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Retina/Vitreous Age-related Macular Degeneration Aflibercept as a Treatment for Age-related Macular Degeneration Michael W Stewart, MD Associate Professor and Chairman, Department of Ophthalmology, Mayo Clinic, Florida, US. Abstract Vascular endothelial growth factor (VEGF) plays a central role in the development of several chorioretinal vascular disorders including exuda- tive age-related macular degeneration (AMD). Detailed understanding of VEGF biochemistry has led to the development of four drugs which specifically inhibit its actions. Bevacizumab and ranibizumab have been the dominant ophthalmic anti-VEGF drugs for seven years and their regular use has significantly decreased vision loss. In late 2011, aflibercept, a high-affinity, fusion protein that acts as a soluble VEGF receptor, was approved for the treatment of exudative AMD. Phase three trials showed that monthly and bimonthly aflibercept maintained vision in 95 % of patients, improved average visual acuity by +8.3 to +9.4 letters, and thinned the macula comparably to monthly ranibizumab. Since its approval, aflibercept has been shown to decrease retinal edema and subretinal fluid, and flatten retinal pigment epithelial detachments in eyes that have responded incompletely to frequent ranibizumab and bevacizumab injections. Aflibercept’s longer duration of action coupled with its comparable unit price (versus ranibizumab) promise to decrease the total cost of treatment. Keywords Aflibercept, age-related macular degeneration, choroidal neovascularization, vascular endothelial growth factor (VEGF), VEGF Trap, VEGF Trap-eye Disclosure: Professor Stewart is part of the research support and advisory board for Regeneron, advisory board for Alleragan and a consultant for Boehringer-Ingelheim Received: December 10 2012 Accepted: January 10, 2013 Citation: US Ophthalmic Review, 2013;6(1):58–63 Correspondence: Michael W Stewart, MD, Department of Ophthalmology, 4500 San Pablo Rd., Jacksonville, FL 32224, US. E: Age-related macular degeneration (AMD) has been a leading cause of blindness in developed nations for several decades. 1 Most patients with AMD have only minor visual disturbances due to dry or non-exudative AMD (drusen and retinal pigment epithelium (RPE) mottling or hyperplasia), however, approximately 10 % of AMD patients develop severe vision loss due to wet or exudative AMD. 2 Choroidal neovascular membranes (CNVM) grow from the choriocapillaris and extend beneath the RPE (type one CNVM) or retina (type two CNVM), or infiltrate the neurosensory retina as retinal angiomatous proliferation (type three CNVM). Constant exudation, repeated hemorrhage, and progressive fibrovascular growth result in photoreceptor damage and disciform scarring. Previous treatments— laser photocoagulation and ocular photodynamic therapy—sometimes arrested neovascular growth but only infrequently resulted in improved vision (see Figure 1). 3,4 Effective treatment for exudative AMD derived from what at first appeared to be an unlikely source - cancer research. Folkman (1971) 5 first proposed that tumor growth depended on a soluble angiogenesis factor and Senger (1983) 6 subsequently discovered the vasopermeability factor. Finally, two independent research groups isolated identical cytokines which became known as vascular endothelial growth factor (VEGF). 7,8 This discovery kicked off two decades of intense research into the biochemistry of the VEGF families and resulted in the development of four drugs which specifically bind VEGF to prevent it from activating three trans-membrane receptors (VEGFRs). Pegaptanib (Macugen®, Ophthotech, Palm Beach Gardens, FL), an aptamer to VEGF 165 , slows vision loss by approximately 50  % when administered to patients suffering from exudative AMD, 9 however, only the pan-VEGF-A binding drugs bevacizumab (Avastin®, Genentech, S. San Francisco, CA/ 58 Novartis, Basil, Switzerland) and ranibizumab (Lucentis®, Genentech, S. San Francisco, CA/Novartis, Basil, Switzerland) were able to stabilize vision in nearly all patients (91–94 %) and improve vision in the majority. 10–14 Both drugs possess high binding affinities to all naturally occurring isoforms of VEGF-A (bevacizumab: K D =58–1,1000 pM to VEGF 165 ; ranibizumab: K D =46– 192 pM to VEGF 165 ) 15–17 as well as the cleaved product VEGF 110 . Aflibercept Development Bevacizumab and ranibizumab are full-length antibody and antibody fragments, respectively, both of which were produced from a murine model. The scientists who created the VEGF Trap-eye or aflibercept (Eylea®, Regeneron, Tarrytown, NY), however, decided to employ a different binding strategy to neutralize diffusible VEGF—they created a soluble receptor molecule. Naturally occurring binding domains from native VEGF receptors were fused to the Fc (fragment crystallizable) backbone of a human IgG molecule. 18 The first or ‘parent’ VEGF-Trap (VEGF-Trap R1R1R1 ) contained the first three VEGF-binding domains from VEGF receptor one (VEGF R1 ). Since VEGFR1 has a higher binding affinity for VEGF 165 than has VEGF R2 , this strategy was expected to create the molecule with the highest VEGF binding affinity. Though the resultant trap had a high binding affinity to VEGF 165 (K D =5 pM), it exhibited unfavorable in vivo pharmacokinetic behavior because its basic amino acid sequences resulted in rapid sequestration within the intercellular matrix. Subsequent molecules (VEGF-Trap ΔB1 and VEGF-Trap ΔB2 ) had better pharmacokinetic properties than the parent trap and the fourth and final molecule, which contained the second binding domain from VEGFR1 and the third binding domain from VEGFR2 (VEGF-Trap R1R2 ), exhibited minimal binding to the matrix. Furthermore, a three-dimensional stoichiometric analysis suggests © Touc h ME dical MEdia 2013