Verteporfin : a review of its use in the management of subfoveal choroidal neovascularisation

Verteporfin (Visudyne) therapy (photodynamic therapy with intravenous liposomal verteporfin) is the first treatment to effectively prevent the loss of visual acuity in patients with subfoveal choroidal neovascularisation (CNV) secondary to age-related macular degeneration (AMD), pathological myopia or presumed ocular histoplasmosis syndrome (POHS).In adult patients with classic subfoveal CNV or occult with no classic subfoveal CNV secondary to AMD, or subfoveal CNV secondary to pathological myopia or POHS, verteporfin therapy slows or prevents loss of visual acuity. In well designed clinical trials, verteporfin therapy was superior to placebo in patients with subfoveal classic-containing CNV and occult with no classic CNV secondary to AMD at 12 and/or 24 months (Treatment of Age-related macular degeneration with Photodynamic therapy [TAP] Investigation and Verteporfin In Photodynamic therapy [VIP-AMD] trial) and in patients with pathological myopia at 12 months (Verteporfin In Photodynamic therapy [VIP-PM] trial). Limited data suggest that verteporfin therapy also prevents loss of visual acuity in patients with subfoveal CNV secondary to POHS.Verteporfin therapy was generally well tolerated in clinical trials; most adverse events were mild to moderate in intensity and transient. The most frequently reported verteporfin therapy-related adverse events (incidence >2%) were visual disturbance, injection-site reactions, photosensitivity reactions and infusion-related back pain. Approximately 5% of patients with occult with no classic subfoveal CNV secondary to AMD reported severe vision decrease within 7 days of treatment in clinical trials; 3 months later, several patients had recovered some of this loss. CONCLUSION: Photodynamic therapy with verteporfin, the first photosensitiser approved for the treatment of subfoveal CNV, is a well tolerated treatment that stabilises or slows visual acuity loss in adult patients with predominantly classic or occult with no classic subfoveal CNV secondary to AMD, and subfoveal CNV secondary to pathological myopia or POHS. Thus, verteporfin therapy provides a valuable option for the management of these patients for whom treatment options are few, and should be considered as a first-line therapy in these difficult-to-manage conditions.     

Spotlight on verteporfin in subfoveal choroidal neovascularisation

Verteporfin (Visudyne) therapy (photodynamic therapy with intravenous liposomal verteporfin) is the first treatment to effectively prevent the loss of visual acuity in patients with subfoveal choroidal neovascularisation (CNV) secondary to age-related macular degeneration (AMD), pathological myopia or presumed ocular histoplasmosis syndrome (POHS). In adult patients with classic subfoveal CNV or occult with no classic subfoveal CNV secondary to AMD, or subfoveal CNV secondary to pathological myopia or POHS, verteporfin therapy slows or prevents loss of visual acuity. In well designed clinical trials, verteporfin therapy was superior to placebo in patients with subfoveal classic-containing CNV and occult with no classic CNV secondary to AMD at 12 and/or 24 months (Treatment of Age-related macular degeneration with Photodynamic therapy [TAP] Investigation and Verteporfin In Photodynamic therapy [VIP-AMD] trial) and in patients with pathological myopia at 12 months (Verteporfin In Photodynamic therapy [VIP-PM] trial). Limited data suggest that verteporfin therapy also prevents loss of visual acuity in patients with subfoveal CNV secondary to POHS. Verteporfin therapy was generally well tolerated in clinical trials; most adverse events were mild to moderate in intensity and transient. The most frequently reported verteporfin therapy-related adverse events (incidence >2%) were visual disturbance, injection-site reactions, photosensitivity reactions and infusion-related back pain. Approximately 5% of patients with occult with no classic subfoveal CNV secondary to AMD reported severe vision decrease within 7 days of treatment in clinical trials; 3 months later, several patients had recovered some of this loss. CONCLUSION: Photodynamic therapy with verteporfin, the first photosensitiser approved for the treatment of subfoveal CNV, is a well tolerated treatment that stabilises or slows visual acuity loss in adult patients with predominantly classic or occult with no classic subfoveal CNV secondary to AMD, and subfoveal CNV secondary to pathological myopia or POHS. Thus, verteporfin therapy provides a valuable option for the management of these patients for whom treatment options are few, and should be considered as a first-line therapy in these difficult-to-manage conditions.     

