Pegaptanib sodium for ocular vascular disease

Pegaptanib sodium (Macugen) is a selective RNA aptamer that inhibits vascular endothelial growth factor (VEGF) 165 , the VEGF isoform primarily responsible for pathologic ocular neovascularization and vascular permeability, while sparing the physiological isoform VEGF 121 . After more than 10 years in development and preclinical study, pegaptanib was shown in clinical trials to be effective in treating choroidal neovascularization associated with age-related macular degeneration. Its excellent ocular and systemic safety profile has also been confirmed in patients receiving up to three years of therapy. Early, well-controlled studies further suggest that pegaptanib may provide therapeutic benefit for patients with diabetic macular edema, proliferative diabetic retinopathy and retinal vein occlusion. Notably, pegaptanib was the first available aptamer approved for therapeutic use in humans and the first VEGF inhibitor available for the treatment of ocular vascular diseases.     

Photodynamic therapy with verteporfin in a rabbit model of corneal neovascularization

PURPOSE: To determine the efficacy of photodynamic therapy (PDT) with verteporfin (Visudyne; Novartis AG, Basel, Switzerland) for treatment of corneal neovascularization in a rabbit eye model. METHODS: Corneal neovascularization was induced in Dutch belted rabbits by placing an intrastromal silk suture near the limbus. Verteporfin was administered by intravenous injection at a dose of 1.5 mg/kg, and the pharmacokinetics of verteporfin distribution in the anterior segment or PDT-induced (laser energy levels 17, 50, and 150 J/cm(2)) regression of corneal blood vessels were then determined. To assess PDT-induced toxicity of the anterior segment, corneal and iris/ciliary body histology, and IOP were evaluated after PDT. RESULTS: Verteporfin accumulation in vascularized regions of the cornea and the iris/ciliary body tissue were time dependent and maximum levels achieved at 60 minutes after injection. In rabbits, PDT of corneal vessels using laser energy of 17 or 50 J/cm(2) resulted in 30% to 50% regression of corneal neovascularization; however, in these animals, a rapid regrowth of new blood vessels occurred between 3 and 5 days. In the rabbits receiving PDT using laser energies of 150 J/cm(2), the mean vessel regression was 56%. During the nine days of the laser therapy follow-up period, no vessel regrowth was observed in these rabbits. Histologic examination of the anterior segment after PDT (150 J/cm(2)) showed localized degeneration of the corneal blood vessels without observable change in other anterior segment structures. CONCLUSIONS: These results provide evidence that PDT can produce significant regression of neovascular corneal vessels with no observable toxicity to the anterior segments. However, the optimal laser energy necessary to induce long-term regression (150 J/cm(2)) was three times that used to treat choroidal neovascularization.     

Targeting angiogenesis, the underlying disorder in neovascular age-related macular degeneration

Angiogenesis has a causal role in many diseases, including neovascular age-related macular degeneration (AMD). Identification of key regulators of angiogenesis, including vascular endothelial growth factor (VEGF), fibroblast growth factor 2, pigment epithelium-derived growth factor, angiopoietins and extracellular matrix molecules, has facilitated the development of novel therapeutic agents that target the underlying pathological angiogenic process. Among these, VEGF serves as a "master switch" for many ocular neovascular conditions through its promotion of endothelial cell proliferation and survival, vascular permeability and ocular inflammation. Two anti-VEGF agents are now clinically available: bevacizumab, an antibody for metastatic colorectal cancer, and pegaptanib sodium, an aptamer for neovascular AMD. Unlike bevacizumab, which binds all VEGF isoforms, pegaptanib targets only VEGF165, the isoform responsible for pathological ocular neovascularization and thus an ideal target for treatment of AMD. Although other therapies targeting angiogenesis in AMD are in clinical development, to date, pegaptanib is the only therapy approved by the Food and Drug Administration of the United States for the treatment of all neovascular AMD and represents a valuable addition to the hitherto limited options available for patients.     

Safety and efficacy of intravitreal bevacizumab followed by pegaptanib maintenance as a treatment regimen for age-related macular degeneration.

