Glaucoma
Retinal injections, up close and in depth

Intravitreous injection through pars plana.
Source: Karl Brasse, M.D.; EyeLand Design Network

By the time 2011 rolls around, retinal specialists are going to be confronted with a vexing situation. Data from a government-sponsored head-to-head comparison of some of the best treatments available for wet age-related macular degeneration (AMD)—namely Lucentis (ranibizumab, Genentech, South San Francisco, Calif.) and Avastin (bevacizumab, Genentech)—is slated for release. Already, research suggests Lucentis is safe and effective, and has the ability to improve vision. A growing body of evidence also suggests Avastin improves vision, and is cheap (at $50-$100 per dose, compared to $2,000 per dose of Lucentis). But using Avastin in the treatment of wet AMD is off-label. The Comparison of Age-Related Macular Degeneration Treatments Trials (CATT), sponsored by the National Eye Institute, will answer this question: What is the change in visual acuity of patients with subfoveal neovascular AMD after one year of treatment with either Lucentis or Avastin? Ophthalmologists would love to know the answer (i.e., which is really better?) right now. But because they have to wait, by the time they do know, another new treatment for wet AMD will be closer to entering the market, with a good set of its own data. That therapy is called VEGF Trap (Regeneron Pharmaceuticals, Tarrytown, N.Y.), a fusion protein designed to bind all forms of vascular endothelial growth factor A (VEGF-A) and placental growth factor (PLGF). Both VEGF-A and PLGF are proteins involved in the abnormal growth of new blood vessels, according to the company. Phase II trial data for the Food and Drug Administration (FDA) has suggested it has a longer duration of action, said Jason S. Slakter, M.D., Vitreous-Retina-Macula Consultants of New York, New York. Head-to-head trials with Lucentis also are underway. What’s more, Regeneron is partnering with Bayer (Leverkusen, Germany) to bring it to market. If the data looks to be anywhere near as good as the Lucentis data, ophthalmologists will again be dazed and confused over which wet AMD treatment actually is best. Dr. Slakter explained, “Probably by May 2011, we should have some answers about Avastin versus Lucentis,” he said. “If Lucentis and Avastin are similar, the first thought is, well, Avastin is cheaper. But if the VEGF Trap data [likely released around the same time] is similar to Lucentis—but there is any indication that Trap has longer durability—then ‘great.’ Avastin is similar to Lucentis and is cheap. But VEGF Trap lasts longer and is similar to Lucentis. From a physician’s point of view, that makes things difficult.” 
In other words, it’s difficult because if outcomes swing the way Dr. Slakter suggests they could, physicians once again will wonder whether they should be prescribing one drug versus another (and in this hypothetical scenario, Avastin or VEGF Trap). “But from the patient point of view, it’s great because it means we have new therapies,” Dr. Slakter said.
Consider everything

Dr. Slakter turns his attention to VEGF Trap specifically because “timeline-wise, it’s the closest [drug for wet AMD to FDA approval].” But he acknowledges there are many other options in the mix. “There’s a lot of recent data on combination PDT [photodynamic therapy] and Lucentis,” Dr. Slakter said. “It’s a little disappointing. The combination did not give a better benefit visually.” The combination was tested against Lucentis alone. However, PDT still may have a positive role in combination with Lucentis for a certain portion of the Japanese population with polypoidal choroidal vasculopathy disease, Dr. Slakter said. “It’s a variation of macular degeneration in Asian patients,” he said. Dr. Slakter was even less hopeful about the continued importance of Macugen (pegaptanib sodium, OSI Eyetech, Melville, N.Y.). “I don’t know if there is more than a handful of physicians using this for AMD in the U.S.,” Dr. Slakter said. “[Some data suggests] using Macugen as a longer-term stabilizing agent may have some benefit based on the concept that it has a theoretically better safety profile than Lucentis. But from what we know in the literature, we think Lucentis is a low-risk medication systemically.” The Ophthalmic Technology Assessment, sponsored by the American Academy of Ophthalmology and published in the October 2008 issue of Ophthalmology, suggested that Macugen has the longest track record of demonstrated safety and efficacy, but it appears to only halt visual decreases—not improve vision in many cases.
James Maisel, M.D., Hauppauge, N.Y., and Hicksville, N.Y., prefers Lucentis, and he says many ophthalmologists are like-minded about the drug. “I’m pretty much using Lucentis about 90% of the time for wet AMD,” Dr. Maisel said. “The results are so good with Lucentis, with over 90% of patients stabilizing and over 30% improving vision. I think that’s the preferred medication for wet AMD.”
He said that “Macugen has very much fallen out of favor” in the ophthalmic community, while many are indeed awaiting results of the CATT trial to determine once and for all the advantages of Lucentis over Avastin (or vice versa). “Lucentis is designed to be a smaller molecule and penetrate the retina better than Avastin,” Dr. Maisel said. However, bioactivity data suggests the drugs are very close in efficacy, he said.
In the dry corner …

Meanwhile, some companies, such as Acucela (Bothell, Wash.), are focused on eradicating dry AMD, which currently has no FDA-approved treatment. Company executives suggest if they do that, they also can stop the progression to wet AMD (which is always predated by the dry form). “We would like to stop wet AMD from happening with ACU-4429,” said Ryo Kubota, M.D., Ph.D., founder, chairman, president, and CEO, Acucela. ACU-4429 is a visual cycle modulator for dry AMD. It aims to prevent rod cell deterioration, which is a cause of AMD, according to Dr. Kubota. Even beyond the vast problem of patients with dry AMD alone, patients with wet AMD also may benefit from a dry AMD medication, Dr. Maisel said. “There are patients with wet AMD that are treated and respond well, but dry AMD still progresses,” he said. Still, Dr. Slakter remains skeptical that drugs like ACU-4429 could completely prevent wet AMD from occurring. Although Dr. Slakter noted that ACU-4429 could slow the buildup of components of drusen—one of the major features in the progression of AMD—it may not be enough to stop drusen development altogether, he said. “It’s not a miracle drug in modulating the entire disease,” Dr. Slakter said. ACU-4429 may still have a role to play, Dr. Slakter acknowledged. “In theory, if the damage is from the buildup of toxic intermediates, it may have the ability to slow that process down,” Dr. Slakter said. “No one yet knows how much it will slow it down.”
Both dry and wet AMD forms remain vast challenges to conquer. Ninety percent of the world’s AMD patients have the dry form, yet Dr. Maisel noted that the dry form only accounts for perhaps 10% to 15% of severe AMD-related visual loss. Visual loss is obviously much more problematic in the wet form. Fortunately, both forms may soon have treatments, but with drug competition as tight as ever, there are no gold standards in sight.

Editors’ note: Dr. Slakter has financial interests with Acucela (Bothell, Washington), Genentech (South San Francisco, Calif.), and OSI Eyetech (Melville, N.Y.). Dr. Maisel has financial interests with Genentech and OSI Eyetech. Dr. Kubota is founder, chairman, president, and CEO, of Acucela.

Contact information

Kubota:  425-527-3272, rkubota@acucela.com
Maisel: 516-939-6100, zydocmd@yahoo.com
Slakter: 212-861-9797, jslakter@aol.com