The approval of ranibizumab (Lucentis; Genentech, San Francisco) in June 2006 marked an important step forward in management of patients with neovascular age-related macular degeneration (AMD);1 however, we must continue to look for better ways to treat our patients with this devastating disease. Much like oncologists who target tumors with more than one chemotherapeutic drug, we should also look to combination treatment to improve our outcomes. Additionally, we need to look at ways to decrease the number of treatments while still achieving the visual outcomes of the ranibizumab trials. Finally, treatments that offer long duration of action and excellent safety should top the list for combination therapy in managing all subtypes of neovascular AMD.

TREATMENT HISTORY
Treatment for the exudative form of AMD has evolved rapidly in recent years. In the 1990s, laser photocoagulation was the only tool retinal physicians had for treating subfoveal choroidal neovascularization (CNV) associated with neovascular AMD. In 2000, photodynamic therapy (PDT) with verteporfin (Visudyne; Novartis, East Hanover, NJ) was introduced, and slowed, but did not stop the loss of visual acuity in patients (Figure 1). Pegaptanib (Macugen; OSI/Eyetech and Pfizer, both in New York, NY), approved in December 2004, was the first drug to selectively block an angiogenic factor, vascular endothelial growth factor (VEGF).2,3 In 2005, anecdotal evidence encouraged ophthalmologists to use bevacizumab (Avastin; Genentech, San Francisco),4-6 an anti-VEGF colorectal cancer drug, to treat AMD. In addition to these approved therapies, VEGF-Trap (Regeneron Pharmaceuticals, Tarrytown, NY), bevasirinab (formerly Cand5; Acuity Pharmaceuticals, Philadelphia), Sirna-027 (Sirna Therapeutics, Boulder, CO), and anecortave acetate (Retaane; Alcon Laboratories, Fort Worth) are in clinical trials in the United States. Anecortave acetate has gained regulatory approval in Australia and will launch in several more countries in the coming months. These treatments have been or are currently being tested as a monotherapy, however, combining some of these drugs may improve outcomes.

ARE WE THERE YET?
Although modern AMD treatment has advanced significantly, it has not yet progressed sufficiently to meet the needs of all patients. There remain a large number of neovascular AMD sufferers who do not respond to current therapies. For example, VEGF appears to be vital during the development and maturation of CNV; however, its role in mature vessels is less vital, and anti-VEGF agents may not be effective in patients at this stage of disease. This may be one reason why even ranibizumab significantly improves vision in less than half the patients treated.

Results from the Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) study demonstrate that verteporfin PDT helps maintain vision in neovascular AMD patients (Figure 2), however, PDT monotherapy resulted in a decline in visual acuity of 1.5 lines at 24 months and 1.6 lines at 60 months from baseline7 (Figure 3). Similarly, in a study investigating four doses (ie, 0.3 mg, 1.0 mg, 3.0 mg, and sham) of pegaptanib, 1,186 patients were injected intravitreously every 6 weeks for 48 weeks.3 After 54 weeks, 70% of patients who received 0.3 mg pegaptanib lost <15 letters, compared to 55% among the control group, but again a significant number of patients were unresponsive to treatment and lost vision during the course of the study. Lucentis has shown the best results to date, with a mean improvement in vision after 24 months in the Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA) study and most patients having stable vision.8 This required monthly injections for 24 months, however. Additional studies need to be performed to see if similar results can be obtained with a reduced dosing scheme.

COMBINATION THERAPY
Given the well-described multifactorial nature of ocular angiogenesis, combination therapy appears to be a promising strategy for more effective management of neovascular AMD. Recently, combinations of drugs have been used to maximize the strengths and minimize the weakness of individual medications. In the last several years, for example, PDT is often considered in conjunction with intravitreal triamcinolone to reduce the post-PDT inflammation in the retinal tissues. Case series have shown promising results, and the randomized Verteporfin Intravitreal Triamcinolone Acetonide (Kenalog, Bristol Meyers Squibb) Study (VERITAS) is currently exploring this treatment as well as PDT combined with pegaptanib. A study using combination treatment of PDT and ranibizumab showed very promising results while dramatically reducing the number of PDT treatments required (Figures 3 and 4).9

Unfortunately, the study did not explore whether the number of ranibizumab injections could also be decreased with combination therapy. This theory will be tested in the VERITAS 2 study that will be starting shortly. Many physicians have already begun exploring other multifactorial approaches to AMD treatment with anti-VEGF drugs. For example, combining steroids with anti-VEGF agents or even different anti-VEGF agents have all been proposed.10

Another interesting possibility for combination treatment is anecortave acetate, a modified steroid derivative. Anecortave acetate is delivered via a noninvasive posterior juxascleral depot (PJD) in contact with the posterior scleral surface and has not been associated with any serious complications after thousands of injections worldwide. Several studies have shown that, similar to the anti-VEGF agents, anecortave acetate can help preserve vision in neovascular AMD patients, however, the true value of the drug is likely in combination via attenuating multiple angiogenic stimuli over a longer treatment period.11

Because anecortave acetate and anti-VEGF drugs have different, but not mutually exclusive mechanisms of action that affect different stages in the angiogenic cascade and have different treatment schedules (Table 1), they may work very well together. A multistep combination approach, for example, using ranibizumab to acutely improve the leakage and neovascularization, and anecortave acetate to chronically prevent recurrence of the CNV may potentially reduce the frequent need for Lucentis injections while maintaining the good visual outcomes. This theory is being evaluated in the National Eye Institute’s BRIDGE study.

Patients with neovascular AMD currently have a better prognosis than they have had in years; however, we need to continue to advocate for innovative combination therapy such as PDT, ranibizumab, and anecortave acetate, as a way to enhance the long-term efficacy and safety of each therapeutic regimen, with hopefully even better visual outcomes.

Peter K. Kaiser, MD, is in the Vitreoretinal Department at the Cole Eye Institute, Cleveland Clinic. Dr. Kaiser disclosed that The Cole Eye Institute has received research grant support from Alcon Laboratories, Allergan, Eyetech Pharmaceuticals, Genentech, Regeneron, Novartis, QLT and Sirna Therapeutics. Dr. Kaiser disclosed that he is a member of the scientific advisory boards and/or a consultant for Alcon, Allergan, Novartis, and TargeGen. He is a member of the Retina Today Editorial Board. Dr. Kaiser may be reached at pkkaiser@aol.com or 216-444-6702.

1. FDA Approves LUCENTIS for the Treatment of Wet Age-Related Macular Degeneration. Available at http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=9787&categoryid=4. Accessed May 18, 2007.
2. Pfizer Global Research and Development. Available at http://www.pfizer.com/pfizer/lajolla/index.jsp. Accessed May 18, 2007.
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10. Augustin AJ, Puls S, Offermann I.Triple therapy for choroidal neovascularization due to age-related macular degeneration: verteporfin PDT, bevacizumab, and dexamethasone. Retina. 2007;27:133-140.
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