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February 2007

Clinical Update: Retina
The Other AMD: Dry but Drawing Research Attention
By Miriam Karmel, Contributing Writer

Wet AMD has garnered enormous medical and pharmaceutical attention lately. But dry AMD sufferers are legion, and the news for them is both discouraging and promising.

The discouraging bit arrived last November with the announcement by the Complications of Age-Related Macular Degeneration Prevention Trial (CAPT) group that there is no evidence to support the use of prophylactic laser treatment for drusen.1

“People had always hoped that if you make the drusen go away, the risk of vision loss would be less,” said Alan J. Ruby, MD. Those hopes were dashed by the CAPT findings that though laser can eliminate or reduce the size of some drusen, laser treatment is not any better than doing nothing when it comes to preventing vision loss. At five years, laser treatment had no effect on either visual acuity or late AMD. And it was only partially successful in reducing the extent of drusen in the treated eyes.

After five years, the intervention and control groups had the exact same amount of vision loss: 188 (20.5 percent) of both the treated and observed eyes had visual acuity scores three lines worse than at baseline.

The results surprised Dr. Ruby, a retina specialist in practice with Associated Retinal Consultants in Royal Oak, Mich., and an investigator at one of the 22 CAPT centers. “Based on the small number of studies being done prior to CAPT, I would have thought we could show some associated visual improvement. And that absolutely did not bear out,” he said.


Take your vitamins. With that news, the treatment options have dwindled to one: vitamins. “Right now we’re at a standstill,” said Dr. Ruby. “There really are no treatments that have been shown in large prospective studies to reduce the risk of vision loss except the vitamin studies.”

He was speaking, of course, about the Age-Related Eye Disease Study (AREDS), which in 2001 found that high levels of antioxidants and zinc reduced by 25 percent the risk of progression in eyes with moderate and advanced AMD. It has become the standard of care. Srilaxmi Bearelly, MD, assistant professor of ophthalmology, Duke University, agrees. “The best thing that we have currently is AREDS. That’s it.”



The AREDS study group is back, this time with additional clinics, hoping to build on its initial success with a new formulation to slow the development and progression to advanced AMD. AREDS2, a six-year, multicenter, randomized trial will test the benefits of adding high doses of lutein and zeaxanthin and/or omega-3 fatty acids DHA and EPA to the original AREDS formulation.

The study also will test the effect of lowering the zinc from 80 mg to 25 mg, and deleting betacarotene, which has been associated with a risk of lung cancer in smokers. At enrollment, the 4,000 participants, aged 50 to 85, will have either bilateral large drusen, or large drusen in one eye and advanced AMD (CNV or geographic atrophy) in the other.

The addition of lutein and zeaxanthin, carotenoids that exist in natural concentrations in the macula, was inspired by observation of dietary intake and blood samples in the original AREDS population. People with high dietary levels of these carotenoids were less likely to develop advanced AMD, both neovascular and geographic atrophy, during the course of the study, said Emily Y. Chew, MD.

Similarly, AREDS2 is adding omega-3 fatty acids, found in fish oil, because participants in the first study who ate at least two servings of fish a week showed almost a 50 percent reduction in the risk of having advanced AMD at baseline, said Dr. Chew, who is deputy director, division of epidemiology and clinical research, National Eye Institute.

AREDS2 will involve up to 100 clinics, representing a mix of private and academic practices. This large number of clinics throughout the country should guarantee a study cohort that’s representative of the U.S. population. The hope is to increase the power of the original AREDS formulation, Dr. Chew said. “If you add another 10 percent reduction, that’s a lot for a disease that’s a public health issue.”

In the meantime, she advised physicians to continue recommending the AREDS formulation, which contains 500 mg of vitamin C, 400 IU of vitamin E, 15 mg of betacarotene (except for smokers), 80 mg of zinc and 2 mg of cupric oxide.

“AREDS,” said Dr. Chew, “should be a standard of care.”


Low Vision Patients: Catch Them Early

Nutritional supplements may be the only current medical treatment for dry AMD. But doctors also can offer patients hope in the form of low vision rehabilitation.

And they should offer it sooner rather than later, said Janet S. Sunness, MD, medical director of the Richard E. Hoover Rehabilitation Services for Low Vision and Blindness, Greater Baltimore Medical Center. Most referring doctors wait until the visual acuity is 20/200, noted Dr. Sunness.

Her advice: Don’t wait. “If you have a patient who has difficulty reading or recognizing people, even if their visual acuity is still good, even if it’s 20/30, they still would benefit from low vision rehabilitation.”

Dr. Sunness explained that with geographic atrophy in which the foveal center is not yet involved, patients may have relatively good visual acuity when measured by single letters, but may have significant difficulty reading or recognizing people because of blind spots near the fovea that block off parts of words or facial features.

