CLINICAL TRIAL SPOTLIGHT
Othera Banks on Eyedrop to Stop Dry AMD
Company will run its own in-house trial on OT-551 concurrent with NEI trial.
Othera Pharmaceuticals, Inc. (Exton, Pa), is conducting a randomized, double-masked, dose-ranging, multicenter efficacy and safety study of its novel small-molecule drug OT-551, in a trial designed to test the compound’s ability to halt and reverse geographic atrophy (GA), an end stage of dry age-related macular degeneration (AMD). Among the aspects of this trial that make it of particular interest to the posterior-segment community is that the drug is being delivered to the macula with eyedrops. Al Reaves, PhD, Othera’s senior vice president of clinical development, spoke with Retinal Physician about the new OT-551 trial and why the company elected to conduct a trial along with an ongoing pilot phase 2 National Eye Institute (NEI)-sponsored study. “There is a major difference in the design of the 2 studies,” Dr. Reaves says. “The study being conducted at the NEI is on a small number of subjects , and because of the small size, they’re looking at a unique population that has bilateral disease. Our study, on the other hand, is different in that it encompasses a broader population of GA patients with unilateral or bilateral disease.” As a result, Othera intends to eventually enroll 200 subjects in 20 sites across the United States. “There are data in the literature showing that eyes with symmetric bilateral disease degenerate more rapidly than those with unilateral disease,” Dr Reaves says, explaining the NEI’s rationale. “But those with bilateral disease are rather hard to come by.” The primary endpoint of Othera’s study will be to determine whether OT-551 affects the rate of progression of the GA lesion area, although other endpoints, including visual function, will also be considered. Dr. Reaves describes the mechanism of action of OT-551 as antioxidative, antiangiogenic, and antiinflammatory through its ability to downregulate the overexpression of nuclear factor kappa B, as indicated in an April 19 Othera press release. Regarding the antioxidant effect of OT-551, Dr. Reaves says, “Photo-oxidative stress is triggered by exposure of certain molecules of the eye tissues to light as it passes through the eye tissue and is focused toward the macula.When that reaction is triggered, free radicals and other toxic compounds are generated. This is caused by everyday exposure to light.” By reducing the amount of free radicals inside the eye and also targeting the inflammatory response, Othera hopes OT-551 can minimize the progression of the area affected by GA and thereby preserve vision. Previously, only visual-function measurements had been considered as endpoints by the Food and Drug Administration (FDA) for approval of new drugs. “However,” Dr. Reaves explains, “at a meeting sponsored by the Association for Research in Vision and Ophthalmology (ARVO) last November, the NEI and FDA discussed appropriate endpoints for GA. It was extremely timely in our case,” Dr. Reaves continues, “because it was agreed at that meeting that FDA would consider the rate of change from baseline in the GA lesion area as a primary endpoint.” A secondary endpoint will be to determine whether OT-551 has the ability to prevent conversion from dry to wet AMD. This is particularly relevant as Othera also plans to initiate a second trial shortly to study the use of OT-551 adjunctively to ranibizumab (Genentech, Lucentis) as a treatment for neovascular AMD. The other truly significant aspect of this trial, as well as the NEI trial, is the mode of administration of OT-551. “The good news is that the mode of administration will be eyedrops,” Dr. Reaves says. “We shouldn’t take anything away from drugs that have been recently approved for intravitreal administration, particularly for neovascular AMD, but a better route of administration is from an eyedrop. Our preclinical studies show that after eyedrop application, OT-551 is absorbed into the various eye compartments and can reach the retinal tissues within 15 minutes.” He continues, “This is a truly unique and remarkable finding. To deliver drugs to the back of the eye with eyedrops is a major breakthrough.” Enrollment for Othera’s OT-551 trial for dry AMD has already begun. More information is available on page 68 of this issue.