Clinical Trial Spotlight

Acucela tests oral treatment for AMD


Acucela Tests Oral Treatment for AMD

Company is hopeful that administration via the easiest route will lead to a better treatment.


In the ongoing battle against age-related macular degeneration (AMD), delivery continues to be a key issue for any company that might be considering developing a drug to treat this disease. Intravitreal injection is the delivery method for ranibizumab (Lucentis, Genentech), the most efficacious AMD drug that has already been approved by the US Food and Drug Administration. But intravitreal injection brings with it a certain amount of unavoidable pain and discomfort, so alternate delivery forms are constantly being investigated in trials.

While implants and eyedrops are being seen more and more in clinical trials for retinal conditions, there has been little in the way of oral administration. However, Acucela Inc. (Bothell, WA) — a company that describes itself on its Web site as a "clinical stage biotechnology company focused on developing therapies for blinding eye diseases" — has recently initiated a trial of ACU-4429 (formerly called ACU-02), a novel compound that can be taken by mouth. Retinal Physician spoke with Ryo Kubota, MD, PhD, president and chief executive officer of Acucela, about ACU-4429 and the trial the company is currently enrolling for to test it.

Asked about the mechanism of action of ACU-4429, Dr. Kubota said, "Visual-cycle modulation is the mechanism of action. Our compound will slow down the regeneration of 11-cis-retinal within the visual cycle. We have been able to stop the accumulation of retinoid-related, toxic byproducts, such as the lipofuscin fluorophore A2E. A2E is considered an upstream of complement factor activation, which is also believed to play a significant role in the pathogenesis of AMD."


Acucela developed ACU-4429 with AMD specifically in mind. "However," Dr. Kubota said, "we were able to evaluate the drug's efficacy in ischemic retinal disease using a retinopathy of prematurity model that was done at the lab of Anne Fulton, MD, at Harvard, and we observed an improvement in the retinal abnormalities. This is a common model used for retinal ischemic disease. Our study was done in rats."

Dr. Kubota's collaboration with Dr. Fulton has buoyed Acucela into believing that ACU-4429 may be beneficial not only for dry AMD (the condition for which the drug is currently being tested), but also neovascular ("wet") AMD, diabetic retinopathy, branch retinal vein occlusion, central retinal vein occlusion, and other ischemic eye diseases. The company's initial target, however, is the dry form of AMD, which encompasses approximately 90% of the AMD market.


The clinical trial testing ACU-4429 in dry AMD has just begun. "So there are no known systemic side effects," Dr. Kubota said. "Our compound's target protein complex resides only in the eye, so we are not expecting off-target side effects. Our target — the protein complex for isomerization of vitamin A — is very specific to the eye, unlike other approaches. This is why we are able to deliver the drug orally, yet we still have the effect only in the eye." However, with the method of excretion for the drug not yet known, what effects it may have on the kidneys, liver, or other organ systems are also unknown.

The single-dose escalation study Acucela is currently running is a phase 1 study. "We expect to go up to 5 dose levels," Dr. Kubota said. "Each cohort will have 5 treated patients and 1 given a placebo. This will be done in a double-masked manner." He continued, "We will be dosing about 30 subjects total, with 6 subjects per cohort. We started the trial at the end of May, and we are currently recruiting healthy normal volunteers between the ages of 55 and 80." For more information on this trial, please turn to Clinical Trial Update. RP