But good, direct lighting, magnification and bold text can help for almost any stage of degeneration. “Lighting is absolutely critical for these people,” Dr. Sunness said, explaining that patients with geographic atrophy who have good acuity have a profound drop in vision in dim environments, such as restaurants.


Novel Approaches

Though 90 percent of all AMD is the dry type, research has focused on CNV, said Dr. Bearelly. But Dr. Bearelly, whose area of expertise is using autofluorescence imaging to predict progression of the disease, said interest in dry AMD is on the rise.

She cited a number of investigations that employ novel approaches—either genetic or pharmacologic—to inhibit the destructive processes within the eye. Among the studies that have advanced beyond the early trial stages are:


Anecortave acetate. Alcon has launched a four-year, phase 3 study to evaluate the safety and effectiveness of anecortave acetate in patients with dry AMD who are at risk of progressing to wet AMD. The trial will test 15-mg and 30-mg doses of the drug vs. sham in 2,500 patients with wet AMD in one eye and dry AMD in the fellow eye.

Anecortave acetate, an angiostatic agent, works by slowing or stopping the growth of new blood vessels. This trial is testing a novel drug delivery method known as posterior juxtascleral depot administration.

The procedure requires a special blunt-tipped cannula for slow, sustained delivery of the drug behind the eye. It was developed to avoid the complications associated with intravitreal injection, including intraocular infection and retinal detachment.

Final results of the trial, which is ongoing at more than 100 centers worldwide, are expected in 2010. Enrollment is closed.


Ciliary neurotrophic factor. Phase 2 trials testing human ciliary neurotrophic factor (CNTF) for atrophic macular degeneration, as well as early and late stages of retinitis pigmentosa, are now under way. In general, neurotrophic factors have been investigated for their ability to retard progression of neurodegenerative diseases.

CNTF was first identified as a survival factor in ciliary ganglion neurons in chick eyes. In mouse models of amyotrophic lateral sclerosis, it reduced motor neuron loss. It has also slowed progression of photoreceptor degeneration in animal models of retinitis pigmentosa.

In the phase 2 trial, CNTF will be delivered by genetically engineered cells that are housed in a patented delivery system called Encapsulated Cell Technology.

This technology was developed by Neurotech USA for long-term delivery of therapeutic agents to the retina via genetically engineered human cells that are encapsulated in a semipermeable hollow fiber membrane.

They are surgically implanted through the pars plana into the vitreous and anchored to the sclera in a 30-minute outpatient procedure. It was designed to bypass the blood-retinal barrier, thus overcoming the challenge of delivering therapeutic agents to the back of the eye.


Compound ST-602. In December, Sirion Therapeutics announced a two-year, phase 2 clinical trial to evaluate the effectiveness of oral compound ST-602 (fenretinide) in slowing the progression of geographic atrophy in patients with AMD.

Fenretinide is believed to interrupt a biochemical process that leads to the destruction of the retina and the retinal pigment epithelium. Specifically, it aims at reducing an accumulation of toxins that are end products of a biochemical process that involves vitamin A (retinol), which is essential for transmission of images to the brain.

During that biochemical process certain toxic by-products of vitamin A are produced. Healthy, younger eyes have mechanisms to eliminate those toxins, which accumulate in the form of lipofuscin.

But in aging eyes that elimination slows down, the toxins accumulate and the damage ensues. It has been hypothesized that an accumulation of lipofuscin in the eye results in vision loss in diseases such as geographic atrophy and Stargardt’s disease, in addition to dry AMD. Sirion hopes to enroll up to 225 patients at 20 sites in the United States.


OT-551. The NEI has begun a phase 2 trial testing the effect of an antioxidant eye drop for reduction of the area of geographic atrophy in persons with dry AMD.

Ten patients with bilateral geographic atrophy will receive three daily doses of OT-551, developed by Othera Pharmaceuticals, over two years. In addition to measuring the percentage change in the area of geographic atrophy, the study will measure progression to CNV.

OT-551 is a low molecular weight compound that rapidly metabolizes to the agent TP-H, a potent free-radical scavenger. Its anti-inflammatory and antiangiogenic effects have been demonstrated in animal models of AMD. The eye drop is formulated to penetrate the cell membrane so it can reach the back of the eye. Uptake is in both the choroid and retina.

If successful, OT-551 might be used to treat or prevent common ocular disease resulting from oxidative damage, including AMD, cataract and dry eye syndrome.


1 Ophthalmology 2006;113:1974–1986.


New Studies for Dry AMD

Progress for treating dry AMD may come soon if the relevant studies complete their enrollment goals. The study sites for anecortave acetate and OT-551 are already closed to new enrollment. But the other trials mentioned in this article are looking for good participants. Here is contact information for them.

AREDS2 study centers A list of study centers and eligibility requirements can be found by visiting, or calling 1-877-AREDS-80.

Ciliary neurotrophic factor Interested ophthalmologists should call 401-333-3880 (ext. 3105).

ST-602 Information can be requested from