Aflibercept for the treatment of neovascular age-related macular degeneration

Age-related macular degeneration (AMD) can have devastating effects on vision, especially in its neovascular form. In the last decade, the use of intravitreal pharmacotherapy targeted to vascular endothelial growth factor (VEGF) has significantly improved the visual outcomes in patients with neovascular AMD. Although we have become accustomed to these unprecedented improvement outcomes, maintaining good visual results with anti-VEGF therapy requires tremendous effort, time and cost, typically involving monthly clinic visits and intravitreal injections. The introduction of aflibercept, an anti-VEGF drug that targets all isoforms of VEGF as well as placenta growth factor, has shown promise throughout recent clinical trials as an equally effective treatment for neovascular AMD that requires less frequent dosing than either ranibizumab or bevacizumab. Based on clinical trial results, the U.S. Food and Drug Administration approved aflibercept in November 2011 for use in neovascular AMD, giving patients the hope of alleviating some of the burden associated with treatment.     

Neovascular age-related macular degeneration: potential therapies

Age-related macular degeneration (AMD) affects an estimated 14 million people worldwide, and is the leading cause of severe, irreversible vision loss in individuals over the age of 50 years in Western societies. Choroidal neovascularization (CNV), the hallmark of 'wet', 'exudative' or 'neovascular' AMD, is responsible for approximately 90% of cases of severe vision loss due to AMD. Vascular endothelial growth factor (VEGF) has been shown to play a key role in the regulation of CNV and vascular permeability. Ranibizumab, the current gold standard in the US for the treatment of neovascular AMD, exerts its effect through binding and inhibition of all isoforms of VEGF. Randomized controlled clinical trials have established ranibizumab as the first US FDA-approved therapy for neovascular AMD to result in improvement in visual acuity. Despite impressive outcomes, treatment with ranibizumab requires sustained treatment regimens and frequent intravitreal injections. In this review, we discuss promising emerging therapies for neovascular AMD that aim to improve outcomes, safety and treatment burden through novel mechanisms of action. Currently in phase III clinical trials, VEGF Trap is a receptor decoy that targets VEGF with higher affinity than ranibizumab and other currently available anti-VEGF agents. Another promising therapeutic strategy is the blockade of VEGF effects by inhibition of the tyrosine kinase cascade downstream from the VEGF receptor; such therapies currently in development include vatalanib, TG100801, pazopanib, AG013958 and AL39324. Small interfering RNA technology-based therapies have been designed to downregulate the production of VEGF (bevasiranib) or VEGF receptors (AGN211745) by degradation of specific messenger RNA. Other potential therapies include pigment epithelium-derived factor-based therapies, nicotinic acetylcholine receptor antagonists, integrin antagonists and sirolimus.     

VEGF Trap-Eye for the treatment of neovascular age-related macular degeneration

Background: Age-related macular degeneration (AMD) affects > 14 million individuals worldwide. Although 90% of patients with AMD have the dry form, neovascular AMD accounts for the vast majority of patients who develop legal blindness. Until recently, few treatment options existed for treatment of neovascular AMD. The advent of anti-VEGF therapy has significantly improved the safe and effective treatment of neovascular AMD. In addition to two anti-VEGF drugs currently in widespread use, ranibizumab and bevacizumab, a number of medications that interrupt angiogenesis are currently under investigation. One promising new drug is aflibercept (VEGF Trap-Eye), a fusion protein that blocks all isoforms of VEGF-A and placental growth factors-1 and -2. Objective: To review the current literature and clinical trial data regarding VEGF Trap-Eye for the treatment of neovascular AMD. Methods: Literature review. Results/conclusion: VEGF Trap-Eye is a novel anti-VEGF therapy, with Phase I and II trial data indicating safety, tolerability and efficacy for the treatment of neovascular AMD. Two Phase III clinical trials (VIEW-1 and VIEW-2) comparing VEGF Trap-Eye to ranibizumab are currently continuing and will provide vital insight into the clinical applicability of this drug.     

