The anti-VEGF agents bevacizumab (Avastin) and ranibiz-umab (Lucentis) have transformed the treatment of neovascular macular degeneration. Finally, there is a treatment that stops the leakage, dries the retina and in many cases restores normal anatomy.
Still, some patients lose vision. Philip J. Rosenfeld, MD, PhD, the doctor who pioneered the use of the Avastin in the eye, wanted to know why. After analyzing data from the MARINA and ANCHOR trials, he found there was no difference in terms of CNV leakage between those who lost and those who gained three lines of vision.
“We expected patients who lost vision to have a greater amount of leakage from their CNV over time, but that just wasn’t the case,” said Dr. Rosenfeld, who is professor of ophthalmology at Bascom Palmer Eye Institute. “It appeared as though we successfully converted the wet AMD back to dry AMD. My hypothesis is that patients lose vision because their underlying dry macular degeneration continues to progress.”
Dr. Rosenfeld noted that interest remains high in developing new treatments for wet AMD, with a focus on combining therapeutic agents, similar to the paradigm for cancer chemotherapy. Unlike cancer, in which cells are genetically unstable and are always trying to find new ways to proliferate, AMD is a genetically stable disease, he explained. “We don’t expect these drugs to become ineffective over time because of mutations within the macula.”
Dry Needs Work
Now the attention turns to dry AMD, which ranges from patients with good vision and drusen to patients with geographic atrophy and visual acuities as poor as 20/200. Dr. Rosenfeld explained that dry AMD, just like any neurodegenerative disease, represents a challenging situation. In that regard, “Neovascular AMD was the low-hanging fruit. Now we’ve got a very difficult problem in attacking the dry AMD,” he said.
People with dry AMD will welcome this shift in attention. “Over and over they’re told, ‘You’re lucky you have dry AMD,’” said Lylas G. Mogk, MD. Yet patients with dry AMD, whose vision loss is associated with drusen or geographic atrophy, can have just as many problems as patients with CNV, she said. Dr. Mogk is director of the Visual Rehabilitation and Research Center of the Henry Ford Health System in Detroit. In an analysis of 467 patient charts from 1999 to 2003—before the anti-VEGF treatments were in use—Dr. Mogk found that patients with dry AMD suffered as much as those with CNV in most measures, including reading, depression, contrast sensitivity loss and the need for rehabilitation training. “They’re trying to figure out why they’re lucky,” she said.
The neglected thief of vision. Janet S. Sunness, MD, medical director of the Rehabilitation Services for Low Vision and Blindness at the Greater Baltimore Medical Center, agreed that there’s nothing lucky about having advanced dry AMD. She noted that about 40 percent of eyes with geographic atrophy, which presents as loss of retinal pigment epithelium and photoreceptors, have visual acuity worse than 20/200.1
What’s more, the prevalence of geographic atrophy is far greater in the very old than wet AMD. Geographic atrophy affects 22 percent of those older than 90, while CNV affects 7 percent.2 And most patients have bilateral disease. “Geographic atrophy is the neglected thief of vision,” Dr. Sunness said.
Why is it neglected? Geographic atrophy is more gradual than CNV, Dr. Sunness explained. “Geographic atrophy is a more orderly process. It progresses in a more predictable way.” And as the disease progresses, blind spots develop around the center, coalescing into a horseshoe and then a ring of atrophy. “It’s as though there’s a continent of atrophy sitting in a sea of retina,” said Dr. Sunness. Throughout much of the progression, the foveal center is spared, so the patient often maintains good visual acuity. Finally, the center is lost.