BACKGROUND AND OBJECTIVE: Vascular endothelial growth factor (VEGF)-A, both necessary and sufficient in promoting ocular neovascularization, is an attractive therapeutic target. Combining nonselective and selective VEGF blockade may provide clinical benefit with minimal risks in the treatment of neovascular age-related macular degeneration (AMD). PATIENTS AND METHODS: Twenty patients with all subtypes of neovascular AMD and a broad range of baseline vision were treated with intravitreal bevacizumab followed by pegaptanib sodium for 54 weeks. Visual acuity measurements, biomicroscopy, funduscopy, fluorescein angiography, optical coherence tomography, and adverse event assessments were performed. RESULTS: Mean visual acuity improved from approximately 20/200 at baseline to 20/80. All patients experienced an improvement in retinal thickness, ranging from -47 to -297 microns. Adverse events were limited to transient irritation or redness. No significant elevation in intraocular pressure occurred following either bevacizumab or pegaptanib injections. CONCLUSIONS: Nonselective VEGF blockade with bevacizumab induction and selective VEGF165 blockade with pegaptanib as maintenance therapies may offer clinically meaningful outcomes with acceptable safety profiles in patients with AMD.     

Pegaptanib for the treatment of age-related macular degeneration

Although neovascular (wet) age-related macular degeneration (AMD) only accounts for 10-20% of all AMD, the majority (about 90%) of severe vision loss associated with AMD is due to this form. Results from recent studies have implied that vascular endothelial growth factor (VEGF), particularly VEGF(165), plays a predominant role in the development of ocular neovascularization and vascular leakage secondary to AMD. Thus VEGF is an important therapeutic target in neovascular AMD. Pegaptanib, an anti-VEGF aptamer, can selectively bind with VEGF(165) and inhibit both the growth of blood vessels and vascular leakage, and was approved by the Food and Drug Administration in the United States as the therapy for the treatment of all subtypes of neovascular AMD in December 2004. This review summaries the mechanism, preclinical and clinical studies, and adverse events of pegaptanib treatment.     

Regression of ocular neovascularization in response to increased expression of pigment epithelium-derived factor

PURPOSE: Several pharmacologic treatments have been shown to reduce ocular neovascularization when administered before the onset of angiogenic stimuli, but none have been shown to cause regression of already established ocular neovascularization. In this study, the authors tested the effect of adenoviral vectored pigment epithelium-derived factor (PEDF) gene transfer on established neovascularization in transgenic mice with expression of vascular endothelial growth factor (VEGF) in photoreceptors (rho/VEGF mice) and in a model of choroidal neovascularization. METHODS: Two weeks after the onset of VEGF transgene expression in rho/VEGF mice or 2 weeks after laser-induced rupture of Bruch's membrane in wild-type mice, subgroups of mice were killed, and the baseline amount of neovascularization was measured by image analysis. The remainder of the mice received an intravitreous or subretinal injection of adenoviral vector containing a PEDF expression construct (AdPEDF.11) or control vector (AdNull.11). RESULTS: Seven days after injection in rho/VEGF mice or 10 days after injection in the choroidal neovascularization model, the amount of neovascularization in AdPEDF.11-injected eyes was significantly less than the baseline level, indicating that regression of neovascularization had occurred. There was TUNEL staining within choroidal neovascular lesions in eyes injected with AdPEDF.11. Eyes given a subretinal injection of AdNull.11 had TUNEL-positive cells in the retina, but none within areas of choroidal neovascularization. CONCLUSIONS: These data indicate that increased expression of PEDF causes regression of ocular neovascularization by promoting apoptosis of cells within neovascular lesions and possibly represents a new treatment paradigm for patients with established ocular neovascularization.     

Role of vascular endothelial growth factor in ocular angiogenesis

VEGF-A is a critical regulator of ocular angiogenesis and vascular permeability and is involved in the pathogenesis of several ocular diseases involving neovascularization or increased vascular permeability, such as neovascular AMD, diabetic ME, and diabetic retinopathy. Currently available therapies for neovascular AMD, such as laser photocoagulation, PDT with verteporfin, and pegaptanib sodium, slow visual loss but do not improve vision for most patients. In contrast, an emerging anti-VEGF agent, ranibizumab, improved vision in 25% to 34% of treated patients in one clinical trial, rather than slowing visual loss and is the first treatment for neovascular AMD to demonstrate visual improvement in a substantial number of patients. This represents a major advance in the treatment of ocular diseases involving neovascularization or increased vascular permeability and provides hope to patients with these debilitating diseases. Since the submission of this article, ranibizumab was approved by the FDA for the treatment of neovascular AMD.     