Targeting vascular endothelial growth factor: a promising strategy for treating age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in the industrialised world. While treatment options for advanced AMD have been rather limited until recently, the introduction of intravitreal injections of anti-angiogenic agents appears to be a promising and revolutionary mode of treatment for this blinding disease. Vascular endothelial growth factor (VEGF) appears to play a pivotal role in the pathogenesis of choroidal neovascularisation, one of the cornerstones of advanced AMD. Pegaptanib, the first anti-VEGF treatment approved for AMD patients, is a VEGF-neutralising aptamer that specifically inhibits one isoform of VEGF (VEGF-165). Although evidence suggested that pegaptanib was superior to previous treatment options, results with this agent were still unsatisfactory. Ranibizumab is a humanised anti-VEGF monoclonal antibody fragment that inhibits all isotypes of VEGF. This new drug has demonstrated a high efficacy profile in terms of inhibiting disease progression and even improving visual acuity. Bevacizumab is a full-length anti-VEGF antibody that was originally approved for use in metastatic colon cancer and is under investigation as a low-cost off-label alternative for patients with AMD. There is growing evidence that this drug may be an effective and safe alternative to the more expensive ranibizumab, although prospective multicentre trials are required to fully investigate this issue. Undoubtedly, the concept of directly injecting anti-VEGF drugs into the vitreal cavity brings new hope to many AMD patients.     

雷珠单抗的大肠埃希菌胞外分泌表达、纯化及结构表征

抗血管内皮细胞生长因子(VEGF)抗体可抑制新生血管的形成和生长,在年龄相关性黄斑变性眼科疾病的临床治疗中具有重要应用价值,特别是已上市的商品名为雷珠单抗的VEGF抗体Fab片段,在市场上取得巨大成功。本研究探索了雷珠单抗在大肠埃希菌中的胞外分泌表达技术,所表达的产品利用SDS-PAGE、Western Blot、肽谱图全序列分析和纳米差示扫描量热法(Nano DSC)等手段进行了初步的结构表征。结果显示,本研究成功实现了雷珠单抗的大肠埃希菌胞外分泌表达,经过进一步的Capto L亲和色谱获得了有正确氨基酸序列的Fab产品,经质谱分析具有正确的二硫键配对,且具有与标准品相似的热稳定性,为其进一步的工业生产奠定了基础。     

Systemic adverse drug reactions secondary to anti-VEGF intravitreal injection in patients with neovascular age-related macular degeneration

The wet form of age related macular degeneration (AMD), known also as exudative or neovascular, is characterized by the formation of a pathological choroidal neovascular membrane (CNV) responsible for most cases of severe blindness. Vascular endothelial growth factor (VEGF) is a homodimeric glycoprotein acting as a growth factor selective for endothelial cells; it regulates angiogenesis and enhances vascular permeability and plays a leading role in this disorder. The consistent association between CNV and increased VEGF-A expression provides a strong reason for exploring the therapeutic potential of anti-VEGF agents in the treatment of neovascular AMD. The importance of VEGF for the development of AMD-related CNV has led to the development of a strategy able to block its pathologic effects. The rationale is that a blockade of VEGF actions could be effective in arresting choroidal angiogenesis and also reducing the vascular permeability, which is frequently the main cause of visual acuity deterioration. However, VEGF has also important functions in vascular physiology. The effects of anti-VEGF therapy may inhibit these functions. Herein we report the systemic adverse events secondary to intravitreal administration of these compounds i.e. the main cardiovascular effects (thrombosis, hemorrhage, hypertension, proteinuria), as well as the less frequent cerebrovascular accidents, myocardial infarction, transient ischemic attacks, deep vein thrombosis, pulmonary embolism and thrombophlebitis.     

Anti-angiogenesis drugs in diabetic retinopathy

The vascular endothelial growth factor (VEGF) plays a key role in the development of proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME), resulting in a significant visual loss among patients with diabetes mellitus. Systemic VEGF-A and the interplay between membrane-bound VEGF receptors and VEGF-R1 (soluble form) are key to angiogenesis and vasculogenesis. Furthermore, patients with diabetes have a higher risk of hypertension and proteinuria, two surrogate markers of systemic VEGF inhibition. Pegaptanib, ranibizumab, bevacizumab and roboxistaurin are the currently available anti-VEGF agents. Agents with activity occurring later down the angiogenic pathway and those drugs with potential to synergize with anti-VEGF-A technologies are being developed. In recent years, inhibition of ocular VEGF has emerged as a promising treatment modality for diabetes and is currently undergoing evaluation in clinical trials. A potential role for these anti-VEGF agents in the prevention of PDR and DME are also emerging.     

