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Dr. Paul Sternberg, Jr., professor and chairman of Vanderbilt’s Department of Ophthalmology and Visual Sciences, with a patient.

Age-related macular degeneration (AMD) is the leading cause of severe vision loss in Americans 60 years and older. Although the macula makes up only about 5 percent of the retina, it is the portion responsible for central vision including face recognition, reading, watching television and driving.

With growth in the demographic sector of older Americans, retina specialists are seeing increases in the disease, which had no effective treatment options until just a few years ago.

Carl C. Awh, MD, managing partner of Tennessee Retina, recalled, “When I was in training, examining AMD patients was so discouraging. We could make a proper diagnosis, but that was virtually all we could offer patients, in addition to comforting and counseling. Now,” he continued, “it’s a tremendously exciting time to be involved in the treatment of this disease.”

Awh added that advances over the last several years provide the first really effective treatment options for this large group of patients and offer even more promise for improved treatment in the years to come.

Driving that promise of ‘things to come’ are innovative bench research and clinical trials occurring around the nation and here in Middle Tennessee. Both Vanderbilt University Medical Center and Awh’s group, which is affiliated with Baptist Hospital, are participating in significant AMD studies to refine current treatment regimens and search for new ones.

Paul Sternberg, Jr., MD, professor and chairman of Vanderbilt’s Department of Ophthalmology and Visual Sciences, has been involved in AMD research for the past 25 years. He actively participated in the laser studies of the 1980s, the vitamin studies of the ‘90s, and many of the current surgical and injection studies.

“Wet macular degeneration has been the area where there has been the most advancement,” Sternberg said, noting that anti-VEGF (vascular endothelial growth factor) therapy has proven to be effective … most notably Lucentis® (ranibizumab injection) and the off-label use of Avastin® (bevacizumab), which are both manufactured by Genentech.

“The areas where we’re lagging behind are both prevention and treating dry macular degeneration,” he continued.

Although all cases of AMD start as the “dry” form, it is the more rare “wet” form of AMD –– in which abnormal blood vessels develop beneath the macula –– that has traditionally been responsible for about 90 percent of vision loss. However, with the improved treatments for wet AMD and an increased frequency in dry AMD, Sternberg said, “We now have the feel that dry AMD causes more than 20 percent of the severe vision loss of patients with macular degeneration.”

Furthermore, he continued, by slowing the progression of the disease in patients with dry AMD, “you both reduce the number of patients who progress to wet AMD and the number of patients who lose vision due to dry AMD … effectively treating dry AMD will affect both.”

Sternberg’s laboratory and colleagues at Vanderbilt are conducting basic research studies to find the underlying causes of macular degeneration.

“From that work, we have identified a series of biomarkers that we think are potential markers of macular degeneration,” he said of efforts to identify increased risk through blood tests.

Vanderbilt is preparing to launch a Phase I trial aimed at bolstering the body’s antioxidant defenses.

“Part of it is diet … part of it is dietary supplements … and part of it is a new class of drugs called inducers,” Sternberg explained.

“The second thing we’re doing,” he continued, “is studies looking at genetic changes linked to macular degeneration.”

To that end, researchers at Vanderbilt became the first to examine the mitochondrial genome for changes associated with AMD and did, indeed, identify genetic variation in the “power plants” of cells.

“Most people don’t realize that we have two genomes,” said lead author Jeff Canter, MD, MPH, an investigator in Vanderbilt’s Center for Human Genetics Research. “We have the nuclear genome –– the ‘human genome’ –– that makes the cover of all the magazines, and then we also have this tiny genome in mitochondria in every cell.”

Canter teamed with Sternberg and Jonathan Haines, PhD, to examine whether a particular variation in the mitochondrial genome could play a role in AMD. The researchers found the genetic change, mitochondrial haplogroup T, does occur in about 10 percent of Caucasians.

Canter noted the supposition is that this is one of a small group of important underlying genetic variations that will ultimately help clinicians more accurately predict who is at risk for AMD.

Haines led a study at Duke and Vanderbilt that identified a variant in the Complement Factor H (CFH), which is a gene that accounts for up to 43 percent of AMD. Sternberg said preliminary numbers on the mitochondrial variation show an even stronger correlation to the disease than CFH.

“We’re at the stage where we can use genetic information to predict who is likely to develop AMD well before they actually develop it,” said Haines, director of the Center for Human Genetics Research. “Now we can conduct trials of preventative treatments –– something that’s never been possible before.”

