Taking Aim at Dry AMD
Researchers strive to gain ground on the dry form of the disease.
BY DIANE DONOFRIO ANGELUCCI, CONTRIBUTING EDITOR
As medical advances continue to improve the outlook for patients with neovascular age-related macular degeneration (AMD), researchers are digging in deep to learn more about the roots of AMD and studying potential treatments for dry (or non-neovascular) AMD, which accounts for 85% to 90% of AMD cases. In this article, we will examine their findings, as well as potential treatments.
Non-neovascular AMD
There are two categories of non-neovascular AMD — early AMD, or drusen, and the advanced form of non-neovascular AMD, geographic atrophy. Early AMD is characterized by drusen deposits under the retinal pigment epithelium (RPE), which contain lipids, cellular proteins and complement. "In general, patients who have only this form of macular degeneration remain relatively stable," says Karl G. Csaky, M.D., Ph.D., associate professor of ophthalmology and director of the ophthalmic unit, Duke Clinical Research Institute, Duke University Medical Center. "There might be a minor loss of vision, but typically it does not result in severe vision loss by itself " (Figure 1).
Patients with this form of AMD lose fine vision, having difficulty reading, sewing, or possibly pursuing pastimes such as golf or tennis. They also have poor dark adaptation.
In some cases the drusen increase in size and number. This is associated with progressive RPE damage, which continues until the RPE and photoreceptors die. "Advanced dry macular degeneration, which is geographic atrophy, accounts for approximately 20% to 30% of severe vision loss caused by AMD," says Scott W. Cousins, M.D., director, Duke Center for Macular Diseases, Duke University Eye Center, Durham, N.C. (Figure 2).
"Every day I see several cases with big patches of geographic atrophy that are marching to the center of the fovea, and they're limiting patients' vision. When it hits the fovea, their vision decreases dramatically," says Lawrence J. Singerman, M.D., president of Retina Associates of Cleveland and clinical professor, Case Western Reserve University School of Medicine, Cleveland, Ohio. "It commonly stays right near the center. Even subtle increases in the size of it, when it's on the edge near the center, decrease vision considerably, and if it marches through the center, patients can become legally blind in both eyes."
IMAGES COURTESY OF KARL G. CSAKY, M.D., PH.D.
Figure 1. Fundus photograph demonstrating extensive drusen only in a patient with dry age-related macular degeneration.
Targeting the Origins
Dr. Cousins explains that research is focusing on two components: what causes the onset of drusen, and what causes the onset and progression of RPE and photoreceptor death that occurs with chronic deposits.
A very productive area of research has been studying the genetics of patients in whom various types of macular degeneration develop, Dr. Csaky says. "We think we understand some of the genetic associations, especially between the complement cascade and the development of macular degeneration."
There is no doubt that mutations in some genes involved in the complement cascade play roles in different ways, depending on other patient characteristics, but it is unclear how this will help patients in diagnostics, he says. "In the complement cascade mutations, that correlation is not one to one. So there are many people walking around who have the mutation but don't have the disease and many patients with the disease but don't have the mutation."
Studying Potential Treatments
The only available treatment to help prevent drusen progression into neovascular AMD is the vitamin formulation studied in the Age-Related Eye Disease Study (AREDS), containing high doses of antioxidants and zinc. The vitamins reduced progression of AMD by 25% and visual loss by 20% in patients with stage 3 disease to prevent them from getting to stage 4 disease over a 5-year period, says David S. Boyer, M.D., clinical professor, University of Southern California, Keck School of Medicine, Los Angeles. "I don't know if people are prescribed the vitamins as frequently as they should be, but this is a very significant advance."
The first AREDS study showed no effect on drusen formation or drusen disappearance, Dr. Csaky says. However, a trend suggested that the vitamins might prevent growth of geographic atrophy. The Age-Related Eye Disease Study 2 (AREDS2) will study the effect of lutein, zeaxanthin, docosahexaenoic acid and eicosapentaenoic acid on progression to advanced AMD. It also will examine whether the AREDS formulation is as effective when zinc is reduced and beta carotene is eliminated.
Several therapies being studied are designed to halt progression of geographic atrophy.