Targeted pharmacotherapy of retinal diseases with ranibizumab

Diseases of retinal and/or choroidal blood vessels are the most prevalent causes of moderate and severe vision loss in developed countries. Vascular endothelial growth factor (VEGF)-A plays a critical role in the pathogenesis of many of these diseases. Ranibizumab is a humanized antigen-binding fragment that binds all isoforms of VEGF-A. Intraocular injections of ranibizumab cause significant visual improvement in approximately 40% of patients with choroidal neovascularization due to age-related macular degeneration (AMD). Pilot trials have indicated that intraocular injections of ranibizumab also provide benefits in patients with macular edema due to diabetic retinopathy or retinal vein occlusions. Based upon several case series, bevacizumab, a full-length humanized monoclonal antibody that binds all isoforms of VEGF-A, improves vision in patients with choroidal neovascularization due to AMD and other diseases. Case series also suggest that bevacizumab can cause regression of retinal neovascularization in patients with proliferative diabetic retinopathy. Taken together, results with ranibizumab and bevacizumab suggest that potent antagonists of VEGF will provide the foundation of treatment for a wide variety of diseases complicated by retinal or choroidal neovascularization, or by excessive vascular leakage leading to macular edema.     

Therapeutic anti-VEGF antibodies

Vascular endothelial growth factor (VEGF-A) is a key cytokine in the development of normal blood vessels as well as the development of vessels in tumors and other tissues undergoing abnormal angiogenesis. Here, we review the molecular engineering of two humanized antibodies derived from a common mouse anti-VEGF antibody--bevacizumab, a full-length IgG1 approved for the treatment of specified cancer indications, and ranibizumab, an affinity-matured antibody Fab domain approved for use in age-related macular degeneration (AMD). In clinical trials and as FDA-approved therapeutics, these two anti-VEGF antibodies, bevacizumab (Avastin anti-VEGF antibody) and ranibizumab (Lucentis anti-VEGF antibody), have demonstrated therapeutic utility in blocking VEGF-induced angiogenesis.     

Combination therapy for choroidal neovascularisation

Choroidal neovascularisation (CNV) often leads to severe vision loss and is becoming increasingly prevalent as the aging population grows. Age-related macular degeneration (AMD) is the most common cause of CNV, but CNV also affects younger people with pathological myopia, ocular histoplasmosis syndrome, angioid streaks and idiopathic disorders. The monotherapies available worldwide to treat patients with CNV have primarily been studied in CNV due to AMD, and all have their drawbacks. Combination therapy takes advantage of the strengths of each therapy and their different mechanisms of action to achieve good treatment outcomes with few repeated treatments. For example, combination (triple) therapy with verteporfin photodynamic therapy, anti-vascular endothelial growth factor (VEGF) therapy and anti-inflammatory therapy addresses three main targets of CNV development: the CNV itself, VEGF expression (which promotes CNV growth) and inflammation (which exacerbates the disease process). Such triple therapy has been shown to result in sustained improved vision after only one treatment. Vision outcomes similar to those observed with ranibizumab, the most promising and rigorously proven anti-VEGF monotherapy, may be possible with combination therapy without the need for continued monthly intravitreal injections, which are required if sustained outcomes are to be achieved with ranibizumab. The goal of CNV therapy is improved vision outcomes after one course of treatment. Combination therapy may lead to this goal. Such treatment could also result in fewer safety issues (fewer treatments are required and the unknown effects of continued long-term treatment are avoided), lower cost to both the patient and the medical system and greater convenience for patients (fewer clinic visits). However, combination therapy is beset with several challenges: different therapies, doses, timing and treatment sequences are possible, and it is therefore difficult to conduct large, definitive clinical trials to determine which treatment regimen is safest and most effective. Large controlled studies are needed to more clearly define effective and safe combination regimens for CNV.     

