Drug delivery techniques for treating age-related macular degeneration

Introduction: Currently, the standard therapy for neovascular age-related macular degeneration involves the use of anti-vascular endothelial growth factor (VEGF) drugs, which are delivered by repeated office-based intravitreal injections. This treatment is generally very effective in stabilizing or improving vision, although repeated injections create a burden for patients, family members and physicians. In addition, the cumulative risks of endophthalmitis and other complications increase with the number of injections.

Areas covered: In the clinic, much attention is focused on the relative efficacies of the three major anti-VEGF medications (bevacizumab, ranibizumab and aflibercept) as well as the most popular re-injection regimens (monthly, as-needed and treat-and-extend). In theory, intravitreal anti-VEGF drug delivery with sustained-release devices would offer similar visual results with fewer required re-injections. Various approaches have been studied, including noninvasive techniques, intraocular implants and colloidal carriers, such as liposomes, microparticles and nanoparticles.

Expert opinion: Despite its theoretical appeal, sustained-release drug delivery will not replace current techniques unless it offers one or more advantages in efficacy, safety, convenience or cost. Currently, many patients maintain stable vision with intravitreal injections at intervals of 2 months or longer, so sustained-release techniques will have to lengthen these intervals substantially to become widely accepted. As we continue to collect data from clinical trials, the role of sustained-release techniques will become better defined.     

Pegaptanib sodium for the treatment of age-related macular degeneration

Background: Pegaptanib sodium, the first aptamer therapeutic approved for use and the first antiangiogenic agent used to treat ocular neovascular disease, acts by inhibiting the 165 isoform of vascular endothelial growth factor believed primarily responsible for pathologic ocular neovascularization and vascular permeability. Objective: To briefly present the pharmacology, clinical efficacy and safety, and role of pegaptanib in treating ocular neovascular diseases. Methods: A systematic literature review and synopsis. Results/conclusion: After more than 10 years in development, clinical trials have shown pegaptanib efficacy in treating choroidal neovascularization of age-related macular degeneration. Its excellent ocular and systemic safety profiles have been confirmed in up to 3 years of experience. Early phase, well-controlled studies also suggest therapeutic benefit in diabetic retinopathy and retinal vein occlusion.     

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.     

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.     

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.     

Clinical safety of ranibizumab in age-related macular degeneration

Importance of the field: Clinical safety of pharmaceutical products in the elderly is vital because of their increased risk of cardiac and other adverse events.

Areas covered in this review: Search of the Medline database, including articles and abstracts from 1984 to 2009.

What the reader will gain: Knowledge of ocular and systemic risks: The rate of endophthalmitis was 0.05% per injection (MARINA) and <0.1% per injection (ANCHOR), rates confirmed in a retrospective analysis of 14,320 injections. Moderate increases in intraocular pressure were transient, and incidences of intraocular inflammation were rarely serious. Systemic arterial thromboembolic events occurred in 4.6 and 0% of ranibizumab-treated patients and in 3.8 and 0% of sham-treated patients in MARINA (2 years) and PIER (1 year), respectively. In SAILOR, there was a numerically higher rate of cerebrovascular stroke with 0.5 mg ranibizumab compared with 0.3 mg ranibizumab (1.2 vs 0.7%), which was a non-statistically significant trend in patients with a history of stroke.

Take home message: Although further studies to investigate the risk of stroke with ranibizumab therapy are required, repeated intravitreal ranibizumab was well tolerated and not associated with clinically significant safety risks during up to 2 years of treatment.     

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.     

二氢杨梅素对湿性年龄相关性黄斑变性的影响

目的：探讨二氢杨梅素（DMY）对湿性年龄相关性黄斑变性（AMD）的影响。方法：用532 nm激光对成年日本大耳白兔眼底进行光凝,创建AMD模型。光凝4周后,DMY（100 mg·kg^-1·d^-1）灌胃给药,酶联免疫吸附法（ELISA）检测外周血中血管内皮生长因子（VEGF）和色素上皮衍生因子（PEDF）水平;实验结束时,苏木精-伊红染色法检测脉络膜新生血管（CNV）;解剖实验动物,分别计算肝脏、肾脏和脾脏指数。结果：给药4周,模型组外周血VEGF降低幅度为63.3%,而模型对照组降低幅度为48.6%;给药8周,模型组外周血VEGF降低幅度为46.7%,模型对照组降低幅度为20.1%。给药4周,模型组外周血PEDF降低幅度为55.9%,而模型对照组降低幅度为58.6%;给药8周,模型组外周血PEDF降低幅度为12.1%,模型对照组降低幅度为53.1%。给药8周,模型对照组可见明显CNV,而模型给药组未见明显CNV;模型给药组肝脏指数和脾脏指数明显低于模型对照组（P=0.147和P=0.223）,模型给药组肾脏指数与模型对照组没有明显差异（P=0.874）。结论：DMY具有一定的抑制湿性AMD模型日本大耳白兔CNV生长的药理作用,其作用机制可能与其下调VEGF的表达、上调PEDF表达和益气活血、健脾疏肝有关。     

