Promising new treatments for neovascular age-related macular degeneration

Angiogenesis, the growth of new blood vessels from existing blood vessels, is responsible for vision loss in a variety of ophthalmic diseases. In neovascular age-related macular degeneration (AMD), the leading cause for legal blindness in many industrialised countries, abnormal blood vessels grow in the macula and cause blindness. There are a number of factors important in the angiogenic cascade but VEGF-A has been implicated in recent years as the major factor responsible for neovascular and exudative diseases of the eye. Numerous antiangiogenic drugs are in development but anti-VEGF drugs have shown great promise in treating neovascular AMD and other ocular diseases, and many of these drugs have been adopted from oncology where antiangiogenic therapy is gaining wide acceptance. For the first time in neovascular AMD, anti-VEGF drugs have brought the hope of vision improvement to a significant proportion of patients. This review provides an overview on angiogenic mechanisms, potential antiangiogenic treatment strategies and different antiangiogenic drugs with special focus on neovascular AMD.     

Promising new treatments for neovascular age-related macular degeneration

Angiogenesis, the growth of new blood vessels from existing blood vessels, is responsible for vision loss in a variety of ophthalmic diseases. In neovascular age-related macular degeneration (AMD), the leading cause for legal blindness in many industrialised countries, abnormal blood vessels grow in the macula and cause blindness. There are a number of factors important in the angiogenic cascade but VEGF-A has been implicated in recent years as the major factor responsible for neovascular and exudative diseases of the eye. Numerous antiangiogenic drugs are in development but anti-VEGF drugs have shown great promise in treating neovascular AMD and other ocular diseases, and many of these drugs have been adopted from oncology where antiangiogenic therapy is gaining wide acceptance. For the first time in neovascular AMD, anti-VEGF drugs have brought the hope of vision improvement to a significant proportion of patients. This review provides an overview on angiogenic mechanisms, potential antiangiogenic treatment strategies and different antiangiogenic drugs with special focus on neovascular AMD.     

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.     

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.     

Can [symbol: see text] verteporfin help in macular degeneration?

Age-related macular degeneration (AMD), a disorder affecting older people, is the commonest cause of severe visual impairment in the UK. It involves degeneration of the central retina (the macula) that results in diminished capacity for detailed visual tasks, such as reading, writing and recognising faces. For most people with AMD there is no effective treatment. [symbol: see text]Verteporfin (Visudyne--Novartis Ophthalmics) was licensed last year for use in conjunction with laser activation (photodynamic therapy) for the treatment of "age-related macular degeneration in patients with predominantly classic subfoveal neovascularisation". Here, we review the place of this treatment.     

VEGF inhibitors for the treatment of neovascular age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world for those patients aged 50 years or older. Neovascular AMD, a subtype characterized by the growth of new, pathologic blood vessels, results in most of the cases of severe and rapid vision loss associated with AMD. A critical activator of angiogenesis in neovascular AMD is VEGF. Several therapies have been and are now being developed for neovascular AMD, with the goal of inhibiting VEGF. These VEGF inhibitors include the RNA aptamer pegaptanib, partial and full-length antibodies ranibizumab and bevacizumab, VEGF receptor decoy VEGF Trap, small interfering RNA-based therapies bevasiranib and AGN211745, sirolimus, and tyrosine kinase inhibitors including vatalanib, pazopanib, TG100801, TG101095, AG013958 and AL39324. At present, established therapies have met with great success in reducing the vision loss associated with neovascular AMD, whereas those still investigational in nature offer the potential for further advances.     

State-of-the art pharmacotherapy for non-neovascular age-related macular degeneration

ABSTRACT

Introduction

Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly in the industrialized world. While effective treatment is available for neovascular AMD, no therapy is successful for the non-neovascular form. Herein, the authors report the current knowledge on non-neovascular AMD pathogenesis and the promising research on treatments.     

Pharmacogenetics of antiangiogenic and antineovascular therapies of age-related macular degeneration

Age-related macular degeneration (AMD), the most common age-related disease causing irreversible visual loss in industrialized countries, is a complex and multifactorial illness. Researchers have found components of the complement alternative pathway inside drusen and Bruch's membrane of AMD patients, underlying a possible important role of complement factor H in the pathogenesis of AMD. The neovascular (wet) AMD is the most destructive form and it is characterized by invasion of new blood vessels into subretinal spaces with subsequent exudation and bleeding, resulting in scarring of the macular region and loss of the central vision. The hallmark of the neovascular form is the choroidal neovascularization, where VEGF-A has an important role in the pathogenesis of the disease. SNPs of these genes have recently been investigated as potential pharmacogenetic markers of the antiangiogenic and antineovascular therapy of AMD, which includes verteporfin photodynamic therapy and anti-VEGF-A drugs, such as pegaptanib, bevacizumab and ranibizumab. The CFH rs1061170 CT and TT genotypes have been associated with an improvement of visual acuity in bevacizumab or ranibizumab treated patients, whereas patients harboring VEGF-A rs699946 G allele responded better to bevacizumab-based therapy if compared with patients carrying the A allele. In conclusion, the discovery of pharmacogenetic markers for the personalization of the antiangiogenic and/or antineovascular therapy could be, in the future, a key issue in ophthalmology to obtain a personalization of the therapy and to avoid unnecessary costs and adverse drug reactions.     