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.     

Antineovascular agents in the treatment of eye diseases

Neovascularization is a common and potentially visually threatening complication of eye diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). An antiangiogenic therapy is aimed at inhibiting the growth of new blood vessels and should prevent onset or progression of neovascularization. Accumulated evidence indicates that growth factors, endothelial cell surface receptors, and extracellular matrix (ECM) proteins are major mediators of neovascularization and appealing targets for pharmacotherapeutical intervention. Vascular endothelial growth factor (VEGF) plays a critical role in the pathogenesis of retinal neovascularization (in linking tissue ischemia to angiogenesis), and is likely to contribute also significantly to choroidal neovascularization (CNV). Several antineovascular agents antagonize the function of VEGF, by blocking its proangiogenic activity. Indeed, VEGF targeting or disruption of VEGF signalling is the most effective strategy known so far in the pharmacological treatment of ocular neovascularization. Other compounds such as pigment epithelium-derived factor (PEDF) either aim at balancing the levels of pro-angiogenic and angiostatic molecules, target inflammation (cyclooxygenase inhibitors, steroids) or comprise modifiers of the ECM such as inhibitors of matrix metalloproteinases (MMPs) and agents that block the action of integrins. Vascular targeting agents (combretastatin) promote removal of newly formed vessels. This review provides an update on recent investigations directed at the pharmacotherapeutical management of ocular neovascular diseases, placing special emphasis on the underlying target molecules and relevant intracellular signalling pathways.     

Clinical evidence of intravitreal triamcinolone acetonide in the management of age-related macular degeneration

Triamcinolone acetonide (TA) is one of the first pharmacologic compounds evaluated for the treatment of choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). The most important effects of TA consist in the stabilisation of the blood-retinal barrier and the down-regulation of inflammation. TA also has anti-angiogenic and anti-fibrotic properties. The peculiar characteristic of being well tolerated by ocular tissues and the capability to remain active for many months after a single intravitreal injection, make this drug a safe and effective alternative. In the past decade, intravitreal injection of TA (IVTA) has emerged as a useful treatment of several ocular diseases such as uveitis, macular edema secondary to retinal vasculature disease, neovascularisation and vitreoretinopathy. In this paper, we review all the available evidence of its use in AMD as mono-therapy or in combination with other treatments, and we discuss which role TA will play in the treatment of AMD in the future. The first experiences with IVTA as monotherapy for the treatment of exudative AMD reported a positive outcome in transiently reducing the leakage from CNV. However, in the long-term follow-up, IVTA as monotherapy had no effect on the risk of severe visual acuity loss, despite a significant anti-angiogenic effect found 3 months after the treatment. Consequently, studies using the combination of IVTA and photodynamic therapy (PDT), which acts synergistically, were performed. They reported to improve vision and to reduce the number of re-treatments with PDT. A large number of publications confirmed the positive synergic role of combining TA and PDT (therapies) for the treatment of all types of CNV: classic or predominantly classic, occult or minimally classic and RAP (Retinal Angiomatous Proliferation) lesions. The advantages registered with the use of IVTA plus PDT compared to PDT alone were partially limited by the side effects, such as the rapid evolution of cataract. Nevertheless, cataract surgery may stimulate the development of CNV (result in stimulating CNV). However, in large, randomized, clinical trials on combination therapy of TA and PDT, visual acuity failed to show an improvement, even though the lesion size and subretinal fluid had decreased, compared to controls treated with PDT alone. Some authors reported an increased risk of developing macular atrophy after the combination therapy with IVTA and PDT. Reduction of the PDT fluence rate in association with the use of steroids resulted in reducing the risk of macular atrophy and in a better visual acuity outcome. The introduction of anti-VEGF-based drugs has revolutionized the treatment of AMD and has replaced all the previous therapies used for CNV. Visual improvement becomes an expectation in a higher proportion of patients, previously limited to minimizing vision loss. Anti-VEGF therapy also resulted in superior visual improvement compared to all types of combination therapy with IVT and PDT. Nevertheless, anti-VEGF monotherapy also has many limitations due to the need of repetitive treatments, increased costs and tachyphylaxis. Treatment regimens involving TA in combination therapy with anti-VEGF and PDT may preserve benefits for substantially longer periods. A question remains open on whether a combination treatment with anti-VEGF, triamcinolone and/or PDT may be a treatment option in patients with exudative AMD, by offering, with one cycle of therapy, functional VA benefits comparable to those observed with continued monthly anti-VEGF therapy. Further trials, of higher scientific significance, are needed to study the potential of these treatment options.     

