Emerging drugs for age-related macular degeneration

Age-related macular degeneration (AMD) is a leading cause of blindness that until recently had no recognised drug treatment. In wet AMD, choroidal neovascularisation (CNV) causes a profound loss of central vision. CNV is a complex process in which tissue ischaemia and/or inflammation is thought to trigger production of angiogenic signal molecules. The release of VEGF appears to be particularly important. Verteporfin photodynamic therapy was the first drug therapy to be licensed for the treatment of some types of wet AMD. Other treatments directly targeting VEGF or other aspects of angiogenesis, such as pegaptanib, ranibizumab and anecortave acetate, have either recently been licensed or are in the advanced stages of development. These and other promising treatment options such as combination strategies are reviewed.     

Emerging drugs for age-related macular degeneration

Age-related macular degeneration (AMD) is a leading cause of blindness that until recently had no recognised drug treatment. In wet AMD, choroidal neovascularisation (CNV) causes a profound loss of central vision. CNV is a complex process in which tissue ischaemia and/or inflammation is thought to trigger production of angiogenic signal molecules. The release of VEGF appears to be particularly important. Verteporfin photodynamic therapy was the first drug therapy to be licensed for the treatment of some types of wet AMD. Other treatments directly targeting VEGF or other aspects of angiogenesis, such as pegaptanib, ranibizumab and anecortave acetate, have either recently been licensed or are in the advanced stages of development. These and other promising treatment options such as combination strategies are reviewed.     

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.     

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.     

Nutritional supplements for macular degeneration

Age-related macular degeneration is the commonest cause of blindness in developed countries and the third most common worldwide. Each year in the UK, around 17,000 people become blind or partially sighted as a result of this condition, and its prevalence is likely to increase with an ageing population. Laser therapy and rarely surgery, can slow disease progression in a minority of patients but is unlikely to restore lost vision. A wide range of nutritional supplements are now on sale with promotional claims that they improve eye health. While some specialists recommend their use to patients with advanced disease, these supplements are also increasingly promoted to people with early or no signs of disease. Consequently, GPs come under pressure from patients to recommend, or even prescribe, a nutritional supplement. Here we examine the evidence for nutritional supplements in the management of age-related macular degeneration and consider which, if any, can be recommended.     

Anti-VEGF agents for age-related macular degeneration

Age-related macular degeneration (AMD) is a leading cause of legal blindness in the elderly in the industrialized world and the third major cause of blindness around the globe. Although neovascular AMD is less prevalent than atrophic AMD, it accounts for most cases with severe visual loss from AMD. VEGF seems to be a key contributary factor in the pathophysiology underlying neovascular AMD. Until recently, treatment options for neovascular AMD were limited. With the recent development of anti-VEGF therapies that have demonstrated efficacy in studies with broad eligibility criteria, the repertoire of treatments for neovascular AMD has been significantly expanded to now include the various recognized angiographic lesion subtypes. To discuss recent anti-VEGF agents in the management of AMD. Although therapy with anti-VEGF agents is the gold standard with promising results, many intravitreal injections are often required, and they do not cure all cases of wet AMD. With the recent advances in the medical therapy of exudative AMD, there is reason to be optimistic about future management of AMD as well.     

A review of drug options in age-related macular degeneration therapy and potential new agents

Age-related macular degeneration (AMD) is the leading cause of legal blindness in people > 50 years of age in the developed world. AMD is both a debilitating and costly disease for the individual and the community. Greater understanding of the mechanisms and pathways involved in causing the visual loss in AMD has resulted in the advent of several newer and more effective treatment options, making it an exciting time in the management of AMD. This paper will examine the principles behind the existing drug therapies available, as well as those being developed in the management or prophylaxis of AMD and its vision-threatening complications.     

A review of drug options in age-related macular degeneration therapy and potential new agents

Age-related macular degeneration (AMD) is the leading cause of legal blindness in people > 50 years of age in the developed world. AMD is both a debilitating and costly disease for the individual and the community. Greater understanding of the mechanisms and pathways involved in causing the visual loss in AMD has resulted in the advent of several newer and more effective treatment options, making it an exciting time in the management of AMD. This paper will examine the principles behind the existing drug therapies available, as well as those being developed in the management or prophylaxis of AMD and its vision-threatening complications.     

Wet age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in industrialized nations for those age 65 and above. The majority of patients with severe visual loss suffer from the wet form of AMD wherein there is choroidal neovascularization (CNV) and associated manifestations such as retinal pigment epithelial detachment, subretinal hemorrhages, and fibrovascular disciform scarring. The main focus on understanding the pathogenesis of CNV has been on the hypothesis that the diffuse thickening of Bruch's membrane predisposes it to develop cracks and in-growth of new vessels from choriocapillaries with associated low-grade inflammatory response. Currently, three types of treatments (laser photocoagulation, photodynamic therapy, and anti-Vascular Endothelial Growth Factor (VEGF) therapy) have been demonstrated to limit or delay loss of vision in patients. Only a minority of cases show stabilization of vision and a small proportion of cases show significant improvement in vision. This highlights the need for more and better pharmacologic or other interventions, with the goal of lowering recurrence rates and preventing the development of CNV in order to achieve better functional outcomes.     

Verteporfin photodynamic therapy and anti-angiogenic drugs: potential for combination therapy in exudative age-related macular degeneration

ABSTRACT

Objective: To discuss the rationale for combining anti-angiogenic treatment with verteporfin (Visudyne^*) photodynamic therapy in the management of choroidal neovascularization (CNV) due to age-related macular degeneration (AMD) and evaluate available evidence for the therapeutic benefits of such approaches.