For those with dry AMD, Vanderbilt researchers are also looking at ways to slow the progression of the disease.

“The third thing we’re doing is a trial of an eye drop for dry macular degeneration, which is with a company out of Philadelphia called Othera Pharmaceuticals,” said Sternberg, who serves as the national chairman for the Phase II trial.

Last month, participating clinical researchers completed recruitment of 135 patients across the country to test OT-551 on patients with Geographic Atrophy (GA), a chronic, degenerative form of dry AMD that currently affects about 1 million elderly Americans. With GA, the center of the retina wears out in such a clearly circumscribed area that it looks like the borders of a country.

Sternberg said of the OMEGA Study of OT-551, “This is an eye drop that is a very potent antioxidant that has been chemically modified to reach the retina.”

According to its manufacturer, the proprietary small molecule OT-551 is a potent free radical scavenger that also targets inflammatory pathways. Although being tested on GA, the potential exists that it might be effective against a number of ophthalmic diseases linked to oxidative stress, angiogenesis or inflammation.

Similarly, Awh is also focusing on GA in a separate trial being conducted through his practice, Tennessee Retina (formerly Retina-Vitreous Associates), which looks to impact the condition with a pill by Sirion Therapeutics. Sirion SRFR-001 is a placebo-controlled, dose comparison Phase II study of orally administered fenretinide.

Both the OMEGA and Sirion studies are ‘double-masked’ … the preferred moniker, Sternberg said wryly, since the term ‘double-blinded’ tends to unduly frighten patients facing vision loss.

Awh and his colleagues are currently involved in numerous clinical trials including the potentially groundbreaking CABERNET study at Baptist Hospital to more effectively treat wet AMD. The study combines a device by NeoVista, Inc. with the pharmaceutical Lucentis.

Calling Lucentis a “miracle,” Awh, whose practice was involved in the research trials that led to FDA approval of the drug, said, “This is the first treatment where, if we catch wet AMD early enough, we can keep them (patients) with functional vision the rest of their lives, we believe.”

He added that just a few years ago, any ophthalmologist would have been thrilled to have the option to maintain patients’ sight with monthly injections. However, he said, those regular office visits are becoming a logistical challenge.

“We are now eager to find something that will be equally effective or more effective with a better treatment schedule,” Awh continued.

Enter the NeoVista Ophthalmic System™. Awh said the system, which began pilot studies about two years ago, has shown real promise. Now, the combination radiation device and pharmaceutical injection has moved to a broader, controlled trial with the first procedure in Tennessee being performed at Baptist Hospital in the late spring. Since then, Vanderbilt has also been named one of the study sites.

Ultimately, NeoVista will enlist 30 sites in the United States plus 15 international study centers. The company recently received word the device has been given international approval for commercialization, and NeoVista is now in the process of ramping up production for overseas promotion and distribution.

The idea is that the radiation combined with a single injection could have the same outcome as monthly Lucentis injections, ultimately translating into both cost and time savings. Currently, Lucentis is priced at about $2,000 per dose.

Awh said that during a routinely performed vitrectomy, the surgeon enters the eye through a tiny incision and removes a portion of the vitreous gel to make room for the NeoVista probe, which measures about a millimeter in diameter. Housed within the handle of the device is a tiny radioactive seed that slides downward to the tip of the probe.

“We position the probe over the choroidal neovascular membrane,” explained Awh. “The exposure time is about four minutes or so. Even though it’s a fairly high dose of radiation, it’s very localized so the overall exposure is miniscule.”

Once the probe is removed and the wound sutured, the patient receives an injection of Lucentis –– the same dose as the normal monthly injection in the current treatment protocol. The entire outpatient procedure takes less than an hour. At the one-month check-up, some patients are given an additional injection of Lucentis if needed.

“There is no placebo group where people are going untreated,” Awh stressed of the controlled study. Instead, the NeoVista patients are being compared to those receiving monthly injections of Lucentis.

“People are cautiously enthusiastic about what we’re seeing and hope the results of this controlled study will duplicate results seen in the pilot study,” he said, adding that in the pilot study some patients actually had superior visual outcomes compared to Lucentis injections alone.

Research focused on prevention, slowing progression and stabilizing vision is particularly timely. Awh said some estimates predict a 50 percent increase in macular degeneration cases by the year 2020 as the population ages. Although the clock is ticking, experts feel an increased confidence that effective treatment and prevention for both forms of AMD are now within sight.



July 2008

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