Blind, no, but impaired, yes. Functional problems can occur at any point along the dry AMD continuum, and yet the perception exists, even among some retina specialists, that people with dry AMD don’t lose vision, said Dr. Mogk. She attributes this assumption to a 1984 report stating that 10 percent of wet AMD accounts for 90 percent of legal blindness.3 But legal blindness is a government construct, established to define the point at which to compensate people who are unable to support themselves, she explained. “Legal blindness is not an index of function,” Dr. Mogk said, adding that the functional deficit begins long before 20/200. “You can have significant vision loss without a definable blind spot,” she said, adding that many people with dry AMD and drusen have lost contrast sensitivity, which dramatically affects function. “With respect to acuity, by 20/50 you’re having difficulty, and at 20/70 you’re definitely in trouble.”
Geographic atrophy can be similarly confounding. Before the loss of foveal vision, patients may exhibit good single-letter visual acuity when tested on the chart, yet have difficulty reading or recognizing faces. Drs. Mogk and Sunness both have patients who can read newsprint but not headlines, because a large paracentral scotoma surrounds the spared foveal center that isn’t large enough to contain the whole word. The patient can’t read the 20/400 letter on the chart but can read the 20/50. For such patients, simple magnification is often ineffective.
Investigational Therapies for Dry AMD
Attempts to fight dry AMD are under way. Here are some current investigations:
AREDS2. This NEI trial builds upon results from the earlier Age Related Eye Disease Study, which found that high-dose antioxidant vitamins and minerals reduced the risk of progression to advanced AMD by 25 percent, and reduced the risk of moderate vision loss by 19 percent. AREDS2 will refine the findings by adding lutein and zeaxanthin to the formulation.
Ciliary neurotrophic factor (CNTF). Neurotech has developed an encapsulated cell technology in which cells are engineered to produce large amounts of CNTF, a naturally occurring substance that in animal models protected against further degeneration. The phase 1 study is complete, and a phase 2 study is being organized for patients with retinal degeneration and geographic atrophy.
Complement inhibitors. Support for a paradigm that links aberrant complement activation with AMD was revealed in studies associating AMD with three genes, including factor H. Collectively, the three gene variations account for nearly 75 percent of all AMD cases in European and North American populations.1 The unanswered question is whether inhibiting complement so late in the disease process will alter disease progression or vision loss.
Glatiramer acetate. This drug, marketed as Copaxone, is an immunomodulatory agent approved to treat relapsing-remitting multiple sclerosis. It may also work in the eye. An ongoing study will test whether Copaxone arrests the progression as well as the conversion of dry to wet AMD.
Fenretinide. This agent halts accumulation of lipofuscin and toxic vitamin A metabolites. A two-year, phase 2 dose-ranging trial by Sirion is under way.
POT-4. Potentia Pharmaceuticals announced a phase 1 clinical trial in March 2007 to test this complement inhibitor. POT-4 is designed to shut down the complement activation system that could lead to local inflammation, tissue damage and upregulation of angiogenic factors such as vascular endothelial growth factor.
OT-551. This agent, developed by Othera, may protect RPE cells and photoreceptors from oxidative damage and block angiogenesis stimulated by VEGF and other growth factors. Othera is now conducting a randomized, double-masked, dose-ranging phase 2 trial. The NEI is also testing OT-551 in a pilot study of three-times-a-day dosing to halt progression of geographic atrophy. 1 Gold, B. et al. Nat Gene 2006;38(4):458–462.
Treatment Is Elusive
There is not yet an established medical treatment to offer dry AMD patients. (See “Investigational Therapies for Dry AMD.”) But these patients can be offered hope. “Don’t say nothing can be done,” said Dr. Mogk. “Don’t tell patients they’ll be blind. Tell them they will always have usable vision and that there’s help out there to use it optimally. Offer hope and encouragement, but don’t tell these patients that they’re lucky.”
1 Sunness, J. S. Mol Vis
2 Hirvela, H. et al. Ophthalmology
3 Ferris, F. L. et al. Arch Ophthalmol
Dr. Mogk has no related financial interests. Dr. Rosenfeld is an investigator in clinical trials funded by the NEI, Potentia Pharmaceuticals and Othera. Dr. Sunness has been a consultant for Sytera (now merged with Sirion), Neurotech and Othera.