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Neovascular AMD treatment hinges on VEGF-targeting dosing regimens
The availability of multiple anti-VEGF agents offers the possibility of preserving vision and even improving visual acuity.
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ATLANTIC CITY, N.J. — Recent studies shed valuable light on the treatment of neovascular age-related macular degeneration, a speaker told colleagues here.
At the SUNY Downstate Current Concepts in Ophthalmology meeting, Michael S. Ip, MD, OSN Retina/Vitreous Board Member, reviewed past, present and future wet AMD treatments and key data from large AMD studies.
“The treatment of AMD has gone from bench to bedside. VEGF has been identified as one of the key molecules in the pathophysiology of exudative AMD,” Ip said.
Currently, four anti-VEGF agents for neovascular AMD are available in the United States: Macugen (pegaptanib sodium, Valeant Pharmaceuticals), Lucentis (ranibizumab, Genentech), Avastin (bevacizumab, Genentech) and Eylea (aflibercept, Regeneron). Bevacizumab is not approved by the U.S. Food and Drug Administration for this indication.
“I think having these multiple therapies ultimately benefits all of our patients,” Ip said.
Further study of bevacizumab, ranibizumab, aflibercept and other agents, such as molecules directed against platelet-derived growth factor (PDGF), is warranted, Ip said.
Targeting VEGF
In the early 1990s, photoablation was the gold standard treatment for wet AMD, but patients experienced immediate vision loss, Ip said.
“We then improved the situation by going to photodynamic therapy, which didn’t cause immediate vision loss, but it slowed the rate of vision loss. It didn’t really improve visual acuity,” he said. “And now we’re in the era of anti-VEGF, where now we can not only preserve vision, but in many of our patients, we can improve visual acuity.”
The development of anti-VEGF began when Napoleone Ferrara, MD, PhD, a researcher at Genentech, purified and cloned the VEGF-A gene, Ip said.
“Why target VEGF? If you have a molecule that goes against VEGF, that’s when you get this immediate change in visual acuity and immediate reduction of fluid because you’re stopping the vascular permeability action of VEGF,” he said.
Pegaptanib, the original anti-VEGF agent, targeted VEGF-A165, a VEGF-A isoform. Bevacizumab and ranibizumab are pan-VEGF blockers that target all isoforms of VEGF-A, Ip said.
“Perhaps that is the reason why the results with our pan-VEGF blockers, bevacizumab and ranibizumab, are superior to that of Macugen,” he said.
MARINA, ANCHOR studies
The MARINA and ANCHOR trials compared two doses of ranibizumab to sham injections and photodynamic therapy.
“The results were striking,” Ip said. At 2 years, patients who received monthly ranibizumab injections had visual acuity 20 letters better than those who underwent PDT, he said.
Results evoked concern about cardiovascular adverse events associated with anti-VEGFs. However, evidence of increased risk is not definitive, Ip said.
Some ophthalmologists started using bevacizumab off-label before ranibizumab was approved.
“We had a situation where we were getting comfortable with using Avastin for AMD patients because there was a need for it and because Lucentis was not available for almost a year,” Ip said.
Bevacizumab was less expensive than ranibizumab, at about $50 per injection as opposed to approximately $2,000. Ip and colleagues were faced with a difficult choice when ranibizumab was approved in 2006.
“It’s a very difficult question to try to answer,” Ip said. “You’ve got controversy: economics vs. evidence-based medicine. The cost difference was the 900-pound elephant in the room.”
CATT and IVAN study
The Comparison of Age-related Macular Degeneration Treatment Trials (CATT) compared monthly injections of ranibizumab and bevacizumab out to 2 years, as well as as-needed dosing of both.
One-year results showed that monthly injections of both drugs were clinically equivalent, Ip said.
Data showed that the rate of serious adverse events or hospitalizations was 24% in the bevacizumab group and 19% in the ranibizumab group. In addition, there were more adverse events in the as-needed dosing than in the monthly dosing arm, Ip said. However, evidence of increased risk with bevacizumab is inconclusive, he said.
The IVAN study, conducted in the United Kingdom, compared monthly injections of ranibizumab and bevacizumab out to 1 year. The primary outcome measure was best corrected visual acuity out to 2 years. One-year results were presented at the Association for Research in Vision and Ophthalmology meeting in 2012.
The IVAN study had a non-inferiority margin of 3.5 letters, while the CATT had a margin of five letters.
Results showed that bevacizumab was not clinically equivalent to ranibizumab, using the 3.5-letter threshold.
“Technically, you can say that they’re not clinically equivalent, based on this trial. But had they used a five-letter margin like CATT, then you could have said that [they are equivalent]. I think that’s something that’s important to be aware of,” Ip said. – by Matt Hasson