康柏西普在眼部新生血管性疾病中的应用进展

康柏西普是中国自主研发的一种抗血管内皮生长因子新药。自从2013年被中国国家食品药品管理总局批准用于临床,康柏西普在治疗湿性年龄相关性黄斑变性、脉络膜新生血管、黄斑水肿等眼部新生血管性疾病过程中显示出可靠的安全性和疗效。针对不同的疾病,康柏西普的治疗策略有所不同。本文就近年来康柏西普在湿性年龄相关性黄斑变性、糖尿病性黄斑水肿、病理性近视脉络新生血管、新生血管性青光眼、未成熟儿视网膜病变、角膜新生血管等眼部新生血管性疾病中的应用进展进行综述,总结探讨康柏西普的用药适应证、给药方案和治疗效果。期待康柏西普的用药适应证会更广,给药方案会更多,为眼部新生血管性疾病的治疗带来新的思路。     

Verteporfin PDT for non-standard indications—a review of current literature

Background  

Verteporfin photodynamic therapy (PDT) is approved for the treatment of predominantly classic subfoveal choroidal neovascularization (CNV) due to age-related macular degeneration (AMD), as well as for subfoveal CNV due to pathologic myopia and ocular histoplasmosis syndrome. Verteporfin PDT addresses the underlying pathology of ocular vascular disorders through its angio-occlusive mechanism of action, which reduces both visual acuity loss and the underlying leakage associated with lesions. Verteporfin PDT has also been associated with encouraging treatment outcomes in case studies involving patients with choroidal vascular disorders such as polypoidal choroidal vasculopathy, central serous chorioretinopathy, choroidal haemangioma, angioid streaks, and inflammatory CNV, i.e. conditions currently considered as non-standard indications of verteporfin PDT. In many studies, outcomes were better than expected based on the natural courses of each of these conditions. Although the anti-vascular endothelial growth factor (VEGF) therapies, ranibizumab and pegaptanib, have been approved for CNV due to AMD, their role in these other choroidal vascular disorders remains to be established. We summarize current literature that has documented the use of verteporfin PDT in these conditions.     

Local tolerance and systemic safety of pegaptanib sodium in the dog and rabbit.

PURPOSE: To evaluate the local tolerance, systemic toxicity, and toxicokinetics in dogs and rabbits of pegaptanib sodium, an aptamer that targets vascular endothelial growth factor (VEGF(165)). METHODS: Dogs received biweekly, bilateral, intravitreous (IVT) injections of pegaptanib sodium for 9 months at doses of 0.3 (n = 10), 1 (n = 10), or 3 mg (n = 14); 14 control dogs received phosphate-buffered saline (PBS). In rabbits, pegaptanib sodium was administered by IVT injection biweekly for 6 months at doses of 0.2 (n = 14), 0.67 (n = 14), or 2 mg (n = 18); 18 rabbits received PBS. The systemic and ocular safety of pegaptanib sodium was assessed. Assessments in both dogs and rabbits included complete ophthalmologic examinations, serum chemistry, hematology, urinalysis, and coagulation assessments, as well as gross and microscopic pathologic examination. In addition, dogs were assessed by electroretinography and electrocardiography. In a cardiovascular safety study, loading intravenous boluses and maintenance infusions of pegaptanib sodium or PBS were administered to dogs (n = 4) in an ascending dose design, with each dose level separated by 2-3 days. The pegaptanib dosing regimens were designed to achieve pegaptanib plasma concentrations of approximately 90, 270, or 900 ng/mL. RESULTS: There were no pegaptanib sodium-associated clinical, ophthalmologic, pathologic, or cardiovascular abnormalities at doses of pegaptanib that achieved systemic and ocular exposure levels in excess of those associated with the recommended pegaptanib IVT dosing regimen of 0.3 mg per study eye in patients with age-related macular degeneration. CONCLUSION: These studies, together with data from clinical trials, provide strong evidence that inhibition of VEGF(165) by pegaptanib in the eye is a safe therapy for the treatment of ocular neovascular disease.     

Histological findings of a surgically excised myopic choroidal neovascular membrane after photodynamic therapy

Background The authors describe a myopic choroidal neovascular membrane excised 4 months after photodynamic therapy (PDT).Methods A 68-year-old woman with classic choroidal neovascularization (CNV) due to pathologic myopia underwent PDT with verteporfin in the left eye. Four months after treatment a full-thickness macular hole was diagnosed in the same eye and the patient underwent vitrectomy with submacular membranectomy. The subfoveal membrane was studied by light microscopy and immunohistochemical techniques.Results Light microscopy showed a thin fibrovascular membrane covered by residual retinal pigment epithelium. The membrane contained homogeneous matrix with small collagen bundles, fibroblasts and small blood vessels. The distribution of blood vessels was nonuniform: extravasated red blood cells, macrophages and other inflammatory elements were not present in the fibrous matrix. Endothelial cells were highlighted by CD34 immunostaining and did not show any significant alteration. There was no evidence of inflammatory cells or thrombosis inside vascular lumina.Conclusions Histologic examination of the neovascular membrane showed features similar to those of surgically excised myopic CNV without PDT treatment. Our findings suggest that PDT-induced occlusion is temporary. Fluorescein leakage from CNV after a single PDT treatment can be considered as an sign of blood vessel regrowth or recanalization indicating that multiple treatments are necessary.     

