A topical eye drop (OT-551, Othera) is being investigated to treat geographic atrophy in dry age-related macular degeneration. The treatment is an antioxidant that in vitro protects against antioxidative damage and in vivo protects against light damage. One-year data are expected to be reported in the spring.
Atlanta-One-year data on an antioxidant eye drop (OT-551, Othera) being investigated to treat geographic atrophy (GA) in dry age-related macular degeneration (AMD) are expected to be reported in the spring, said Paul Sternberg Jr., MD, at the American Academy of Ophthalmology annual meeting. He is affiliated with the Vanderbilt Eye Institute, Vanderbilt University School of Medicine, Nashville, TN.
If this therapy proves effective, it will be a big advance against a disease in which, previously, little progress has been made, Dr. Sternberg said. An increasing number of patients have dry AMD, and every patient with wet AMD had dry AMD previously, he added, saying that dry AMD accounts for about one-third of patients with advanced AMD.
"One of the reasons there have been so few studies of dry AMD is that we have limited knowledge of the pathogenesis of the disease," Dr. Sternberg said. "As we have seen with wet AMD, development of drugs follows an increased understanding of the cause of the disease.
Different end point
Because of these issues, Dr. Sternberg said, investigators are seeking a nonfunctional morphologic end point.
"Geographic atrophy represents a subgroup of patients with dry AMD who appear to be at higher risk for progression and will likely develop vision loss in a reasonable length of time," Dr. Sternberg said.
In those patients, he added, monitoring of the lesion size is easy and usually precedes vision loss.
Currently, no effective treatment for GA exists. It causes substantial vision loss in about 3.4% of patients aged more than 75 years, and the understanding of the development of GA is limited, according to Dr. Sternberg. The annual rate of growth of GA is predictable and is symmetrical between eyes.
The drop, a small lipophilic molecule, has been shown in an animal model to penetrate the cornea and sclera easily to reach therapeutic levels in the eye.
"When the eye drop is administered, [it] travels intact via the sclera to the back of the eye but also penetrates the cornea, where esterases within the eye convert [the drop] to TEMPOL-H. Both [the drop] and its TEMPOL-H metabolite possess potent antioxidant, anti-inflammatory, and antiangiogenic activity," Dr. Sternberg said.
"While TEMPOL-H does not penetrate the cornea, [the drop] does," he continued. "When the eye drop is administered, both get into the vitreous cavity, and both have activity inside the eye. [The drop] and TEMPOL-H are rapidly distributed within the eye, and the levels of these compounds are measurable for up to 16 hours in the vitreous, retina, choroid, and optic nerve beginning within 15 minutes after topical administration."
The rationale for the use of this agent initially was that the drop is a di-substituted hydroxylamine antioxidant that in vitro protects against chemically induced oxidative damage and in vivo protects against light-induced oxidative damage.
"[The drop] also seems to protect against retinal degeneration in animals and may have anti-inflammatory and anti-angiogenic properties, although the latter may be secondary to the anti-inflammatory properties," Dr. Sternberg said.
Phase II trial
In clinical studies, the investigators wanted to look primarily at morphologic end points rather than functional end points, such as changes in the area of the GA or in the rate of enlargement. This end point selection is important because measuring visual acuity in these patients is not practical; patients can have a large area of GA and still have good visual acuity.
In a randomized, double-masked, dose-ranging, multicenter 2-year phase II trial, the efficacy of the drop in doses of 0.45% and 0.3% is being compared with placebo to determine the effect of the eye drops in reducing the area of progression of GA following treatment. The patients administer the drug four times daily for 2 years in one eye. The investigators will evaluate the changes in the best-corrected visual acuity and the safety. The first patients were randomly assigned in June 2007, and the final patients were randomly assigned in March 2008.
"Dry AMD remains a major cause of visual loss and probably will increase in its importance," Dr. Sternberg said. "As a result, there is increased interest in developing pharmacologic treatments. In studying those new agents, we believe that morphologic end points may be preferable to functional end points. [This drop] is one of several drugs that we think is promising, is under study, and that, unlike the other agents, is applied topically."