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      Aflibercept for the Treatment of Age-Related Macular Degeneration

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          Abstract

          Aflibercept is a novel, recombinant, fusion protein that consists of portions of vascular endothelial growth factor (VEGF) receptor (R) 1 and VEGFR2 extracellular domains fused to the Fc portion of human immunoglobulin G1. It exhibits higher affinity for VEGF-A/-B and binds all the VEGF isoforms (VEGF-B and -C, placental growth factor). The efficacy of aflibercept was assessed in two randomized, double-masked, multicenter, active-controlled, clinical trials in patients with choroidal neovascularization due to exudative age-related macular degeneration (AMD) and compared it’s efficacy to ranibizumab, which is already Food and Drug Administration (FDA)-approved for patients with wet AMD. In the two trials known as VIEW 1 and VIEW 2, aflibercept was as effective when dosed as 2 mg every 8 weeks after 3 monthly loading doses compared to monthly ranibizumab. Aflibercept was well tolerated with very rare systemic adverse events, including arterial thromboembolic events (ATEs). The incidence of ATEs was 1.8% during the first year of the clinical trials and included non-fatal strokes, non-fatal myocardial infarction, or death from vascular events or an unknown cause. In November 2011, aflibercept received FDA approval and is currently used in clinical practice for patients with wet AMD.

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          Most cited references33

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          Ranibizumab and bevacizumab for neovascular age-related macular degeneration.

          Clinical trials have established the efficacy of ranibizumab for the treatment of neovascular age-related macular degeneration (AMD). In addition, bevacizumab is used off-label to treat AMD, despite the absence of similar supporting data. In a multicenter, single-blind, noninferiority trial, we randomly assigned 1208 patients with neovascular AMD to receive intravitreal injections of ranibizumab or bevacizumab on either a monthly schedule or as needed with monthly evaluation. The primary outcome was the mean change in visual acuity at 1 year, with a noninferiority limit of 5 letters on the eye chart. Bevacizumab administered monthly was equivalent to ranibizumab administered monthly, with 8.0 and 8.5 letters gained, respectively. Bevacizumab administered as needed was equivalent to ranibizumab as needed, with 5.9 and 6.8 letters gained, respectively. Ranibizumab as needed was equivalent to monthly ranibizumab, although the comparison between bevacizumab as needed and monthly bevacizumab was inconclusive. The mean decrease in central retinal thickness was greater in the ranibizumab-monthly group (196 μm) than in the other groups (152 to 168 μm, P=0.03 by analysis of variance). Rates of death, myocardial infarction, and stroke were similar for patients receiving either bevacizumab or ranibizumab (P>0.20). The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with bevacizumab than with ranibizumab (24.1% vs. 19.0%; risk ratio, 1.29; 95% confidence interval, 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern. At 1 year, bevacizumab and ranibizumab had equivalent effects on visual acuity when administered according to the same schedule. Ranibizumab given as needed with monthly evaluation had effects on vision that were equivalent to those of ranibizumab administered monthly. Differences in rates of serious adverse events require further study. (Funded by the National Eye Institute; ClinicalTrials.gov number, NCT00593450.).
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            Prevalence of age-related macular degeneration in the United States.

            To estimate the prevalence and distribution of age-related macular degeneration (AMD) in the United States by age, race/ethnicity, and gender. Summary prevalence estimates of drusen 125 microm or larger, neovascular AMD, and geographic atrophy were prepared separately for black and white persons in 5-year age intervals starting at 40 years. The estimated rates were based on a meta-analysis of recent population-based studies in the United States, Australia, and Europe. These rates were applied to 2000 US Census data and to projected US population figures for 2020 to estimate the number of the US population with drusen and AMD. The overall prevalence of neovascular AMD and/or geographic atrophy in the US population 40 years and older is estimated to be 1.47% (95% confidence interval, 1.38%-1.55%), with 1.75 million citizens having AMD. The prevalence of AMD increased dramatically with age, with more than 15% of the white women older than 80 years having neovascular AMD and/or geographic atrophy. More than 7 million individuals had drusen measuring 125 microm or larger and were, therefore, at substantial risk of developing AMD. Owing to the rapidly aging population, the number of persons having AMD will increase by 50% to 2.95 million in 2020. Age-related macular degeneration was far more prevalent among white than among black persons. Age-related macular degeneration affects more than 1.75 million individuals in the United States. Owing to the rapid aging of the US population, this number will increase to almost 3 million by 2020.
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              An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration.

              To evaluate an optical coherence tomography (OCT)-guided, variable-dosing regimen with intravitreal ranibizumab for the treatment of patients with neovascular age-related macular degeneration (AMD). Open-label, prospective, single-center, nonrandomized, investigator-sponsored clinical study. In this two-year study, neovascular AMD patients with subfoveal choroidal neovascularization (CNV) (n = 40) and a central retinal thickness of at least 300 microm as measured by OCT were enrolled to receive three consecutive monthly intravitreal injections of ranibizumab (0.5 mg). Thereafter, retreatment with ranibizumab was performed if one of the following changes was observed between visits: a loss of five letters in conjunction with fluid in the macula as detected by OCT, an increase in OCT central retinal thickness of at least 100 microm, new-onset classic CNV, new macular hemorrhage, or persistent macular fluid detected by OCT at least one month after the previous injection of ranibizumab. At month 12, the mean visual acuity improved by 9.3 letters (P < .001) and the mean OCT central retinal thickness decreased by 178 microm (P < .001). Visual acuity improved 15 or more letters in 35% of patients. These visual acuity and OCT outcomes were achieved with an average of 5.6 injections over 12 months. After a fluid-free macula was achieved, the mean injection-free interval was 4.5 months before another reinjection was necessary. This OCT-guided, variable-dosing regimen with ranibizumab resulted in visual acuity outcomes similar to the Phase III clinical studies, but required fewer intravitreal injections. OCT appears useful for determining when retreatment with ranibizumab is necessary.
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                Author and article information

                Contributors
                pkkaiser@gmail.com
                Journal
                Ophthalmol Ther
                Ophthalmol Ther
                Ophthalmology and Therapy
                Springer Healthcare (Heidelberg )
                2193-8245
                2193-6528
                25 June 2013
                25 June 2013
                December 2013
                : 2
                : 2
                : 89-98
                Affiliations
                Cole Eye Institute, Cleveland Clinic, 9500 Euclid Avenue, Desk i13, Cleveland, OH 44145 USA
                Article
                15
                10.1007/s40123-013-0015-2
                4108145
                25135809
                e6918576-3722-4752-a8fe-89749d45b1b5
                © The Author(s) 2013
                History
                : 13 May 2013
                Categories
                Review
                Custom metadata
                © Springer Healthcare 2013

                aflibercept,age-related macular degeneration,angiogenesis,choroidal neovascularization,fusion proteins,vascular endothelial growth factor

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