Advances in pharmacotherapy for wet age-related macular degeneration

Introduction: In developed countries, neovascular age-related macular degeneration (AMD) is the leading cause of irreversible central blindness. Although AMD pathogenesis is complex and still not fully understood, many involved mechanisms are already partially known and could be promising targets for future therapies. Currently, anti-VEGF drugs are the standard care of this condition.

Areas covered: This review summarizes both the current available and the emerging pharmacological therapies for the management of neovascular AMD. At first, we briefly focused on anti-VEGF compounds that are commonly used. Then, we reviewed the mechanisms of action and potential advantages of new candidate drugs that are being evaluated in clinical trials.

Expert opinion: Although anti-VEGF drugs have shown mild-term good efficacy and safety profile in the treatment of neovascular AMD, they are far away from being a perfect therapy. Pharmacological research should focus on finding new molecular targets in the AMD pathogenetical pathway and on developing longer lasting agents or new drug delivery systems. Besides the development of new drugs, a better characterization of patients is also needed, taking into account variables such as choroidal neovascularization subtypes and genetic factors, in order to identify a tailored treatment for each patient.     

Aflibercept (VEGF Trap-Eye) for the treatment of exudative age-related macular degeneration

Aflibercept, a soluble receptor molecule that binds VEGF, has been recently approved for the treatment of exudative age-related macular degeneration. This fusion protein with binding sequences from VEGF receptors 1 and 2 possesses high binding affinity for isomers of VEGF-A, VEGF-B and PlGF, and prevents VEGF from initiating proliferation and migration of vascular endothelial cells. Phase III trials showed that intravitreal aflibercept given monthly or every 2 months produces visual improvement and decrease in macular thickness comparable with monthly ranibizumab. The second year of the trials demonstrated that as-needed aflibercept maintained vision with few required injections. Aflibercept promises to decrease the treatment burden faced by patients with exudative age-related macular degeneration.     

New therapies for the treatment of age-related macular degeneration

Age-related macular degeneration (ARMD) is a leading cause of legal blindness in older adults. The visual loss caused by ARMD can be devastating and many of the current treatment modalities are ineffective or only of moderate benefit in preventing the progression of the disease. Furthermore, few treatment options are available to patients with more advanced cases of ARMD. This review highlights some aspects of our current understanding of ARMD and discusses recent patent applications related to the treatment of this disease. In particular, agents that promote retinal pigment epithelium (RPE) cell proliferation and compounds with anti-oxidant properties that may prove useful in the treatment of non-neovascular ARMD will be discussed. In addition, we review photodynamic therapy and anti-angiogenic compounds that show potential promise in the treatment of the neovascular form of ARMD.     

Systemic thromboembolic adverse events in patients treated with intravitreal anti-VEGF drugs for neovascular age-related macular degeneration: an update

Introduction: Intravitreal anti-VEGF is the most effective therapy for wet AMD, although systemic effects on the endothelium cannot be excluded.

Areas covered: The purpose of this review was to evaluate risk of thromboembolic events associated with intravitreal anti-VEGF.

Expert opinion: Current data are insufficient to confirm the safety of these compounds, due to the paucity of specific studies. Thus, pharmacovigilance for all anti-VEGF should be improved to verify the true role of anti-VEGF in the occurrence of systemic adverse events.     

光动力疗法治疗年龄相关性黄斑变性的临床疗效与基因多态性关联研究现状

年龄相关性黄斑变性(AMD)是黄斑的异质性疾病,在西方国家已成为老年人致盲及视力下降的首要因素。光动力疗法(PDT)选择性较高,对周围组织损伤小,是AMD的主要治疗方法之一。但应用PDT治疗的疗效有显著的个体间差异,这种差异与遗传因素有关。本文将对PDT疗效相关的药物基因组学研究进行综述,以期为通过基因检测指导PDT个体化治疗提供参考。     

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: 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.     