Scope: The Medline and EMBASE databases were searched in October 2006 to retrieve relevant articles. Additional articles were obtained from the reference lists of retrieved articles, as well as from recent scientific meetings and company websites.

Findings: Treatments for CNV due to AMD can be directed at either the vascular component of CNV (the new vessels that proliferate and leak blood and fluid) or the angiogenic component that leads to the development of the condition. Verteporfin targets the vascular component, whereas anti-angiogenic agents (such as pegaptanib and ranibizumab) target key mediators of the angiogenic cascade. The different mechanisms of action of these approaches offer the potential for additive or synergistic effects with combination therapy. In addition, anti-angiogenic agents might counteract upregulation of angiogenic factors (including VEGF) that occur after verteporfin photodynamic therapy. Results from preclinical and clinical studies of the combination of ranibizumab or pegaptanib with verteporfin warrant continued investigation.

Conclusions: The use of anti-angiogenic agents in combination with verteporfin may have the potential to improve visual outcomes and reduce the number of treatments in eyes with CNV due to AMD, and requires further evaluation in randomized, controlled clinical trials.     

Innovative therapies for neovascular age-related macular degeneration

ABSTRACT

Introduction: Investigational anti-VEGF treatments for neovascular age-related macular degeneration (nAMD) aim to improve visual outcomes and reduce treatment burden; these include long-acting agents, combination strategies, topical agents, sustained-release, and genetic therapies.

Areas covered: The authors provide a comprehensive review of investigational therapies for nAMD, focusing on therapies currently in clinical trial.

Expert opinion: Long-acting anti-VEGF agents have demonstrated promising results in phase 3 studies, and include Brolucizumab, a single-chain antibody fragment, and Abicipar, a designed ankyrin repeat protein (DARPin). Other unique anti-VEGF agents in current trials include Conbercept – a fusion protein of the VEGF receptor domains, KSI-301 – an anti-VEGF antibody biopolymer conjugate, and OPT-302 – an inhibitor of VEGF-C/D. Strategies to activate the Tie-2 receptor, some in combination with VEGF inhibition, are of interest, with recent trials of Faricimab, ARP-1536, and nesvacumab. Topical anti-VEGF ± anti-PDGF agents, such as pazopanib, squalamine lactate, regorafenib, and LHA510 have shown limited efficacy and/or have not been advanced, although PAN-90806 continues to advance with promising initial results. Sustained-release anti-VEGF treatments, to address treatment burden, include the ranibizumab Port Delivery System, GB-102, NT-503, hydrogel depot, Durasert, and ENV1305. Similarly, genetic therapies, including RGX-314 and ADVM-022, aim to provide sustained anti-VEGF expression from the retina.     

Emerging treatments for wet age-related macular degeneration

Introduction: Wet or exudative age-related macular degeneration (AMD) is the leading cause of blindness in the United States for individuals over the age of 65 years. Wet AMD is characterized by the formation of choroidal neovascularization, which can lead to edema, hemorrhage and scarring of the macula. This leads to metamorphopsia and vision loss. Without treatment, the loss of vision is permanent. The current gold standard treatment of wet AMD consists of intravitreal injections of anti-vascular endothelial growth factor (VEGF) medications.

Areas covered: Numerous new therapies in the drug pipeline aim at addressing limitations of current treatments. Future therapies involve novel compounds that attack different parts of the VEGF cascade, novel delivery systems aimed at reducing the frequency of intraocular injections, combination therapies and the use of radiation in conjunction with intravitreal therapies.

Expert opinion: Limitations of current treatments include the need for repeated injections, the high financial costs and treatment burdens of repeated injections, the risk of adverse ocular and systemic adverse events, and the inability to completely reverse the disease process of wet AMD. There are many new therapies and approaches in the pipeline which hold promise for improving the treatment of wet AMD.     

美国新药创新体系相关因素分析及对我国的启示

科技人才、经费投入、相关产业发展水平及政府引导措施等因素会对一个国家新药研发能力产生重要影响。美国是全球新药研发能力最强的国家,上述因素在促进美国新药研发能力提高上发挥了重要作用。本文通过对美、中2国新药创新体系中上述重要因素的深入对比分析,对如何采取相应措施增强我国新药研发能力进行了探讨。     

Emerging drugs for diabetic macular edema

Introduction: Diabetic macular edema (DME) is the most common cause of visual impairment due to diabetic retinopathy. The treatment of DME has recently undergone a paradigm shift. Traditionally, photocoagulation was standard treatment, but pharmacologic therapies are becoming increasingly used for this purpose. All currently available drug therapies for DME are either anti-VEGF agents or corticosteroids.

Areas covered: The pathogenesis of DME involves angiogenesis, inflammation and oxidative stress. The scientific rationale to treat DME through the pharmacologic blockade of VEGF and other pro-angiogenic factors is discussed. The fluocinolone insert is approved for the treatment of DME in several European countries, but not in the US at this time. Some medications that are already approved for other retinal diseases, most prominently aflibercept and the dexamethasone delivery system, have recently obtained approval for DME in the US. Other compounds are being studied in earlier-phase clinical trials.

Expert opinion: Pharmacologic treatment of DME will likely become increasingly used, especially for patients with edema involving the fovea. At this time, the two main classes of medication for treatment of DME are anti-VEGF agents and corticosteroids. As we continue to collect clinical trials data, the precise role of individual agents, and the continuing role for photocoagulation, will become more clear.