Aflibercept (VEGF Trap-eye): the newest anti-VEGF drug

The introduction of anti-vascular endothelial growth factor (anti-VEGF) drugs to ophthalmology over the past 7 years has revolutionised the treatment of exudative age-related macular degeneration (AMD) and holds great promise for diabetic macular oedema, branch and central retinal vein occlusions, and retinopathy of prematurity. Each of the three available drugs (pegaptanib, bevacizumab and ranibizumab) was eagerly embraced by surgeons, but the subsequent clinical results have been mixed, and the regulatory hurdles, particularly those regarding off-label use of bevacizumab, have been challenging. Into this mix enters aflibercept (VEGF Trap-eye (VTE); Eylea, Regeneron, Tarrytown, New York, USA), for which the US Food and Drug Administration granted approval for the treatment of subfoveal choroidal neovascularisation due to AMD on 18 November 2011. In contrast to the antibody-based VEGF binding strategy used by ranibizumab and bevacizumab, the VTE incorporates the second binding domain of the VEGFR-1 receptor and the third domain of the VEGFR-2 receptor. By fusing these extracellular protein sequences to the Fc segment of a human IgG backbone, in a manner similar to the rheumatoid arthritis drug etanercept, developers have created a chimeric protein with a very high VEGF binding affinity (Kdz1 pM). Like ranibizumab and bevacizumab, the VTE binds all isomers of the VEGF-A family, and although the clinical significance of this is not yet known, it also binds VEGF-B and placental growth factor. The approval application draws on the strengths of two concurrent AMD trials: the VIEW 1 trial, which enrolled 1217 patients in North American centres, and the VIEW 2 trial, which enrolled 1240 patients in South American, European, Asian and Australian centres. Each trial randomised patients among four treatment arms: monthly 0.5 mg VTE, monthly or bimonthly 2 mg VTE, and monthly 0.5 mg ranibizumab. All VTE investigational arms reached the primary endpointdnon-inferiority for maintenance of vision (#15 letters of vision loss) compared to ranibizumab (94% for ranibizumab arms and 95% to 96% for all VTE arms). Physicians will naturally question what advantage, if any, the VTE brings to our treatment of chorioretinal vascular diseases. Though many factors determine drug selection, most retina surgeons will ask three important questions. What is the peak effect of the drug (usually measured by letters of improvement)? What is the duration of action (usually determined by the frequency of drug administration)? Is the drug safe (usually determined by systemic adverse events)? Since pegaptanib use is infrequent, the VTE enters a clinical environment dominated by the two closely related antibody-based drugs, bevacizumab and ranibizumab. The clinical superiority of ranibizumab over both observation and photodynamic therapy was well documented in both the MARINA (7.2 letters vs 10.4 letters) and ANCHOR (11.3 letters vs 9.5 letters) studies, thus establishing ranibizumab as the standard against which all subsequent drugs are compared. Due in part to its off-label use in ophthalmology, bevacizumab has never been subjected to comparable controlled trials, but the recently reported Comparison of Age-related Macular Degeneration Treatment Trials demonstrated its near equivalency to ranibizumab with monthly dosing (8.0 letters vs 8.5 letters) and nonsignificantly poorer outcomes with as needed dosing (5.9 letters vs 6.8 letters). Most physicians, therefore, now believe the two drugs to be clinically equivalent. Several lines of evidence suggest that the VTE is an effective neutraliser of VEGF. The receptor sequences of the VTE provide powerful VEGF binding (140 times that of ranibizumab) and the molecule’s intermediate size 110 kD (compared to 48 kD for ranibizumab and 148 kD for bevacizumab) create a 1 month intravitreal binding activity that exceeds both ranibizumab and bevacizumab. Treatment of neuroblastoma xenografts in mice, with drugs similar to those used in AMD, showed the following comparative efficacies: VEGF Trap >anti-VEGF monoclonal antibody >aptamer to VEGF165. The most important comparison, however, comes directly from the VIEW trials, where the data for the highest dose of VTE (2 mg monthly) are mixed when compared to ranibizumab. The VIEW 1 trial showed that monthly injections of 2 mg VTE led to greater vision gains than ranibizumab (10.9 letters vs 8.1 letters; p<0.05) whereas no statistically significant difference was seen in the VIEW 2 trial (7.6 letters vs 9.4 letters (p$0.05). Since the two trials were comparably sized and followed identical protocols, the reason for this difference in vision improvement is unknown. Since the trials were performed in different parts of the world racial and ethnic differences existed between the two cohortsdpredominantly Caucasian patients in VIEW 1 but higher percentages of Hispanic and Asian patients in VIEW 2. The prevalence of choroidal neovascular membrane types differ among races, with idiopathic polypoidal choroidopathy more common in Asian patients. Compared to types 1 and 2 choroidal neovascular membranes, polypoidal choroidopathy does not respond as well to anti-VEGF therapy, thereby leading many physicians to recommend photodynamic therapy for these lesions. However, since inclusion criteria for the VIEW trials were based on the results of fluorescein angiography but not indocyanine green angiography, lesions may have been mischaracterised and inadequately treated. A comparative subanalysis of the data will be required to address this difference. An analysis of pooled data from the two trials showed that the patients receiving 2 mg VTE every 8 weeks achieved comparable improvements in vision, suggesting that VTE and ranibizumab have comparable peak efficacies. Since the completion of the MARINA and ANCHOR studies, physicians have searched for effective dosing regimens that do not require monthly drug injections or examinations. Efforts to stretch the ranibizumab dosing interval to 3 months (PIER) resulted in forfeiting previous vision gains. The Comparison of Agerelated Macular Degeneration Treatment Trials showed that the letters gained with as needed injections were not statistically inferior to monthly injections (ranibizumab: 6.8 vs 8.5; bevacizumab: 5.9 vs Correspondence to Michael W Stewart, Associate Professor and Chairman, Department of Ophthalmology, Mayo Clinic Florida, 4500 San Pablo Rd., Jacksonville, FL 32224, USA; [email protected] Editorial