3种视网膜新生血管抑制药治疗湿性AMD的临床对比研究

目的:比较3种视网膜新生血管抑制药治疗湿性老年黄斑变性(AMD)的临床疗效,探讨其临床应用价值。方法:按照随机数字法将2013年8月-2016年10月某院收治的114例(114眼)湿性AMD患者分为A、B、C 3组,每组38例。A组患者静脉输注维替泊芬结合光动力疗法,B组与C组患者分别玻璃体内腔注射雷珠单抗与康柏西普,均每月给药1次,治疗3个月,随访3个月。比较治疗前及治疗后1个月、3个月、6个月3组患者的裸眼视力、黄斑中心视网膜厚度、脉络膜新生血管(CNV)渗漏面积以及并发症发生情况。结果:治疗前,3组患者的裸眼视力、黄斑中心视网膜厚度及CNV渗漏面积比较差异无显著性(P>0.05),治疗后,3组患者的裸眼视力均显著提高、黄斑中心视网膜厚度及CNV渗漏面积均显著减小(P<0.05)。A组在治疗后1、3个月的裸眼视力显著低于B与C组、黄斑中心视网膜厚度及CNV渗漏面积显著大于B与C组(P<0.05),C组在治疗后1个月的裸眼视力显著低于B组、黄斑中心视网膜厚度及CNV渗漏面积显著大于B组(P<0.05);治疗后6个月,3组患者的裸眼视力、黄斑中心视网膜厚度及CNV渗漏面积比较差异无显著性(P>0.05);3组患者并发症的发生率差异无显著性(P>0.05)。结论:在湿性AMD的临床治疗中,雷珠单抗的前期效果明显,但3种药物的后期效果相当。     

Systemic thromboembolic adverse events in patients treated with intravitreal anti-VEGF drugs for neovascular age-related macular degeneration: an overview

Introduction: Anti-VEGF therapy improved the quality of life for millions of patients suffering from wet age-related macular degeneration (wet-AMD); unfortunately, this therapy involves multiple injections over many years. The administration of anti-VEGF can overcome the blood-retinal barrier with agents entering the systemic circulation and causing a significant decrease in VEGF serum concentration. Although circulating VEGF protects the integrity and patency of vessels, prolonged anti-VEGF treatment has the potential to increase the risk of thromboembolic events.

Areas covered: In this review, we discuss the safety data from recent trials involving available anti-VEGF drugs.

Expert opinion: During the 2 years of follow-up in the relevant clinical trials, the rates of serious adverse events such as stroke, heart attack and death were similar for patients treated with different anti-VEGF drugs. Moreover the arterial thrombotic risk appears sufficiently low when compared with the natural incidence of arterial thrombotic events in this category of elderly patients and acceptably balanced against the advantage of improved vision. Since the use of these drugs is likely to become increasingly widespread and prolonged, it is desirable that the scientific community improves the pharmacovigilance program on all anti-VEGF drugs, expanding knowledge with studies that compares head to head all four compounds belonging to anti-VEGF armamentarium.     

Emerging vascular endothelial growth factor antagonists to treat neovascular age-related macular degeneration

Introduction: Evolving anti-vascular endothelial growth factor (VEGF) treatments for neovascular age-related macular degeneration (nAMD) include long acting agents, combination strategies involving new pathways, topical agents, sustained-release, and genetic therapy strategies.

Areas covered: Brolucizumab and abicipar pegol have smaller molecular size, facilitating higher concentrations and potentially longer duration than current anti-VEGF agents. Agents being combined with anti-VEGFs include OPT-302 (to inhibit VEGF-C and VEGF-D); pegpleranib and rinucumab (to inhibit platelet derived growth factor, PDGF – but both failed to show consistently improved visual outcomes compared to anti-VEGF monotherapy); and RG7716, ARP-1536 and nesvacumab (to activate the Tie-2 tyrosine kinase receptor, which reduces permeability). X-82 is an oral anti-VEGF and anti-PDGF being tested in phase 2 studies. Topical anti-VEGF ± anti-PDGF drugs under study include pazopanib, PAN-90806, squalamine lactate, regorafinib, and LHA510. Sustained-release anti-VEGF delivery treatments, such as the ranibizumab Port Delivery System, GB-102, NT-503, hydrogel depot, Durasert, and ENV1305 aim to reduce the burden of frequent injections. Gene therapies with new viral vectors hold the potential to induce sustained expression of anti-angiogenic proteins via the retina’s cellular apparatus, and include AVA-101/201, ADVM-202/302, AAV2-sFLT01, RGX314, and Retinostat.

Expert opinion: There are many emerging anti-VEGF treatments that aim to improve visual outcomes and reduce the treatment burden of nAMD.     

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.