Clinical Trial Spotlight

No injection necessary? An oral med for dry AMD


No Injection Necessary?

Undertaking a phase 2 study, Acucela bets on an oral medication for dry AMD.

Andrew E. Mathis, PhD, Medical Editor

Half a dozen drugs are currently in the FDA pipeline for the treatment of nonexudative age-related macular degeneration, with no currently approved treatments available. Only AREDS vitamins have an on-label indication, and they are only used for prevention. Once the eye reaches the advanced stage of the disease, there's little that can be done.

Of the several pharmacological approaches to dry AMD under investigation, visual-cycle modulation offers the possibility of treatment at the level of the retinal pigment epithelium, and one visual cycle modulator is ACU-4429, a target molecule developed by Acucela, Inc. of Seattle. Ryo Kubota, MD, PhD, chairman, president and CEO of Acucela, spoke with Retinal Physician about this drug.

One of the more impressive aspects of ACU-4429 is that it is orally delivered, obviating the need for intravitreal injections and even eye drops. “It wasn't easy,” Dr. Kubota explains, “but we have a very strong research team and research capability. We developed this molecule internally, and we think we have a big advantage over other competitors' drugs, by not having to inject into the eye. This is a focused way to modulate the visual cycle without affecting other parts of the body.”

This absence of effect outside the eye has been proved in the phase 1 trials of ACU-4429, in which there were no related systemic side effects and mostly mild adverse ocular events — primarily delayed dark adaptation, which Dr. Kubota explains was expected.

ACU-4429 works selectively on rod photoreceptors, by reducing or eliminating the accumulation of toxic byproducts in the eye, primarily A2E, that are produced by rod overactivity. Furthermore, ACU-4429 targets RPE65 isomerase, which is specific to the visual cycle. These abilities were demonstrated in preclinical studies, giving rise to the phase 1 studies, which enrolled in 2008.


Given that there are two paths that dry AMD typically takes as it advances — toward geographic atrophy or conversion to neovascular AMD — a dry AMD drug that addresses both possibilities would be a particularly potent way of addressing this condition. Dr. Kubota believes ACU-4429 may fit that bill.

“Our intent is to reverse neovascularization using the current approach,” Dr. Kubota says, “so we don't see why this drug wouldn't work in stopping conversion. Our next long-term study will look at that issue.” The current phase 2 trial is enrolling only patients with geographic atrophy.

However, ACU-4429's applications may go beyond AMD.

“We believe ACU-4429 may be able to treat DME as well,” Dr. Kubota says. “I think we have a good chance of reducing oxygen demand in the retina through cycle modulation. That will usually lead to lessened expression of VEGF and reverse disruption of the blood-retinal barrier. At the very least, reducing toxic byproducts in the retina that reverse the inflammation that destroys the blood-retina barrier.”

Dr. Kubota says there are also plans to test ACU-4429 in Stargardt's disease, which has some similarities to dry AMD.


To date, the currently active phase 2 trial of ACU-4429 has evaluated 56 patients with geographic atrophy with experimental or placebo treatment. Dr. Kubota says that Acucela will be using electroretinography as a primary endpoint. “We're also looking at multiple endpoints,” Dr. Kubota adds. “Besides ERG, we'll be looking at optical coherence tomography, fundus autofluorescence, and the typical endpoint of visual acuity.”

Patients have been enrolled in nine states, and with 90 days in the trial's length, the final data collection on results to date will be taking place imminently.

More information on this trial is available online at RP