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.     

Status of therapies in development for the treatment of age-related macular degeneration

Age-related macular degeneration (AMD) is among the leading causes of visual impairment in the elderly. The FDA has approved only two treatments, laser photocoagulation and Visudyne photodynamic therapy (PDT), approved for the wet form of AMD, a progressive condition characterized by the presence of choroidal neovascularization (CNV). Current pharmaceutical activities aimed at the treatment of wet-type AMD are largely focused on the development of anti-angiogenic drugs that would inhibit further CNV formation or even reduce existing CNV. However, other lines of attack for the treatment of wet AMD include anti-inflammatory agents as well as new PDT agents. This review will summarize ongoing activities for these different approaches.     

Age-related macular degeneration: epidemiology and optimal treatment

Age-related macular degeneration (AMD) is a common macular disease affecting elderly people in the Western world. It is characterised by the appearance of drusen in the macula, accompanied by choroidal neovascularisation (CNV) or geographic atrophy. The disease is more common in Caucasian individuals than in pigmented races. In predominantly Caucasian populations, the age-standardised prevalence of AMD in at least one eye is 7760 cases per million. The age-standardised cumulated 1-year incidence of AMD in at least one eye is 1051 cases per million individuals. AMD is the most important single cause of blindness among Caucasian individuals in developed countries. Blindness resulting from AMD rarely occurs before age 70, and most cases occur after age 80. The age-standardised 1-year incidence of legal blindness resulting from AMD is 212 cases per million. Two-thirds of AMD cases have CNV (exudative cases); the remainder has only geographic atrophy. In cross-sectional population-based studies about 45% of eyes with AMD have visual acuity reduced to 20/200 or worse. This is true both for exudative AMD and pure geographic atrophy. Age and genetic predisposition are known risk factors for AMD. Smoking is probably also a risk factor. Preventive strategies using macular laser photocoagulation are under investigation, but their efficacy in preventing visual loss is as yet unproven. There is no treatment with proven efficacy for geographic atrophy. Optimal treatment for exudative AMD requires a fluorescein angiographic study and a physician capable of interpreting it. For CNV not involving the foveal centre, the only evidence-based treatment is laser photocoagulation. For AMD cases with subfoveal CNV, good visual acuity, and predominantly classic fluorescence pattern on fluorescein angiography, photodynamic therapy with verteporfin is the treatment of choice. Photodynamic therapy is also effective in eyes with pure occult CNV and evidence of recent disease progression. For new subfoveal CNV with poor vision and recurrent CNV, laser photocoagulation can be considered.     

光动力疗法联合曲安奈德治疗年龄相关性黄斑病变

目的探讨光动力疗法联合曲安奈德玻璃体腔注射治疗年龄相关性黄斑病变引起的脉络膜新生血管的临床疗效和安全性。方法15例（15眼）渗出性年龄相关性黄斑病变经过视力、眼压、荧光素眼底血管造影（FFA）、OCT等检查确诊引起脉络膜新生血管患者,采用维替帕芬光动力疗法。PDT治疗10d后,用含25mg曲安奈德溶液注射入玻璃体腔,对持续性CNV渗漏者,6个月后重复以上治疗。结果15眼中,多数患者视力增加或稳定,7只眼视力提高,占46.7% 8只眼视力稳定,占53.3%。1例患者因类固醇导致眼压升高而行局部及系统的青光眼治疗。结论维替帕芬光动力疗法联合曲安奈德玻璃体腔注射可有效治疗年龄相关性黄斑病变继发的CNV,多数患者视力明显提高。     

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.     