■ Fenretinide. This oral drug (Sirion Therapeutics) is being studied in a phase 2 trial of patients with geographic atrophy. "It's based on the hypothesis that there's a stress of the vitamin A cascade on the RPE and photoreceptors," Dr. Csaky says. "Fenretinide reduces that vitamin A–related load, and the hope is that it would reduce the rate of RPE death and photoreceptor death." He explains that the drug came out of the research on Stargardt's macular dystrophy.
"If fenretinide works — and it has significant promise to work — it will be the first thing that will stop the progression of geographic atrophy," Dr. Singerman says.
Figure 2. Fundus photograph demonstrating progression of dry AMD to include extensive geographic atrophy.
■ OT-551. Othera has developed a topical drug, OT-551, that is being studied in patients with geographic atrophy. This eye drop is taken up into the retina and chorioid, acting as a very potent antioxidant and scavenger of free radicals with anti-inflammatory activity and some anti-angiogenic activity, according to Dr. Boyer.
The anti-inflammatory properties may be important because there is some involvement with the inflammation cascade in geographic atrophy, Dr. Csaky says. "So there is the theoretic possibility that by adding a potent anti-inflammatory and antioxidant, that that would prevent the progression of the disease."
"The benefit of the Othera study is that it's an eyedrop," Dr. Singerman says. "If it really does work, it's going to be phenomenal."
OT-551 is also being studied as a possible adjunct to anti-VEGF (vascular endothelial growth factor) treatment and in reducing secondary changes that continue to occur.
■ Ciliary Neurotrophic Factor. Neurotech Pharmaceuticals is conducting a phase 2 trial of NT-501 in patients with geographic atrophy. This intraocular implant contains cells that continuously release ciliary neurotrophic factor (CNTF) into the back of the eye. Small studies have indicated that it was helpful in improving vision in patients with retinitis pigmentosa, and it is hoped that it will improve cell survival in the macular area and improve vision in patients with geographic atrophy, Dr. Boyer says.
However, Dr. Csaky reports that phase 1 studies did not include a placebo or controls, so it is unclear whether the benefit resulted from CNTF or from the surgery placing the implants.
■ Anecortave acetate. The Anecortave Acetate Risk Reduction Trial (AART) is examining whether prophylactic treatment with anecortave acetate (Retaane, Alcon Laboratories) reduces the formation of choroidal neovascularization (CNV), Dr. Boyer says. Once patients have CNV in one eye and high-risk characteristics in the other eye, they have an 8% to 12% per year risk of CNV in the other eye.
■ Glatiramer acetate. Glatiramer acetate (Copaxone, Teva Pharmaceutical Industries), a treatment approved by the FDA to treat multiple sclerosis in subcutaneous doses, has been proposed to possibly reduce drusen over 3 or 4 months when it is injected weekly. "There was actually loss of the drusen that were present at a much higher rate than you would ever expect to see," Dr. Boyer says.
However, he notes that laser treatment reduced drusen, but visual function did not improve. "Copaxone acts in a different manner to reduce the drusen and may be neuroprotective and may prove to be beneficial," Dr. Boyer says. Small studies are examining this as a potential treatment.
■ Implantable Miniature Telescope. In a trial of the Implantable Miniature Telescope (IMT, VisionCare Ophthalmic Technologies, Saratoga, Calif.), patients were able to better ambulate and had an apparent improved quality of life, Dr. Csaky says. However, he explains, the FDA was not convinced that the implant contributed to better vision because patients' cataracts also were removed in implanting the devices.
Dr. Singerman, who was an investigator for the study, explains that the device was difficult for patients to learn to use. "It's possible that it will be approved because it is unique and fills a niche, but it's going to be for a limited number of people," he says.
Diagnostic Advances
Dry AMD usually progresses very slowly, presenting a challenge to researchers in determining whether new drugs are effective. "If you had a way of identifying a subset of patients who are going to progress in the next year or two that would enrich the study for high-risk patients, you could achieve the therapeutic end point in a shorter time for less dollars. That would dramatically enhance the interest of drug companies to test drugs that they are not confident are going to work," Dr. Cousins says.
He explains that fundus autofluorescence may offer that promise in geographic atrophy. Frank Holz, M.D., at the University of Bonn in Germany, identified patterns of fundus autofluorescence that seem to predict which cases will progress more quickly, and this technique is being used in a number of trials to stratify enrollment.
