AMD Therapy Update

What the last 5 challenging years tell us about the even more challenging years ahead

AMD Therapy Update

What the last 5 challenging years tell us about the even more challenging years ahead.

In the wake of the first-year CATT trial results and other studies, practitioners are rethinking dosing regimens, therapy selection and the practical concerns of maintaining a highvolume AMD practice. How do individualized treatment and dosing decisions impact outcomes and the practice?


“I now feel more confident if I have to use bevacizumab (Avastin, Genentech) to begin therapy, such as when patients have no co-insurance and may have $400 co-pays,” says Dr. Boyer. “If I'm not sure which treatment will be needed in the future, I have the patient complete the paperwork for co-pay assistance in case they need to be switched to ranibizumab (Lucentis, Genentech).1,2 I think CATT supports this approach.”3

Dr. Boyer says he's been impressed by aflibercept (Eylea, Regeneron), previously known as VEGF Trap-Eye. The intravitreal treatment for neovascular AMD is expected to decrease the required frequency of treatment and perhaps follow-up.

“I've been involved in clinical research for both ranibizumab and aflibercept,” he notes. “If patients are doing well on ranibizumab, I will leave them on it. But if I see some fluid on OCT in patients receiving monthly treatment, I will try the aflibercept. Since the drug seems to have a slightly better binding affinity and appears to last longer, I'll probably try the drug in a variety of patients with wet AMD to see what kind of results we obtain.”

Dr. Colucciello expects frequency of AMD patient visits to remain high, whether patients are receiving bevacizumab or ranibizumab. “I will try aflibercept, but I will be monitoring these patients very closely, more than every 2 months,” he adds.

“We need to remember that it still requires three loading doses. And counter-acting the decrease in number of visits will be that we expect increased prevalence.”

Dr. Colucciello says cost will be another major consideration. “Nobody knows what the cost of aflibercept will be,” he says. “I won't be surprised if it is high.”


Dr. Antoszyk believes the first-year results of the CATT trial have “clearly validated the outcomes obtained in the pivotal phase 3 studies of ranibizumab in the treatment of exudative AMD and proved that monthly bevacizumab was non-inferior to monthly ranibizumab. The CATT trial also showed that monthly treatment is better than PRN therapy. Patients do best when seen and treated monthly and almost as well when seen monthly but treated as needed (PRN).”

Dr. Antoszyk tries to minimize out-of-pocket costs for patients. If the patients' insurance status is not clear, he initiates therapy with bevacizumab and signs patients up for the Genentech-sponsored patient assistance program. If they qualify, he discusses switching to ranibizumab to minimize the patient's expenses. In addition, Dr. Antoszyk says he uses bevacizumab in fewer than 50% of his AMD patients because of concerns of reduced potency and contamination that could result in severe intraocular inflammation or endophthalmitis. In early September, the FDA announced that repackaged intravitreal injections of bevacizumab caused a cluster of endophthalmitis infections in the Miami area. Earlier, four cases of endophthalmitis were associated with a VA pharmacy in Nashville.

“The bevacizumab used in the CATT trial was standardized to a high degree of confidence, minimizing potential complications,” says Dr. Antoszyk. “You don't get that level of standardization at most compounding pharmacies. I recommend that you choose a pharmacy with a very reliable track record and one that you've been working with for many years.”

He believes aflibercept holds a great deal of promise for reducing treatment burden by decreasing the frequency of treatment of choroidal neovascularization (CNV) in AMD from once every month to once every two months after three monthly loading doses.4,5 “I think physicians will move toward this treatment, but this will also depend on cost and reimbursement,” he adds.


“CATT is an excellent, definitive study,” says Dr. Dugel. “The problem is that these are 1-year results and this is not a 1-year disease, and CATT doesn't address how to reduce the overall treatment burden. The PRN treatment supported by CATT is not treat-and-extend. Patients were still seen on a monthly basis. It's important to emphasize that CATT does not address the treatment burden.”

