Eyeworld

EW RETINA 54 April 2011 by Michelle Dalton EyeWorld Contributing Editor Retinoic acid may be key to dry, wet AMD treatments A synthetic vitamin A derivative has identified a biomarker that may predict treatment response in geographic atrophy A synthetic retinoid deriv- ative has been able to slow lesion growth and preserve visual acuity in patients with geographic atrophy (GA). Further, when the pa- tients were able to achieve sustained reductions in retinol binding protein (RBP) levels of 60-75% (indi- cating a positive response to fenre- tinide), these same patients had a lesion growth rate of about half what those receiving placebo experi- enced when the RBP reduction threshold was met. "Fenretinide may improve clini- cal outcomes for patients with both dry and wet forms of age-related macular degeneration," said Jason Slakter, M.D., clinical professor of ophthalmology, New York Univer- sity School of Medicine, New York. "For the first time ever, we may have a biomarker to predict patient re- sponse to therapy, as about one- third of the patients who achieved a profound and sustained reduction in RBP levels experienced a beneficial treatment effect." Biomarkers are generally consid- ered the "hot topic" in retinal dis- eases, Dr. Slakter said. "The difficulty with retinal diseases is that clinical studies require large numbers of pa- tients and a long duration, and many of the diseases we are treating take a long time before they're seri- ously detrimental to vision. The question is whether we can find something that will give us a hint of what's going on with the treatment for the disease earlier in the course of the study. We're looking for mark- ers to give a hint of what might be effective," he said. Adding to the dilemma in reti- nal diseases is the fact that the tech- nology wasn't initially there to make finding a biomarker viable, and for some diseases a natural animal model didn't exist. "We can test all we want in an animal model, but that doesn't nec- essarily replicate what we might see in humans. Animal models are bet- ter than nothing, but it doesn't mean that a compound will have a positive action in humans just be- cause a mouse was treated success- fully," Dr. Slakter said. In the case of fenretinide, "we may have a marker for the biologic activity of the drug by simply meas- uring the level to which fenretinide is able to reduce RBP in a particular patient, which may then indicate its ability to reduce the progression of the disease," he said. "The results of this Phase II study, which was initi- ated to determine if people who took the pill would have significant and sustained reductions in RBP and an associated delay in the progres- sion of the disease, suggest that this may be possible." The accumulation of retinol-de- rived toxins in the eye "is believed to exacerbate lesion growth leading to progression of GA," said Nathan L. Mata, Ph.D., chief scientific offi- cer, ReVision Therapeutics, San Diego. Fenretinide is a once-daily oral compound being investigated for the treatment of GA, according to ReVision Therapeutics. Because fenretinide limits the delivery of retinol to the eye by reducing the serum RBP, retinol-derived toxin ac- cumulation is also slowed, which, in turn, slows lesion growth, the com- pany said. The U.S. FDA has granted the company Fast Track status for the drug. Fenretinide "has been tested and used for more than 30 years in systemic doses from 100-7,200 mg; with more than 8,000 'patient years,' it's been proven safe," Dr. Slakter said. "Most of the adverse events reported in our study are commonly associated with retinoids." Study details ReVision completed a 2-year, placebo-controlled, double-masked, dose-ranging study enrolling a total of 246 patients with GA. All patients were between 50 and 89 years, and the overwhelming majority of study subjects were white (99.2%). The ini- tial baseline GA readings were within 500 microns of the fovea. Doses studied were 100 mg (n=80) and 300 mg (n=84); placebo com- Breakthrough continued from page 53 phy is a chronic disease, and therapy probably has to go on for a long pe- riod of time." There is obviously more work to be done, but the scientific commu- nity has been highly receptive of the findings so far. "While previous studies have emphasized the importance of ge- netic variations as a major cause of AMD, two recent papers report that disrupting central regulatory mecha- nisms of retinal biology can cause degeneration of retinal cells, giving an appearance in mice quite similar to the dry form of AMD," said Paul Sternberg Jr., M.D., G.W. Hale Pro- fessor and chairman, Vanderbilt Eye Institute, Nashville, Tenn. "Interest- ingly, both studies suggested the im- portance of oxidative stress, which is a well-established risk factor of AMD. The missing links between ox- idative stress, retinal cell dysfunc- tion, and the genetic factors warrant further investigation." Abdhish Bhavsar, M.D., ad- junct assistant professor of ophthal- mology, University of Minnesota, Minneapolis, noted that although this research is an excellent starting point to further the understanding of geographic atrophy in dry AMD, clinical trial results can be unpre- dictable. Just because something looks good on paper and in animals doesn't mean it's going to translate to humans. "The study seems to be well de- signed and well thought out," he said. "The researchers do show a positive jump in our understanding of geographic atrophy in dry AMD. This is a big plus. We need these steps in the beginning to understand on a basic level what's going on. They offer the promise of targets for treatments, so that's reason to be op- timistic. "But in terms of telling us whether or not this is going to be the next treatment, that is difficult to predict," he continued. "There are many examples in ophthalmology where some very reliable thoughts on pathways and disease etiology in terms of targeting those sites for treatment have not come to fruition." If everything goes according to plan, though, new treatment op- tions in under a decade isn't out of the question. Take Lucentis (ranibizumab, Genentech, South San Francisco, Calif.) for wet AMD, for example. VEGF was first identified in the eyes of people with wet AMD in 1996. Just a few years later in 2004, Lucentis not only passed Phase III clinical trials, but was ap- proved by the FDA. "All major breakthroughs in sci- ence started the same way, with something that looks like it might work," said Dr. Bhavsar. "We've got to start with that first and progress to well-designed clinical trials to de- termine if those treatments really benefit patients." EW Editors' note: The physicians inter- viewed have no financial interests re- lated to their comments. Contact information Ambati: jamba2@email.uky.edu Bhavsar: bhavs001@umn.edu Sternberg: paul.sternberg@Vanderbilt.edu A scene as it might be viewed by a person with AMD Source: National Eye Institute, National Institutes of Health

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