Ranibizumab and diabetic macular oedema: after laser therapy

Diabetic retinopathy is sometimes accompanied by macular oedema, leading to a marked decline in visual acuity. The standard treatment, in addition to glycaemic and blood pressure control, is laser photocoagulation, despite its modest efficacy. Ranibizumab (Lucentis, Novartis), a VEGF (vascular endothelial growth factor) inhibitor, was initially authorised for age-related macular degeneration (AMD) in the European Union. It is now also approved for the treatment of visual loss due to macular oedema in diabetic patients. In this setting, clinical evaluation of ranibizumab is mainly based on two double-blind randomised trials comparing ranibizumab + laser photocoagulation versus placebo + laser photo-coagulation in a total of about 1000 patients. Compared with placebo, addition of ranibizumab to laser therapy led to a marked improvement in visual acuity in approximately 15% of patients after 12 months of treatment. The improvement appeared to persist after 24 months of treatment. In a trial that included a group treated with ranibizumab alone, efficacy did not differ from that of the ranibizumab + laser combination. Uncertainties remain concerning the long-term efficacy of ranibizumab and its benefits in patients with poorly controlled diabetes or proliferative retinopathy. The adverse effect profile of ranibizumab in patients with diabetic macular oedema is similar to that reported in patients with AMD, and mainly includes ocular adverse effects such as pain, bleeding and increased intraocular pressure. A risk of systemic adverse effects, particularly cardiovascular disorders, should be kept in mind in case of long-term treatment. Ranibizumab can cause birth defects, even after intravitreal injection during pregnancy. Monthly treatment with ranibizumab is inconvenient, difficult and expensive. In practice, laser therapy remains the standard treatment for diabetic patients with significantly reduced visual acuity due to macular oedema. Ranibizumab, which requires intravitreal injections, should be restricted to second-line use.     

Ranibizumab: the evidence of its therapeutic value in neovascular age-related macular degeneration

Introduction:

Neovascular age-related macular degeneration (AMD) is the leading cause of severe, irreversible visual impairment in people over 60 years of age. Neovascular AMD is characterized by abnormal growth of blood vessels under the retina, specifically the macula. These vessels leak blood and fluids, damaging the retina and its photoreceptors, resulting in permanent loss of central vision. Vascular endothelial growth factor-A (VEGF-A) has been shown to play a critical role in the pathogenesis of neovascular AMD. In the US, ranibizumab, a VEGF-A blocker, is approved and indicated for the treatment of patients with neovascular AMD.

Aims:

To review the clinical evidence for ranibizumab in the treatment of neovascular AMD.

Evidence review:

Phase III clinical trial data have established ranibizumab as a safe and well-tolerated treatment for neovascular AMD. Monthly intravitreal injections of ranibizumab result in a statistically significantly greater proportion of patients losing <15 letters of visual acuity (VA) and statistically significant increases in the mean number of letters gained compared with controls. Anatomically, ranibizumab results in stabilization in the mean area of choroidal neovascularization (CNV) and statistically significant reductions in the mean area of leakage compared with controls. Although there is limited economic evidence available, ranibizumab therapy for neovascular AMD appears to deliver a significant degree of value gain in terms of quality of life when compared with other neovascular AMD interventions.

Place in therapy:

Clinical evidence establishes ranibizumab as a first-line therapy option for virtually all treatable neovascular AMD patients. Updating neovascular AMD treatment guidelines to reflect the evidence base for ranibizumab as a preferred first-line therapy would be beneficial for physicians in making informed treatment choices and ultimately helping to ensure the best care for patients.     

Current advances in the treatment of neovascular age-related macular degeneration

Introduction: Age-related macular degeneration (AMD) is the most common cause of permanent central visual acuity loss in persons over 65 years of age in industrialized nations. Today, intravitreal vascular endothelial growth factor (VEGF) inhibitors are the mainstay of treatment worldwide.

Areas covered: The following review covers the current treatments and challenges of wet AMD management. It also covers emerging therapies including radiation, latest generation anti-VEGF agents, and combination therapies.

Expert opinion: Current neovascular AMD therapy is aimed at decreasing the VEGF effect at the choroidal neovascularization (CNV) complex. The most important existing challenges in the treatment of neovascular AMD are improving visual outcomes, decreasing the treatment burden, and minimizing geographic atrophy. Clinicians are using many treatment strategies to minimize intravitreal injections without sacrificing visual outcomes. Combination of anti-VEGF therapy with other previously available treatments that target a different pathophysiological mechanism may be a reasonable clinical strategy to minimize intravitreal injections. Many exciting novel drugs that target newly discovered pathways associated with CNV development and progression hold clinical promise. The results of ongoing randomized clinical trials will answer the important concerns surrounding new drugs and delivery devices: safety and visual outcomes.     