Verteporfin: a review of its use in the management of subfoveal choroidal neovascularisation

Photodynamic therapy (PDT) with verteporfin (Visudyne), a photosensitising protoporphyrin derivative, is used in the management of subfoveal choroidal neovascularisation (CNV) secondary to age-related macular degeneration (AMD) or pathological myopia (PM). PDT with verteporfin over 1 and 2 years reduces the decline in visual acuity in patients with classic-containing subfoveal CNV secondary to AMD. Verteporfin is generally well tolerated by most patients. Verteporfin is also effective in patients with CNV secondary to PM, although data in this indication are limited and further controlled studies are required. Although verteporfin has shown efficacy in patients with occult AMD-related subfoveal CNV lesions in early trials, data are currently limited on its first-line use in this indication; fully published data from the Verteporfin In Occult (VIO) trial are therefore awaited with interest. Verteporfin should be considered as a first-line treatment in patients with predominantly classic subfoveal CNV secondary to AMD, and in patients with smaller minimally classic subfoveal CNV lesions. It may also be considered an option for the treatment of patients with occult AMD-related subfoveal CNV in whom visual acuity decreases or predominantly classic features develop over time.     

Photodynamic therapy versus thermal laser photocoagulation for the treatment of recurrent choroidal neovascularization due to AMD

The aim of this study was to compare the effectiveness of thermal laser photocoagulation (TLP) to that of photodynamic therapy (PDT) for the treatment of recurrent choroidal neovascularization (CNV) in patients with age-related macular degeneration (AMD). PATIENTS AND METHODS: We prospectively studied 38 patients (40 eyes) with AMD presented with recurrent CNV after TLP. The study eyes were assigned to one of the two groups according to their treatment (repetition of TLP or PDT). PDT was performed according to the standard protocol. The follow-up time ranged from 9 months to 9 years. RESULTS: The mean best-corrected visual acuity (VA) was statistically significantly lower compared to that of the baseline in both groups of the study. There were no statistically significant differences between the two groups with regard to the stabilization, improvement or decline of the best-corrected VA. CONCLUSION: According to our results TLP and PDT are equally ineffective for the treatment of recurrent CNV in patients with AMD.     

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.     

Anti-VEGF compounds in the treatment of neovascular age related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness among elderly patients in developed countries. Although the pathogenesis of AMD is still largely unknown, it is now well known that vascular endothelial growth factor (VEGF) plays a pivotal role in the growth of the abnormal blood vessels (i.e. choroidal neovascularization, CNV) which characterizes the "wet form" of this ocular disease. Therefore, inhibiting VEGF has turned out to be a good way of more effectively controlling neovascular AMD. VEGF is a heparin-binding glycoprotein with potent angiogenic, mitogenic and vascular permeability-enhancing activities specific for endothelial cells. Currently two anti-VEGF compounds have been approved by the US Food and Drug Administration (FDA) for the treatment of neovascular AMD: pegaptanib and ranibizumab. Off-label usage of bevacizumab, an anti-VEGF agent similar to ranibizumab, has also become fairly common. The substantial improvement of visual acuity noticed in patients treated with ranibizumab has made this drug the gold standard for AMD therapy. However, as with many new therapies, there are unresolved issues, including safety, cost, and dosing frequency. This review describes in details the properties and efficacy of the three anti-VEGF agents in use in clinical practice. Promising emerging anti-VEGF strategies (VEGF-trap, small interfering RNA, tyrosine kinase inhibitors) which aim to improve outcomes, safety and treatment burden through novel mechanisms of action are also discussed.     

Verteporfin

Verteporfin, a benzoporphyrin derivative monoacid ring A, is a photosensitising drug for photodynamic therapy (PDT) activated by low-intensity, nonheat-generating light of 689nm wavelength. Activation generates cytotoxic oxygen free radicals. The specificity and uptake of verteporfin for target cells with a high expression of low density lipoprotein (LDL) receptors, such as tumour and neovascular endothelial cells, is enhanced by the use of a liposomal formulation and its rapid uptake by plasma LDL. Verteporfin therapy (at light doses < 150 J/cm) selectively damages neovascular endothelial cells leading to thrombus formation and specific occlusion of choroidal neovascular vessels in subfoveal lesions in patients with age-related macular degeneration (AMD). Repeated applications of verteporfin therapy 6 mg/m2 improved or maintained visual acuity in the majority of patients with some classic subfoveal choroidal neovascularisation (CNV) secondary to AMD at 1 year's follow-up in 2 large multicentre, placebo-controlled, double-blind trials. Furthermore. in a subgroup of these patients with predominantly classic CNV secondary to AMD, there was a significantly more marked visual acuity (VA) benefit with 67.3% of verteporfin-treated eyes experiencing less than a 15-letter loss of VA versus 39.3% with placebo treatment. Multiple applications of verteporfin therapy were well tolerated in patients with subfoveal CNV secondary to AMD. The most common adverse events were visual disturbances, injection site reactions, photosensitivity reactions and infusion-related back pain.     

