hg, so we just didn’t have the unusual occurrence that we had in that first trial.

When we capped netarsudil at below 27 mm Hg, it was the first time anyone had capped starting pressures that low. Typically, the drugs out there do better at higher pressures, so entry criteria for glaucoma trials for average pressures are higher. The FDA also agreed to change the primary endpoint for ROCKET 2. We negotiated the use of ROCKET 2 and ROCKET 1 for the NDA filing. Now we have ROCKET 4.

OM: Are patients’ pressures still down today?

Dr. Anido: We’ve seen evidence of that among several patients who are now drug-free. We’ve had some now after they left the study where their pressures haven’t come back up at all. We’re trying to figure out what’s so unique about them so we can continue following them.

We have evidence in animal models that show the drug is antifibrotic. We’ve run several tests showing it can reverse fibrosis. So we could, in some of these patients, be restoring the tissue to health.

We just completed an overnight study. We know from prior studies that Timolol has no efficacy at night. But patients on netarsudil, their nighttime pressure decreased just as much as their daytime. Overnight control is big, because pressure is highest when the patient is asleep, lying down. Over time, the optic nerve is damaged.

OM: What therapies do you anticipate as competition?

Dr. Anido: In the United States, you have a market of almost 3 million patients and more than 34 million prescriptions every year. The market is about 55% prostaglandins, then all the other adjunctive therapies.

In our netarsudil trials, we showed there is an unusual synergistic effect with prostaglandins: when added to a prostaglandin, or given to a patient who had been on prostaglandin therapy, those patients tend to do better than if you add, say, Timolol. Also netarsudil is a once-daily, has great efficacy and is mild, with easily treated adverse effects. Compare that to other adjunctive medications, which require multiple daily doses, aren’t as effective and have ocular and systemic adverse effects. We think netarsudil will become the drug of choice for patients treated with a prostaglandin and who need their pressure even lower.

Roclatan could be the drug of choice for patients who either have very high pressures or who have sustained optic nerve damage and need to get their pressure down. Our responder analysis shows we had about 25% to 30% of patients get the pressure into the low teens, and below. That was about 50% better than what we saw in the latanoprost arm.

OM: Will Aerie branch into other disease states?

Dr. Anido: [Likely not.] The more we learn about the chemical structures we have made, we find ophthalmology gives us all the breadth we need. We’re looking at a molecular cousin of netarsudil to see if it can help treat wet AMD. Research suggests that the RHO-kinase blocking activity may help in wet and dry AMD, since inflammation is a huge component of that condition. We’re looking at a drug delivery system that can deliver this molecule over a six-month period. And, we’re looking at how we can we deliver netarsudil to the front of the eye over an extended period via injection. We hope to make public our progress soon. OM