Ranibizumab: new drug. Macular degeneration: second-line use due to risks

(1) Due to a lack of any better alternatives, photodynamic therapy is the standard treatment for subfoveal lesions due to neovascular age-related macular degeneration (AMD). It consists of intravenous injection of a photosensitizer, verteporfin, followed by local red laser activation. This treatment, sometimes repeated every 3 months, stabilises the loss of visual acuity for 2 years in about 50% of patients. Adverse effects are generally acceptable. (2) Ranibizumab is an antibody fragment targeting vascular endothelial growth factor (VEGF). VEGF is implicated in the neovascularisation involved in age-related macular degeneration. Ranibizumab is injected into the vitreous in the same way as pegaptanib, the first VEGF antagonist to be approved for an ocular indication. (3) Clinical evaluation of ranibizumab includes 2 placebo-controlled trials (900 patients in total), a trial versus verteporfin (423 patients), and a trial testing ranibizumab in combination with verteporfin (162 patients). More than 90% of patients treated with ranibizumab in these two trials had no tangible loss of vision for one to two years, compared to about 68% of patients treated with verteporfin (statistically significant difference). These trials did not attempt to determine the optimal interval between intravitreal injections. (4) No trials have directly compared ranibizumab with pegaptanib; indirect comparisons suggest that ranibizumab is better than pegaptanib. (5) Intravitreal injection of ranibizumab can have local adverse effects, similar to pegaptanib. These include inflammatory reactions, infections, and elevated intraocular pressure. Arterial thromboses at distant sites, in particular strokes, have been reported with ranibizumab, at a higher frequency with 0.5 mg per infection (about 1%) than with 0.3 mg per injection. (6) When visual acuity continues to deteriorate in patients with age-related macular degeneration despite treatment with verteporfin, ranibizumab provides an effective alternative for patients with no particular risk factors for stroke.     

A safety evaluation of ranibizumab in the treatment of age-related macular degeneration

Introduction: The use of intravitreal ranibizumab has transformed the outcomes for thousands of patients with wet age related macular degeneration (AMD), which is the leading cause of blindness in developed countries. Prior to its introduction, most patients with wet AMD would rapidly lose central vision. The use of intravitreal ranibizumab has been shown to reduce certifiable visual loss by about a half. Current treatment regimens with ranibizumab in wet AMD require multiple injections over several years and so it is highly relevant to review the safety record of this important drug.

Areas covered: This review considers the important ocular and systemic adverse events (AE) that have been reported in the literature, particularly in the context of the pivotal clinical trials that have been performed. It also reviews the safety of other anti-VEGF drugs that are used in wet AMD, namely bevacizumab and aflibercept, and compares these drugs with ranibizumab.

Expert opinion: Overall, intravitreal ranibizumab can be considered a safe and highly effective drug for patients with wet AMD. However recent concerns about retinal thinning following ranibizumab therapy, possible systemic AE associated with all anti-VEGF drugs and the occurrence of complications relating to drug preparation and delivery must be considered.     

Ranibizumab: the evidence of its therapeutic value in neovascular age-related macular degeneration

INTRODUCTION: Neovascular age-related macular degeneration (AMD) is the leading cause of severe, irreversible visual impairment in people over 60 years of age. Neovascular AMD is characterized by abnormal growth of blood vessels under the retina, specifically the macula. These vessels leak blood and fluids, damaging the retina and its photoreceptors, resulting in permanent loss of central vision. Vascular endothelial growth factor-A (VEGF-A) has been shown to play a critical role in the pathogenesis of neovascular AMD. In the US, ranibizumab, a VEGF-A blocker, is approved and indicated for the treatment of patients with neovascular AMD. AIMS: To review the clinical evidence for ranibizumab in the treatment of neovascular AMD. EVIDENCE REVIEW: Phase III clinical trial data have established ranibizumab as a safe and well-tolerated treatment for neovascular AMD. Monthly intravitreal injections of ranibizumab result in a statistically significantly greater proportion of patients losing <15 letters of visual acuity (VA) and statistically significant increases in the mean number of letters gained compared with controls. Anatomically, ranibizumab results in stabilization in the mean area of choroidal neovascularization (CNV) and statistically significant reductions in the mean area of leakage compared with controls. Although there is limited economic evidence available, ranibizumab therapy for neovascular AMD appears to deliver a significant degree of value gain in terms of quality of life when compared with other neovascular AMD interventions. PLACE IN THERAPY: Clinical evidence establishes ranibizumab as a first-line therapy option for virtually all treatable neovascular AMD patients. Updating neovascular AMD treatment guidelines to reflect the evidence base for ranibizumab as a preferred first-line therapy would be beneficial for physicians in making informed treatment choices and ultimately helping to ensure the best care for patients.     