A view on new drugs for macular degeneration

Estimates suggest that in Europe 2.3% of people older than 65 years have neovascular age-related macular degeneration, which can lead to loss of central vision. The condition is the leading cause of blindness in the estern world, and the third commonest worldwide. It is characterised by growth of new blood vessels beneath the retina (choroidal neovascularisation), a process stimulated by the secretion of vascular endothelial growth factor (VEGF).3 Two new drugs, pegaptanib sodium (Macugen - Pfizer) and ranibizumab (Lucentis -Novartis), that block the effects of VEGF are now licensed in the UK for patients with neovascular age-related macular degeneration. A third drug that inhibits VEGF activity, bevacizumab (Avastin - Roche), is also used for this condition but is licensed only for metastatic colorectal or breast cancer. Here we consider the role of pegaptanib, ranibizumab and bevacizumab in patients with neovascular age-related macular degeneration.     

Preclinical and clinical profile of verteporfin, a potent photodynamic therapy drug for CNV secondary to AMD

Age-related macular degeneration (AMD) is the leading cause of blindness among people aged over 50 years in the western world. Verteporfin (Visudyne) is the first light-activated drug indicated for the treatment of patients with AMD caused by subfoveal choroidal neovascularization (CNV). This form of AMD is characterized by the development of abnormal blood vessels on the back of the retina that leak and cause scarring, resulting in central vision loss. Following intravenous administration, verteporfin selectively accumulates within proliferating tissue, including neovasculature, probably via low density lipoprotein receptors. The verteporfin is then activated by shining a specific wavelength of light with a nonthermal laser on the affected area in the eye. This process, called photodynamic therapy (PDT), generates reactive free radicals and highly reactive singlet oxygen in the target cells in the eye, causing damage and occlusion of the CNV and resulting in closure of the abnormal vessels and cessation of leakage. In experimentally induced CNV in animal models and in randomized, controlled clinical trials of patients with CNV due to AMD, verteporfin PDT has been shown to selectively occlude abnormal vessels without significantly altering overlying photoreceptors. Verteporfin therapy for CNV in Japanese patients had a similar or better angiographic and vision effect as that observed in Caucasian patients, with the same safety profile.     

Pegaptanib for wet macular degeneration

Pegaptanib sodium injection (Macugen, Eyetech Pharmaceuticals, Pfizer, New York, NY, USA) is a relatively new medication intended to treat the so-called wet (neovascular ) form of age-related macular degeneration (AMD). This form of AMD is characterized by the growth of unwanted new blood vessels into the macula (angiogenesis). The aqueous solution containing pegaptanib is injected into the vitreous of the eye, where it binds to the 165 amino acid isoform of vascular endothelial growth factor (VEGF), a secreted protein that is thought to play a major role in the pathologic angiogenesis that occurs in wet AMD. Neovascular AMD is the leading cause of severe vision loss in people over age 60 in the United States and other industrialized countries (1). Pegaptanib acts as a selective VEGF antagonist through its molecular structure as an aptamer, a pegylated modified oligonucleotide that adopts a three-dimensional configuration, enabling it to bind to extracellular VEGF (Fig. 1). Aptamers are macromolecules composed of chemically synthesized single-stranded nucleic acids (either RNA or DNA) that bind with a high degree of selectivity and affinity when exposed to target proteins. Pegaptanib binds VEGF165, and bound VEGF165 is not able to bind to the VEGF receptor, thereby negating its ability to cause angiogenesis and vascular permeability. Other aptamers exist, as do other forms of treatment for AMD. To date, however, no treatment for AMD has allowed for better vision after treatment, with most surgical treatments leading to almost immediate loss of some vision in the expectation of preventing more severe loss. Research in the field of macular degeneration is advancing rapidly, and treatment with an aptamer such as pegaptanib is a viable option despite the possibility of adverse events.     

An update on photodynamic therapy in age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of irreversible loss of central vision in people aged > 50 years in the western world. Until recently, the only proven treatment to reduce the risk of vision loss from its more severe neovascular form was laser photocoagulation, but this treatment was suitable for only 15% of cases. Photodynamic therapy (PDT) with verteporfin was recently proposed to be effective in reducing the risk of visual loss for an estimated 20 – 30% of neovascular AMD patients. This review covers AMD epidemiology, the mechanism of PDT, the 2-year results of the two major clinical studies of PDT with verteporfin, the cost-effectiveness of PDT and the current research status of other drugs for PDT in AMD.     

