Investigative drugs may battle age-related macular degeneration

Accumulation of toxins in the retina resulting from environmental and/or genetic factors causes retinal degeneration.

"In a normal eye, retinol or vitamin A is used to produce vision and is then recycled and regenerated by the retinal pigment epithelium [RPE]," said Dr. Singerman during retina subspecialty day at the annual meeting of the American Academy of Ophthalmology. "In AMD, the recycling process is compromised and the waste products of vitamin A build up and damage the RPE."

Before the RPE and the photoreceptors atrophy, fluorescent debris containing the waste products accumulates. These accumulated toxins are the target of the pharmacotherapies under investigation. Dr. Singerman described two such drugs under consideration, ACU-4429 and fenretinide.

ACU-4429 (Acucela) is an oral drug that slows the visual cycle and as a result decreases the accumulation of toxins. The drug is orally bioavailable and selective for rods. The drug has shown efficacy in a number of disease models, for example, genetic disease models, aged animal models, a light damage model, and a retinopathy of prematurity model, explained Dr. Singerman, clinical professor of ophthalmology, Case Western Reserve University School of Medicine, Cleveland, and voluntary professor of clinical ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine.

"The drug specifically inhibits an isomerase that is specific to the visual cycle needed to convert transretinol to 11-cis-retinal in the RPE, slowing the visual cycle in rod receptors and decreasing accumulation of A2E," he said. A2E is one of the most toxic byproducts of vitamin A metabolism in patients with AMD.

ACU-4429 has only one site of action, namely, in the RPE. Enzymes are present there that contribute to the visual cycle. However, in AMD, the enzymes lead to toxic byproducts, which are theoretically reduced by ACU-4429, Dr. Singerman said.

A phase II, randomized, double-masked, placebo-controlled trial (ENVISION Clarity Trial) of ACU-4429 to treat dry AMD began in January 2010 to study the efficacy and safety of three escalating doses and up to two additional dose levels. Patients receive either the oral drug or placebo for 3 months, he said.