Triple therapy of intravitreal triamcinolone, photodynamic therapy, and pegaptanib sodium for choroidal neovascularization

PURPOSE: To report the six-month results of subfoveal choroidal neovascularization that had been treated with combined therapy of high-dose intravitreal triamcinolone acetonide (HDIVTA), photodynamic therapy (PDT), and pegaptanib sodium injection. DESIGN: Retrospective, interventional case series study. METHODS: Medical files of 16 patients with this treatment were reviewed (22 eyes); 13 eyes had had previous treatment with HDIVTA and PDT; nine eyes were newly diagnosed choroidal neovascularization. Patients were treated with an injection of HDIVTA (10 mg), followed by PDT and pegabtanib sodium injection at two-week intervals. The main outcome variables were visual acuity (VA) and macular thickness by optical coherence tomography (OCT). RESULTS: The mean VA improved 2.2 lines (P = .013 in the new treatment group); the previous treatment group (HDIVTA + PDT) improved only 0.7 lines (P = 0.55, Wilcoxon ranked test). The mean of macular thickness before and after treatment was statistically significant in both groups. CONCLUSION: This combination therapy showed improvement and/or stabilization in VA, particularly when used as first-line therapy.     

骨桥蛋白与眼部新生血管性疾病研究进展

眼部新生血管是眼部疾病中致盲的主要原因之一.常见的致盲眼病,如糖尿病视网膜病变、年龄相关性黄斑变性、感染性角膜炎等均与新生血管存在一定的关系.骨桥蛋白（OPN）是一种能够促进血管再生与组织修复的糖蛋白,在角膜、脉络膜和视网膜新生血管中表达增多,能够促进新生血管的发生.OPN与新生血管的关系为新生血管性疾病的研究和治疗提供了新的方向.从OPN促进角膜新生血管、脉络膜新生血管、视网膜新生血管生成3个方面对OPN与眼部新生血管性疾病的关系研究进展进行综述.     

Inhibitors of vascular endothelial growth factor (VEGF) in the management of neovascular age‐related macular degeneration: a review of current practice

We review the fundamental changes that are now occurring to the management of neovascular (wet) age‐related macular degeneration (AMD). An improved understanding of the role of vascular endothelial growth factor (VEGF) in the genesis of choroidal neovascular membranes has led to the creation and use of intravitreous anti‐VEGF antibodies (bevacizumab and ranubizumab) and an aptamer (pegaptanib) in the treatment of these lesions. These new intravitreous injections for AMD have supplanted previous treatments in both efficacy and safety and are now the standard of care for neovascular AMD. We discuss the biochemistry of the anti‐VEGF pathway. While there is substantial evidence for the use of ranubizumab and pegaptanib, the intravitreous administration of bevacizumab has not been tested in randomised controlled clinical trials. We review the evidence base for all three agents and the patho‐physiological basis for adverse reactions to intravitreous VEGF blockade.     

Treatment of rubeosis iridis with photodynamic therapy with verteporfin--A new therapeutic and prophylactic option for patients with the risk of neovascular glaucoma?

Patients with ischaemic retinopathy who show iris neovascularization despite panretinal laser photocoagulation (PRP) very often develop a neovascular glaucoma. Photodynamic therapy (PDT) has been shown to occlude neovascularization without damage to physiologic vessels or adjacent tissue in the treatment of choroidal neovascularization (CNV) and might also be of value for patients with neovascular glaucoma who did not benefit from the PRP. First results of a monocentre, open label, intra-individual controlled, pilot phase I/II, dose-finding study demonstrate that PDT with verteporfin is capable of occluding neovascular vessels for a defined period of time without damaging adjacent tissue or physiologic iris vessels. Whether this vessel occlusion will have an impact on the progression of rubeosis or neovascular glaucoma will be the subject of further investigation.     

Retinal pigment epithelial tear following intravitreal pegaptanib sodium

PURPOSE: To report two cases of a retinal pigment epithelial tear after intravitreal injection of pegaptanib sodium. To our knowledge, this is the first report of this finding after intraocular antivascular endothelial growth factor therapy. DESIGN: Observational case reports. METHODS: Two patients presented with occult choroidal neovascularization and associated serous pigment epithelial detachment that was a result of age-related macular degeneration. Both patients were treated with an intravitreal injection of pegaptanib sodium. RESULTS: One patient developed a retinal pigment epithelium tear one week after the intravitreal injection. The second patient developed a retinal pigment epithelium tear eight weeks after treatment. CONCLUSIONS: Although these cases may represent natural history, there should be a high index of suspicion for retinal pigment epithelium tears in patients who report significant visual deterioration after intravitreal injection of pegaptanib sodium. Further studies are needed to determine whether angiographic subtypes of choroidal neovascular membranes are more susceptible to developing retinal pigment epithelium tears after treatment with antivascular endothelial growth factor agents.     