An update on photodynamic therapy in age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of irreversible loss of central vision in people aged > 50 years in the western world. Until recently, the only proven treatment to reduce the risk of vision loss from its more severe neovascular form was laser photocoagulation, but this treatment was suitable for only 15% of cases. Photodynamic therapy (PDT) with verteporfin was recently proposed to be effective in reducing the risk of visual loss for an estimated 20 - 30% of neovascular AMD patients. This review covers AMD epidemiology, the mechanism of PDT, the 2-year results of the two major clinical studies of PDT with verteporfin, the cost-effectiveness of PDT and the current research status of other drugs for PDT in AMD.     

Looking into anti-angiogenic gene therapies for disorders of the eye

Age-related macular degeneration (AMD) and proliferative diabetic retinopathy (DR) are the most common causes of visual impairment in the developed world. Because the key factor in AMD and DR is aberrant neovascularization in the retina (DR) or in the choroid (AMD), strategies to inhibit abnormal neovascularization represent a compelling therapeutic approach. Here we review various anti-angiogenic strategies for the treatment of ocular neovascular diseases with special emphasis on gene transfer as a way of achieving high, sustained concentrations of anti-angiogenic proteins in the back of the eye without concomitant systemic toxicity.     

Pharmacotherapy of age-related macular degeneration

Background: Age-related macular degeneration is the leading cause of blindness in the developed world. The number of persons with vision loss from age-related macular degeneration is projected to increase dramatically over the next few decades. Therefore, effective therapeutic and prophylactic agents are greatly needed. Objective: This article will discuss some of the newer treatment strategies that may help to reduce the incidence of visual loss from age-related macular degeneration. Some of these therapies and strategies can be implemented today, while many are hypothetical based on current laboratory data and ongoing clinical trials. Methods: A review of the literature and ongoing clinical trials was undertaken. Conclusion: Current therapies using antioxidants for prevention of the progression of age-related macular degeneration and anti-vascular endothelial growth factor therapies for neovascular age-related macular degeneration have given us tools for tackling this disease better and reducing the number of patients with vision loss. Combinations of some of the existing treatments and new forms of therapy may yet further decrease the treatment burden in the future.     

Current choice of treatments for neovascular AMD

Age-related macular degeneration is the leading cause of irreversible blindness in developed countries with the neovascular form accounting for the majority of severe vision loss in the disease. The management of wet age-related macular degeneration has improved drastically in the past decade as anti-VEGF agents took its place at the forefront of treatment. As the choice of therapy is based on a number of factors, this review summarizes the pivotal studies that brought these agents to use and compares the different agents currently available. This review also briefly describes the promising new therapies that are in development.     

Current and emerging concepts in the management of neovascular age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly worldwide. The more severe form of the disease, known as neovascular AMD, is characterized by aberrant growth of blood vessels from the choroid into the subretinal space. This pathologic choroidal neovascularization can have drastic consequences, often seriously impairing vision in affected individuals. Current treatment approaches focus on combination therapies that include photodynamic therapy in conjunction with numerous forms of antiangiogenic or anti-inflammatory drug intervention. To date, however, no adequate treatment is available for the majority of affected individuals. The threat of a rapidly aging population provides the impetus for aggressive efforts to control the prevalence and progression of this disease. This review will outline the currently available pharmacotherapies, discussing the justification for their use as well as their shortcomings. Furthermore, drugs that are currently under investigation as monotherapies and adjuncts will be highlighted. The potential for alternate targets will also be examined, with a focus on the most promising candidates.     

哌加他尼钠的药理作用和临床评价

哌加他尼钠（pegaptanib sodium，其注射剂商品名为Macugen）为选择性血管内皮生长因子（VEGF）抑制剂，美国FDA于2004年12月20日批准其用于治疗年龄相关性黄斑变性（AMD）。本品能减慢脉络膜新生血管的形成，降低病变血管的渗漏。临床研究表明，其治疗渗出性AMD疗效显著，且耐受性良好。现对其药理作用、药动学及临床评价及不良反应做一综述。     

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.     

A new era in the treatment of age-related macular degeneration: from Factor X to antiangiogenesis

Age-related macular degeneration has become the most common cause of visual loss leading to legal blindness in the industrialised world. This progressive disorder of the posterior pole of the eye involves the retinal pigment epithelium, its basal membrane (Bruch's membrane), as well as the choriocapillaris and retina. Multiple factors are thought to be involved, including oxidative damage, retinal pigment epithelium cell lysosomal dysfunction, immunological responses to extracellular matrix proteins and an imbalance between pro- and antiangiogenic cytokines. While little therapeutic options are available for the atrophic form of the disease, several treatment modalities have been developed for the exudative form of age-related macular degeneration. The first therapeutic interventions consisted in laser photocoagulation of choroidal neovascular membranes in the 1970s. In the late 1990s, photodynamic therapy with the photosensitiser verteporfin was the first step towards a more specific therapy, allowing treatment of subfoveal choroidal neovascular membranes without causing retinal damage. However, visual acuity tended to slowly deteriorate despite therapy in most patients. With the new antiangiogenic drugs available today and more in the pipeline to come, the probability to maintain or gain visual acuity has dramatically increased. This review gives an overview of the recent therapeutic advances in age-related macular degeneration with emphasis on antiangiogenic drugs, and will discuss available and future therapeutic concepts.