Age-Related Macular Degeneration Before and After the Era of Anti-VEGF Drugs

NEI-funded study of bevacizumab and ranibizumab examines their effects at five years

In a study of nearly 650 people with age-related macular degeneration (AMD), half still had vision 20/40 or better, typically good enough to drive or to read standard print, after five years of treatment with anti-VEGF drugs that are injected into the eye. The authors of the study, funded by the National Eye Institute (NEI), say those outcomes would have been unimaginable about 10 years ago, prior to the drugs' availability.

The results were published in the journal Ophthalmology and presented May 2 at the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO) in Seattle.

“This is the most comprehensive study of anti-VEGF therapy for AMD to date,” said NEI Director Paul A. Sieving, MD, PhD. “It points to the importance of long-term follow-up in studies evaluating disease treatments.”

AMD is the leading cause of vision loss among older Americans. It causes damage to the central part of the retina, the light-sensitive tissue at the back of the eye. AMD often has very few symptoms in its early stages; but in later stages, it causes loss of the central, straight-ahead vision needed for activities like reading and driving.

There are two types of late AMD—geographic atrophy and the more common neovascular AMD, also known as wet AMD. In neovascular AMD, fragile blood vessels grow under the retina and leak fluid. This usually starts in one eye, and is stimulated by a protein called VEGF. Just 10 years ago, people diagnosed with neovascular AMD were almost certain to develop severe vision loss in their affected eye and likely to lose vision in their other eye, too.

The new study looked at people with AMD who had regular treatment with drugs designed to block VEGF. After five years, 50% of them had 20/40 vision or better, 20% had 20/200 vision or worse, and the rest were in between.

Ten years ago, the best available treatment for AMD was photodynamic therapy—in which an intravenous drug (injected into a vein) and laser are used to seal off leaking blood vessels. Past studies have found that just one year after diagnosis, less than 15% of patients given this therapy alone retain 20/40 vision, and up to 40% decline to 20/200 vision. Without any treatment, less than 10% of patients retain 20/40 vision at one year, and up to 75% of untreated patients decline to 20/200 vision.

In the U.S., state drivers’ licenses generally require 20/40 vision in at least one eye. A best-corrected vision of 20/200 in both eyes is considered legally blind for the purpose of federal disability benefits.

The Comparison of AMD Treatments Trials (CATT) began in 2008 and was designed to compare the anti-VEGF drugs bevacizumab (Avastin, Genentech) and ranibizumab (Lucentis, Genentech). VEGF is important in the growth and development of new blood vessels in normal and cancerous tissues. Bevacizumab was approved by the FDA in 2004 for the treatment of metastatic colon cancer. Other drugs were later developed specifically to target blood vessels in the retina, with ranibizumab coming to the market in 2006 and aflibercept (Eylea, Regeneron) in 2011. For treating AMD, the drugs are injected into the eye. Before ranibizumab was available, many ophthalmologists began treating the disease with bevacizumab off-label, which appeared to have similar benefits, at least in the short-term. The difference in the cost of the drugs also made bevacizumab appealing. Bevacizumab cost $50 per dose compared with $2,000 for ranibizumab.

In the trial, more than 1,200 participants with neovascular AMD were randomly assigned to receive either ranibizumab or bevacizumab for two years, through monthly or as-needed injections. During that time, the two drugs were equally effective at preserving visual acuity. These results were later confirmed in five multicenter clinical trials around the world.

The current study followed up with CATT participants between March 2014 and 2015, an average of 5.5 years after enrollment in the trial. After two years on their assigned drug, participants were free to work with their eye care providers to choose their own course of therapy. During that 3.5-year period, more than half received at least one treatment with a drug or therapy other than the drug assigned to them. The investigators obtained visual acuity measurements for 647 of 914 participants who were still living.

In addition to the overall effects of anti-VEGF therapy at five years, the investigators compared the outcomes of participants who received bevacizumab or ranibizumab during the trial.

“Some experts had speculated that two years of treatment with ranibizumab might have long-term benefits superior to bevacizumab. However, at five years, there were no differences in visual acuity between the two drugs,” said Daniel F. Martin, MD, Chair of the Cleveland Clinic Cole Eye Institute and CATT Study Chair.

The study also found that after five years, participants assigned to ranibizumab during the trial had a higher rate of strokes and heart attacks (7.6%) than those assigned to bevacizumab (4.5%). Since most participants received treatments other than their assigned drug after the two year-trial, the investigators are cautious about attributing this difference to the study drugs.

Finally, the study provides information on the general course of AMD with treatment. It was already known that many people with neovascular AMD eventually develop geographic atrophy, which has no treatment. In the trial, participants were more likely to develop geographic atrophy when they received monthly, rather than as-needed injections of bevacizumab or ranibizumab. After the trial, almost all participants stopped monthly injections in favor of as-needed treatment, with an average of four to five injections per year. By five years, the rate of geographic atrophy increased from 20% of participants at two years to 41% at five years. The fraction of participants with geographic atrophy was similar between the bevacizumab and ranibizumab groups.

“Although anti-VEGF treatment has greatly improved the prognosis for patients overall, we still need to find ways to avoid poor vision in these patients and to decrease the burden of ongoing treatment,” said Maureen G. Maguire, PhD, the study’s Principal Investigator and a Professor of Ophthalmology in the Perelman School of Medicine at the University of Pennsylvania in Philadelphia.

The CATT studies were supported by cooperative agreements EY017823, EY017825, EY017826, and EY017828 from NEI. For more information, visit www.clinicaltrials.gov (NCT00593450).

Source: NIH; May 3, 2016.