Angiogenesis and hypertension: the dual role of anti-hypertensive and anti-angiogenic therapies

Essential hypertension may be a consequence of structural and functional alterations of the microvascular network growth resulting partly from abnormal regulation of vascular endothelial growth factor (VEGF), one of the most potent known angiogenic factors. As data from clinical trials on anti-VEGF drugs are becoming available, it is increasingly recognized that VEGF, in addition to being a proliferation and migration factor, is also a maintenance and protection factor for endothelial cells, whose altered regulation may cause a disturbance of vascular homeostasis. Elevated VEGF levels in hypertensive patients were shown to correlate with cardiovascular risk, early microvascular and target organ damage; accordingly treatment of hypertension significantly reduced VEGF levels. Recently and in agreement with the theory that impaired angiogenesis can contribute to increased peripheral resistance and raised blood pressure (BP), an involvement of VEGF gene promoter polymorphisms in the pathophysiology of hypertension has been hypothesized. In the last decade, anti-VEGF drugs have been used in clinical practice, especially in the oncology field. This review will summarize the present understanding of the contribution of VEGF to neoangiogenesis in hypertension and its possible role as a marker of vascular damage. Given the well established effects that antihypertensive drugs exert on the vasculature beyond BP lowering (pleiotropic effects), we will also discuss the effects of antihypertensive treatment on circulating VEGF levels. The biological mechanism and clinical impact of hypertensive complications during anti-angiogenic treatments will also be reviewed.     

An update on the pharmacotherapy of neovascular age-related macular degeneration

Introduction: Neovascular age-related macular degeneration (AMD) is currently the most common cause of legal blindness in industrialized countries. The advent of pharmacotherapy with intravitreal VEGF inhibitors has greatly improved outcomes for the treatment of this disease.

Areas covered: The present review is divided into two major sections: the period prior to the use of anti-VEGF agents (triamcinolone acetonide, verteporfin photodynamic therapy) and the period following their introduction (pegaptanib sodium, bevacizumab, ranibizumab, aflibercept). The main pharmacological and clinical characteristics of each therapy are summarized.

Expert opinion: Monotherapy with anti-VEGF agents is currently the ‘gold standard' for treating neovascular AMD, but, with several drug choices and various different dosing regimens available, there is still wide variability in how individual clinicians manage their patients. Despite improved visual outcomes, there remains a significant unmet need for better treatments as the frequent office visits and injections associated with anti-VEGF therapy are costly and place a significant burden on patients, their family members and physicians.     

Aflibercept (VEGF-TRAP): the next anti-VEGF drug

The inflammatory cytokine, vascular endothelial growth factor (VEGF), plays a central role in human growth and development, and vascular maintenance. VEGF mediated angiogenesis is essential for tumor growth, as well as exudative age-related macular degeneration, proliferative diabetic retinopathy and retinopathy of prematurity, all of which are characterized by abnormal neovascularization. Ischemia and inflammation also lead to VEGF-mediated breakdown of the blood-retinal barrier, which causes vision diminishing macular edema. To combat these effects, anti-VEGF drugs (antibodies, aptamers, and tyrosine kinase inhibitors) have been developed for both systemic and local (intraocular) use. The next drug to receive regulatory approval will probably be aflibercept (VEGF-Trap), a fusion protein with high VEGF affinity attributed to binding sequences from the native receptors VEGFR1 and VEGFR2. Aflibercept monotherapy significantly reduces tumor growth and extends survival in several orthotropic animal models, and has both prevented and reduced the growth of experimental choroidal neovascularization. Ongoing phase III trials are evaluating the effectiveness of aflibercept combined with chemotherapy in patients with advanced carcinomas. The phase III VELOUR trial determined that patients receiving aflibercept with irinotecan/5-FU as second line chemotherapy for metastatic colorectal cancer experienced extended progression free survival and overall survival. Intravitreal aflibercept improved visual acuity in patients with exudative age-related macular degeneration and was non-inferior to standard therapy (ranibizumab). Ongoing phase III trials are investigating the use of aflibercept for retinal vein occlusions and diabetic macular edema. A regulatory approval application for use in exudative macular degeneration has been filed, with a decision expected by late 2011.