Clinical and differential utility of VEGF inhibitors in wet age-related macular degeneration: focus on aflibercept

Abstract

Age-related macular degeneration (AMD) has become a major public health problem and a leading cause of blindness in industrialized nations. AMD results from the ageing eye's inability to metabolize and dispose completely of photoreceptor outer segments and other waste products. As a result, lipids, particularly apolipoproteins, accumulate within Bruch's membrane, leading to chronic ischemia and inflammation. The subsequent upregulation of inflammatory cytokines and growth factors, including vascular endothelial growth factor (VEGF), induces the growth of neovascular membranes from the choriocapillaris into the subretinal or subretinal pigment epithelium spaces. To counter this, intravitreally administered drugs (pegaptanib, bevacizumab, ranibizumab) that specifically target VEGF have become the standard treatment for exudative AMD. Aflibercept, a recently approved fusion protein, binds to all isoforms of both VEGF-A and placental growth factor with high affinity. Phase III trials showed that monthly or every other month injections of aflibercept prevent vision loss (fewer than 15 letters) in 95% of patients. Additionally, aflibercept injections every 4 or 8 weeks produce average vision gains of 6.9 letters to 10.9 letters, comparable with those achieved with monthly ranibizumab. After one year of regularly administered aflibercept injections, patients required an average of only 4.2 injections during the second year. Aflibercept promises to decrease the injection frequency required for many patients and appears to serve as an effective "salvage" therapy for patients who respond poorly to other anti-VEGF drugs.

Keywords: VEGF trap; aflibercept; age-related macular degeneration; bevacizumab; choroidal neovascularization; ranibizumab; vascular endothelial growth factor.

Figure 1

Left panel: carotenoids, vitamin E and cholesterol are delivered to the retinal pigment epithelium from the choriocapillaris. After initial processing within the retinal pigment epithelium, these molecules are presented to the photoreceptors. Central panel: continuous shedding of photoreceptor outer segments results in high levels of cholesterol and other lipids within the retinal pigment epithelium which, because of decreasing peroxisome activity with advancing age, are only partially metabolized. These are secreted toward the choriocapillaris, but some, particularly apolipoprotein B, accumulate within Bruch’s membrane. Right panel: lipid accumulation within Bruch’s membrane induces inflammation and ischemia, resulting in neovascular sprouting from the choriocapillaris. Abbreviations: ApoB, apolipoprotein-B, LDL-R, receptor-bound low density lipoprotein, LHP, linoleate hydroperoxide.

Figure 2

Sequential optical coherence tomography scans of patient’s right eye show worsening subretinal fluid and an expanding retinal pigment epithelial detachment despite 6-monthly injections of bevacizumab (A) and (B). After one injection of aflibercept 2 mg, the subretinal fluid had decreased (C), and after the second injection of aflibercept, the subretinal fluid had resolved and the retinal pigment epithelial detachment had completely flattened (D).