Dr. Dugel says he primarily uses bevacizumab for neovascular AMD, diabetic macular edema, and retinal vein occlusion. “I present the studies to the patients and let them decide,” he says. “Often, patients don't have the Medigap coverage that would cover 20% of the ranibizumab treatment and they may not qualify for the assistance program. I think many base their decisions on economic considerations.”

Dr. Dugel is taking a wait-and-see attitude toward aflibercept.

“Efficacy isn't an issue and the change in frequency will not be that drastic, such as it would be if we were to switch to a visit every quarter or every 6 months,” he says. “Aflibercept will likely appeal to ranibizumab users, depending on how it is priced. However, this will only be a band-aid, not a permanent solution. The treatment burden is our biggest challenge. It is currently insurmountable. Our patients are, therefore, simply not doing as well as the studies would suggest. This is an uncomfortable topic that few of us are willing to discuss. However, for the sake of our patients, we must be honest and admit to this disconnect between trials and clinical practice.”


“My contention is that most U.S. physicians are already treating AMD as if bevacizumab and ranibizumab are equivalent,” says Dr. Rosenfeld. “Their decisions on what to use are driven by the economics of their practices, including penalties or incentives, and on their patients' insurance coverage.”

Dr. Rosenfeld sees a big advantage in the use of aflibercept. “Being able to extend from 4 to 6 weeks and possibly up to 12 weeks will be helpful,” he says. “But this will only be a short-term solution because the system will keep filling up with patients.”

He doesn't expect aflibercept to be approved or reimbursed for diabetic macular edema or occlusion anytime soon. “We will have to put in a special request for local coverage from Medicare, demonstrating that it will reduce the number of visits,” he says.

In the near future, he adds, “Aflibercept will change the treatment paradigm by decreasing the number of injections, but we shouldn't expect better visual acuity outcomes. Visual acuity will only be improved once we have a treatment for dry AMD.”


Like Dr. Rosenfeld, Dr. Pieramici says the first year of the CATT trial doesn't really change much.

“If you preferred ranibizumab, you will emphasize the data suggesting that there might be a slightly lower risk and trend toward better vision,” he says, noting, in particular, the superior anatomic results of ranibizumab reflected on OCT and angiography. “You would also be comforted by the fact that there were fewer hospitalizations among the ranibizumab patients, suggesting perhaps a safer profile.

“If you preferred bevacizumab,” he continues, “the study confirmed noninferiority to ranibizumab on most counts. The study also armed you with good phase 3 evidence supporting your use of bevacizumab. If you were looking for support of a monthly or PRN treatment strategy, you could find aspects of the data to support either as well.”

Dr. Pieramici tends to use more bevacizumab than ranibizumab. He follows PRN and treat-and-extend strategies to reduce the treatment burden. “Many of these patients couldn't tolerate monthly treatments for years,” he says. “I check vision, examine the fundus and review OCT images every 4 to 12 weeks, except for patients who are dry for long periods. Some lesions involute and go a year without needing retreatment, while others require monthly injections for years. It can be quite variable.”

The results of aflibercept seem very similar to that of ranibizumab, according to Dr. Pieramici. “The question is whether the increased durability of aflibercept will allow for fewer treatments and longer follow-up periods than ranibizumab/bevacizumab, which on average require treatment about six times a year,” he observes. “We'll probably try aflibercept on patients who aren't responding well to bevacizumab/ranibizumab to determine if it can be efficacious in these difficult cases. We'll also be interested in seeing whether the treatment burden can be reduced by reducing the frequency of visits. I will also consider aflibercept for new patients. The data is there, we just have to see how much it will cost.”


1. Rosenfeld PJ, Brown DM, Heier JS, et al; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419-1431.
2. Brown DM, Kaiser PK, Michels M, et al; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1432-1444.
3. CATT Research Group, Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897-1908.
4. Heier JS. VEGF Trap-Eye Phase III Trial Results. Paper presented during Angiogenesis, Exudation, and Degeneration; Miami; February 12, 2011.
5. Schmidt-Erfurth U. VEGF Trap-Eye Phase III Trial Results. VIEW 2 results. Paper presented during Angiogenesis, Exudation, and Degeneration; Miami; February 12, 2011.