Acucela, Turning 10, Gears Up for Pivotal Test With Eye Drug

Any one of a thousand little decisions can trip up an experimental drug on its long journey to the marketplace. Now, after 10 years in business, Seattle-based Acucela will be making a lot of important decisions that will determine whether it someday sells a drug that could help many people from going blind.

Acucela, along with its partner Otsuka Pharmaceutical, is designing the key clinical trial this year for a first-of-its-kind daily pill for the so-called “dry” form of age-related macular degeneration. Acucela has been emboldened to take that step, investing years of effort and millions of dollars, after it passed a mid-stage clinical trial of this drug, ACU-4429.

“Some important decisions are in front of the company now,” says founder and CEO Ryo Kubota. “It’s a really exciting moment for us.”

The 80-person company, founded when Kubota left his job as an ophthalmology researcher at the University of Washington, has spent the last decade maneuvering into position to find out if it can come up with a new drug to help stop elderly people from losing their sight. Acucela, which has raised $40 million in three rounds of venture financing, is betting that it has discovered the first treatment that can slow down the accumulation of toxic metabolites in the retina, which causes progressive vision loss in elderly folks.

Ryo Kubota, Acucela CEO

While there have been some notable advancements in treatment of the “wet” form of macular degeneration, in which blood vessels leak behind the eye to obscure vision, there hasn’t been much progress in treating the “dry” form of disease Acucela is going after. If Acucela can prove its drug can make a difference over the next couple of years, it could put itself in position to sell the first FDA-approved drug for the “dry” form of macular degeneration—a condition that damages the eyesight of more than 20 million people worldwide. That number is expected to double in the next 20 years, as populations age around the world.

Acucela still has a lot of work to do before it can even think seriously about marketing its drug, dubbed ACU-4429.

Here’s what is known so far: Acucela’s compound was recently tested in a mid-stage study of 56 patients, who were between 75 and 80 years old and got the new once-daily pill or a placebo. These patients had their pupils dilated, and were exposed to three minutes of bright light. Researchers then looked at electroretinograms to see how their rod cells recovered over time.

What the test showed was that the Acucela drug could slow down the visual cycle of rod cells in the eye. That’s thought to be an indicator that a drug might slow down the disease, because as people live longer, they essentially experience many cell divisions that yield toxic byproducts—particularly one called A2E, which ends up accumulating in the retina and obscuring vision over time.

Researchers said the Acucela drug reached a steady state after about 14 days, and the effect continued for the full 90 days patients were observed in the study, according to data presented last month at the Association for Research in Vision and Ophthalmology (ARVO) conference. The higher the dose, the more effective the drug was at slowing down the rod visual cycle. The highest dose tested, 10 milligrams a day, was well-tolerated and far lower than the 75 milligram dose Acucela tested in an earlier safety study in healthy volunteers.

While that all sounds nice, those results don’t offer the kind of proof Acucela will need to show that this drug is an important advance for age-related macular degeneration. But the study does provide Acucela the evidence it needs to advance to the next stage, the third and final phase of clinical trials normally required for FDA approval of a new drug.

The critical decisions are being made now, which will determine if Acucela has a successful drug, say, five years from now. Many of the details are still being worked out, but here’s what Kubota says to expect:

The next trial will enroll “a few hundred patients,” and it will randomly assign patients to get a dose of the Acucela drug or a placebo. The study will enroll patients with an advanced form of macular degeneration known as “geographic atrophy,” in which small deposits of metabolic byproducts have killed retinal cells in the eye. The main goal will be show, with precise measurement, that the Acucela drug can slow the rate of expansion in that area of atrophied retinal cells.

Because this is a slow-moving disease, patients will have to be followed for two years, Kubota says, although the trial will be designed to provide researchers an interim look at the data to see if the drug is offering a clear benefit before the full two years are up.

Once the key details are worked out—the number of patients, the clinical sites around the world, the exact protocols on who can enroll and who can’t—Acucela hopes to get the study under way in 2013, Kubota says. He didn’t offer a prediction on when Acucela might be able to seek FDA approval, but given how long it takes to enroll patients in clinical trials, and the time of observation required, it’s hard to imagine the company seeking FDA clearance before 2015.

I quizzed Kubota a bit about the validity of the study goal, since other drugs in the past for age-related macular degeneration were required to show they helped patients read more lines on an eye chart. But Kubota says that trial goal, of improved visual acuity, can be misleading because it can be influenced by whether a patient comes in for examination in the morning or the afternoon, or whether they are tired. The FDA, in collaboration with researchers in the field, has determined that slowing the rate of growth in atrophy of the retinal cells is the best way to consistently measure whether a drug is having an impact on a patient’s eyesight.

“Visual acuity isn’t that reliable of an endpoint,” Kubota says.

The bigger question could end up being, essentially, “How much improvement in geographic atrophy is good enough?” While a 50 percent slowdown in the rate of atrophy expansion would be considered a huge success, opinions vary on how clinically meaningful it might be to patients if a drug slows down the rate of atrophy by 10 or 20 percent, Kubota says. Some ophthalmologists say that any improvement that’s statistically significant will be a worthy advance, because patients have no other options, Kubota says.

Like any field of drug development where there are potentially millions of patients involved, Acucela isn’t alone in its pursuit of new therapies for “dry” age-related macular degeneration. GlaxoSmithKline has an antibody drug designed to hit amyloid proteins, which is also in Phase II clinical trials, Kubota says. Cheshire, CT-based Alexion Pharmaceuticals (NASDAQ: ALXN) also has an antibody in mid-stage testing. And a new Boston-based startup called Alkeus Pharmaceuticals, with Vertex Pharmaceuticals (NASDAQ: VRTX) founder Josh Boger as executive chairman, is going after dry age-related macular degeneration and a couple of other eye disorders.

Kubota, like any entrepreneur, keeps a close watch on his competitors, and can list off a series of reasons why he thinks his drug will be better. Now Acucela’s task is to get the data to prove it. “A lot of people are interested in what we’re doing,” Kubota says.

Trending on Xconomy