In addition, because researchers believe certain high-risk haplotypes may indicate future progression, genetic testing also may be used to stratify patients for clinical trials, Dr. Cousins says.
| Helping Patients Now |
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| As ophthalmologists await potential treatments, there are a number of ways they can help patients with dry AMD. "In general in the United States, it is believed that all patients with intermediate or large drusen should be on AREDS vitamins," Dr. Cousins says. These can be used if patients tolerate the vitamins and are not smokers. Furthermore, Dr. Boyer urges ophthalmologists to encourage patients to participate in the AREDS 2 study so results can be obtained as quickly as possible. "In general, it's probably a good idea to tell patients that a heart-healthy diet is probably a macula-healthy diet," Dr. Cousins says. "Although there is no proof that lowering your cholesterol or taking a statin drug is helpful, there is suggestive evidence." "We know people who eat a lot of dark, leafy green vegetables, don't smoke and have diets high in omega-3 fish oils all reduce the possibility of developing wet macular degeneration and progression," Dr. Boyer says. He encourages sharing these prevention strategies with patients and their children in the hope of protecting them. Patients need to be reminded that smoking makes everything worse, Dr. Csaky says. "It makes the geographic atrophy worse, makes the neovascularization worse and makes the progression to severe macular degeneration worse." Low vision aids also can be helpful. "One of the best things you can do for the patients is to train them in how to optimally use the vision that is left," Dr. Singerman says. "We think of low vision as patients who are legally blind, but in fact, this group of AMD patients — who have 20/40, 20/50, 20/60, and 20/70 vision and whom you would not consider to be legally blind yet function at a very low level because the retina is just sick — are sometimes helped tremendously by a low vision evaluation," Dr. Csaky says. Cataract extraction also may help some patients with macular degeneration, although some ophthalmologists disagree. "I think most of us feel that it's always a balance, but there are patients even with severe geographic atrophy, if the cataract is dense enough, who do benefit to some degree from cataract surgery. So I think cataract surgery should still be considered an option even for patients with severe geographic atrophy," Dr. Csaky says. |
Spectral-domain optical coherence tomography (OCT) also is considered a useful tool in assessing dry AMD, allowing ophthalmologists to measure the amount of drusenoid material present and where drusen are so they can determine whether progression is occurring.
Furthermore, autofluorescence and spectral-domain OCT may help researchers better understand the disease. For example, Dr. Csaky explains that lipofuscin autofluoresces and can be detected by imaging devices that measure autofluorescence, so researchers can study the relationship between the development of autofluorescence and the progression of severe dry AMD and determine whether therapies can target that pathway.
These modalities are expected to be particularly useful in examining dry AMD. "One of the problems with geographic atrophy is its variability and the way it grows," Dr. Boyer says. "There are patients who may have a large area of geographic atrophy with perfectly normal vision and others who have a similar size or similar area of geographic atrophy who unfortunately have significant or severe visual loss."
Therefore, using visual acuity alone to capture visual results will be difficult, he says. Researchers will need to assess the size of the geographic atrophy, the autofluorescence of that lesion, microperimetry and multifocal electroretinography to determine whether a drug is working, rather than relying on lines of vision.
"We'll also have to see if the FDA will agree to these other factors," Dr. Boyer says. "They usually use vision as the end result, and if they use vision, it's going to be very hard for some of these trials to prove a point."
Looking Ahead
"Many biotech companies and pharmaceutical companies are in preclinical research looking at other kinds of agents," Dr. Cousins says. "Those should be entering clinical trials in the next year or two. So the landscape for having a variety of agents being tested for the late form of dry AMD, geographic atrophy, looks very promising over the next 3 or 4 years."
Just as strides have been made by understanding the links among cholesterol, C-reactive protein, and other factors in treating heart disease before a heart attack occurs, Dr. Csaky explains that the same approach will be taken with AMD. Researchers will try to develop genetic blood tests, blood tests that measure degrees of inflammation or other tests allowing ophthalmologists to identify high-risk patients or those with early disease, treat them with medications to alter those pathways early and potentially prevent the development of macular degeneration. "I think that's the goal right now for dry AMD," he says. OM
Editor's Note: Dr. Boyer is a consultant for Alcon, which is conducting the AART trial and is an investigator in the trial. He is also an investigator in the AREDS2, CNTF and Othera OT-551 trial. Dr. Singerman has received research grants for fenretinide, OT-551 and IMT research. Dr. Csaky and Dr. Cousins have no financial interest related to products discussed in this article.
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