Aflibercept – How does it compare with other Anti-VEGF Drugs?

Research Article

Austin J Clin Ophthalmol. 2014;1(3): 1016.

Aflibercept – How does it compare with other Anti–VEGF Drugs?

Yog Raj Sharma*, Koushik Tripathy, Pradeep Venkatesh and Varun Gogia

Department of Ophthalmology, All India Institute of Medical Sciences, India

*Corresponding author: Yog Raj Sharma, Department of Ophthalmology, All India Institute of Medical Sciences, New Delhi, India

Received: February 14, 2014; Accepted: March 12, 2014; Published: March 21, 2014


Aflibercept is the newest approved anti–VEGF drug for intraocular use. This chimeric protein targets vascular endothelial growth factors: VEGF–A, VEGF–B and placental growth factor (PlGF). In this article, we review the available literature regarding this drugs ocular use in clinicians perspective. Aflibercept has higher affinity, less frequent dosing, equivalent cost of therapy, non–inferiority to ranibizumab in efficacy and safety. It is effective in choroidal neovascular membrane, macular edema following venous occlusion, retinal pigment epithelial detachment or diabetic macular edema that is recurrent or resistant to ranibizumab. It penetrates all retinal layers and does not induce apoptosis. Thus it promises to be a useful addition to anti–VEGF therapies already available for managing an array of retinal disorders.

Keywords: Aflibercept; VEGF–trap Eye; Eylea; ARMD; Ranibizumab; Bevacizumab; VEGF; Anti–VEGF; Diabetic Macular Edema; Macular edema following venous occlusion.


For people older than 50 years, age related macular degeneration (AMD) causes approximately 46% of cases of severe visual loss (visual acuity 20⁄200 or worse) in United States [1]. Neovascular or wet AMD (wAMD) is responsible for almost 90% of severe vision loss due to AMD [2]. AMD causes 5% of Global blindness [3]. Pegaptanib (Macugen®, EyetechInc, Florida, USA) was the first anti–VEGF drug approved by food and drug administration (FDA, USA) for subfoveal choroidal neovascular membrane (CNVM) due to wAMD in 2004 [4]. Now, anti–VEGF drugs have become gold standard treatment for CNVM due to AMD. Currently there are 4 drugs in this categoryaptamer (Pegaptanib), monoclonal antibodies (Ranibizumab or Lucentis®, GenentecInc, San Francisco, USA and bevacizumabor Avastin®, Genentech, USA, off label use) and chimeric protein (Aflibercept®, VEGF–trap eye, Eylea, Regeneron Pharmaceuticals, NY, USA).

The Vascular endothelial growth factor (VEGF): chronological perspective

In 1948, Isaac Michaelson was the first to postulate that a diffusible factor produced by the retina (“factor X”) was responsible for retinal and iris neovascularization associated with conditions such as proliferative diabetic retinopathy and central retinal vein occlusion [5]. In 1983, Senger and Galli et al., [6]. Identified a protein that could induce vascular leakage in skin. They named this protein “tumor vascular permeability factor” or VPF. In 1989, Ferrara and Henzel [7] isolated a diffusible protein from bovine pituitary follicular cells that showed cell specific mitogenic activity for vascular endothelium. They named this protein vascular endothelial growth factor (VEGF). VPF and VEGF seemed to have the similar molecular structure. VEGF is produced by the retinal pigment epithelial cells (RPE), all types of neurons, glia, pericytes, macrophage, smooth muscle cells, T cells and endothelial cells of the retina in response to hypoxia through hypoxia–inducible factor 1 (HIF–1), which is a basic helix–loop–helix transcription factor and inflammatory stimuli [8]. The VPF⁄VEGF [now called VEGF–A, to differentiate from other related genes: VEGF–B, VEGF–C, VEGF–D, and PlGF (placental growth factor)] gene is at chromosome 6p21.3. VEGF–A is a key regulator of blood vessel growth [9]. VEGF–B is a ‘survival factor’ for blood vessels and neurons [9]. VEGF–C and VEGF–D regulate lymphangiogenesis [9,11]. Alternative splicing of VEGF–A gives rise to at least 6 different protein isoforms –121, 145, 165, 183, 189, and 206 amino acids in length [12]. The larger isoforms (VEGF–189 and VEGF–206) bind heparin with high affinity and are sequestered in the extracellular matrix. The smaller isoform, VEGF– 121, does not bind heparin and is freely diffusible. VEGF–165 has both bioavailability and biologic potency. VEGF–165 is the predominant isoform and the primary mediator of neovascularization in the eye [13]. All VEGF isoforms contain a plasmin cleavage site. Cleavage at this site creates a freely–diffusible, 110–kD, bioactive form of VEGF (VEGF–110). VEGF has 3 receptor tyrosine kinases: VEGFR–1, VEGFR–2 (Figure 1), and VEGFR–3. VEGFR–1 (Flt–1) the first discovered & highest affinity receptor of the three, functions to act during embryonic development as a “decoy” by sequestering VEGF, thereby preventing the activation of VEGFR–2 [13]. VEGFR–1 also plays a key role in pathological ocular neovascularization through mediating monocyte chemotaxis to VEGF. VEGFR–2 (Flk–1 or KDR) is the primary mediator of the pathologic effects of VEGF in the eye [12]. VEGFR–3 helps lymphangiogenesis [14]. All three receptors are necessary for proper mammalian development. Mice with null mutations for any of the receptors die in utero between days 8.5 and 9.5 [15]. VEGFR–2 knock–out models also suggest the possible role of VEGF in hematopoiesis [16]. VEGF is pro–angiogenic. It stimulates endothelial cell proliferation (mitogenic), invasion, migration, and enhancement of cell survival [9].