Anti-angiogenic effects of the receptor tyrosine kinase inhibitor, pazopanib, on choroidal neovascularization in rats

Neovascularization in the eye is a major cause of irreversible vision loss. The present study was undertaken to determine mechanisms through which pazopanib, a drug that targets multiple receptor tyrosine kinases such as VEGF receptors, inhibits angiogenesis and experimental choroidal neovascularization (CNV). Pazopanib inhibited VEGF expression by retinal pigment epithelium (RPE) cells and choroidal endothelial cells (CEC), decreased VEGF-induced cellular migration in a dose-dependent manner and suppressed extracellular signal-regulated kinase (ERK)-1/-2 phosphorylation. To assess the impact of pazopanib in vivo, CNV was induced in rats by rupturing the Bruch's membrane by laser coagulation. These experiments demonstrated that twice-daily topical eye drop treatment significantly (P<0.001) decreased leakage from photocoagulated lesions by 89.5%. Furthermore, the thickness of the developed CNV lesions was significantly inhibited by 71.7% (P<0.001) in pazopanib-treated eyes, and immunoreactivity of VEGF was lower than in control eyes. Our data suggest that pazopanib is a promising inhibitor of angiogenesis leading to an effective inhibition of CNV development in vivo. This activity can be largely ascribed to the down-regulation of VEGF release in the retina as well as to impaired VEGF-induced signaling and chemotaxis. Using a convenient topical dosing regimen, pazopanib may prove useful for treating a variety of ocular neovascular diseases such as neovascular age-related macular degeneration.     

Predictive role of coagulation-balance gene polymorphisms in the efficacy of photodynamic therapy with verteporfin for classic choroidal neovascularization secondary to age-related macular degeneration

OBJECTIVES: Age-related macular degeneration (AMD) represents the leading cause of blindness in Western populations. The majority of severe vision loss occurs in the exudative form of AMD, characterized by the development of choroidal neovascularization (CNV) beneath the fovea. Photodynamic therapy with verteporfin (PDT-V) represents one of the most largely employed modality that maybe achieves the subfoveal CNV inactivation in AMD patients. Although several ocular factors have been hitherto investigated as predictors, these researches have weakly contributed to PDT-V optimization. As PDT-V benefit is determined by CNV photothrombosis, we have retrospectively studied several coagulation-balance gene polymorphisms as predictors of PDT-V efficacy. METHODS: Ninety Caucasian patients with neovascular AMD were subdivided in responder and nonresponder, on the basis of CNV responsiveness to PDT-V application. Six gene polymorphisms, that is factor V G1691A, prothrombin G20210A, factor XIII-A G185T, methylenetetrahydrofolate reductase C677T, methionine synthase A2756G, and methionine synthase reductase A66G, were genotyped in the entire cohort. RESULTS: Logistic regression models showed that PDT-V responders were more prevalent within patients with prothrombin G20210A mutation [odds ratio (OR)=5.6, 95% confidence interval (CI) (1.2, 27.2), P=0.03], and within methylenetetrahydrofolate reductase 677T carriers [OR=6.9, 95% CI (2.7, 18.1), P<0.001]. Conversely, PDT-V nonresponders were overrepresented in carriers for factor XIII-A 185T [OR=0.13, 95% CI (0.05, 0.36), P<0.001]. CONCLUSION: These results provide evidences for the presence of pharmacogenetic relationship between peculiar coagulation-balance gene polymorphisms and different levels of PDT-V effectiveness in patients with AMD-related CNV.     

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.     

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.