Use of intravitreal injection of triamcinolone acetonide in the treatment of age-related macular degeneration

Age-related macular degeneration (AMD) is now considered an important and leading cause of blindness among elderly patients in developed and developing countries. AMD has two forms, dry and wet; both can lead to visual loss. However, occurrence of subfoveal choroidal neovascular (CNV) membrane in the wet form results in severe visual impairment. Treatment options for choroidal neovascularization are available in order to maintain and in some cases improve vision. Photodynamic therapy (PDT) has been used to treat both classic and occult membranes. It has known to cause choroidal hypoperfusion and production of vascular endothelial growth factor. Intravitreal steroid can possibly reduce the damage caused due to these undesirable effects. In the recent past, intravitreal injection of triamcinolone acetonide (IVTA) has been used extensively as an adjunct to PDT in AMD in order to reduce the number of PDT sessions and evaluate possible beneficial effects on vision. This article reviews the pharmacological attributes of triamcinolone, available evidence of its use as monotherapy or combination therapy to treat AMD, ocular side-effects thereof and ongoing clinical trials on IVTA.     

Long-term efficacy and safety profile of pegaptanib sodium for age-related macular degeneration with choroidal neovascularization--evaluation of extended phase II clinical trial

Long-term efficacy and safety profile of pegaptanib was evaluated for age-related macular degeneration (AMD) with choroidal neovascularization. Sixty-one AMD patients from phase II clinical trial were entered into an extended trial and followed up for more than 2 years. Pegaptanib sodium 0.3 mg was administered once every six weeks. Changes in visual acuity were evaluated using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. The number of responders and adverse events were monitored. The mean change in visual acuity decreased by 10.3 letters for up to 199 weeks (62-199 weeks; mean 140 weeks) during follow-up. There were 77.4% responders at the beginning (54 weeks since the beginning of phase II trial) and 56.6% at the end of the extended trial. Adverse events were found in 57 of 61 patients (93.4%); 36 of the events (59.0%) were due to a preparation procedure, while 12 adverse events (19.7%), including retinal hemorrhage (3 events; 4.9%), anterior chamber inflammation (2 events; 3.3%), macular degeneration, floaters, photopsia, retinal vessel aneurysm, vitreous hemorrhage, ocular hypertension, arteriosclerosis obliterans and hypertension (1 event; 1.6%, respectively) were associated with pegaptanib sodium. Thus, the majority of adverse events was at least in part a result of the preparation procedure for injection. Based on the long-term efficacy and tolerability data of this trial, pegaptanib sodium appears to be beneficial for preventing the worsening of visual acuity caused by age-related macular degeneration with choroidal neovascularization.     

Vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor: implications for ocular angiogenesis

PURPOSE: Pigment epithelium-derived factor (PEDF) has been demonstrated to suppress ocular angiogenesis in several animal models. In this study, we sought to measure the levels of PEDF and vascular endothelial growth factor (VEGF) in the vitreous of patients with and without ocular neovascular disorders. DESIGN: Case-control study of patients undergoing intraocular surgery for a variety of neovascular and nonneovascular conditions. METHODS: Vitreous samples were collected from 65 eyes of 65 patients with no neovascular disorder (n = 24), choroidal neovascularization (n = 9), active proliferative diabetic retinopathy (n = 16), and inactive proliferative diabetic retinopathy (n = 16). The levels of VEGF and PEDF in these vitreous samples were determined by enzyme-linked immunosorbent assay. RESULTS: The VEGF levels were at or below the level of detectability in the reference and choroidal neovascularization groups. The VEGF levels were significantly elevated in both the active and inactive PDR groups, and significantly higher in the active PDR group as compared with the inactive PDR group. The PEDF levels, which were present at relatively high concentrations in all groups, were higher in patients with active PDR compared with the control and choroidal neovascularization groups. CONCLUSIONS: High levels of immunoreactive PEDF are present in the vitreous of individuals with or without ocular neovascularization, but PEDF levels are significantly higher in patients with active PDR compared with patients with choroidal neovascularization or nonneovascular retinal diseases. Although these results do not preclude the possibility that endogenous PEDF helps to modulate ocular neovascularization, they do not support ischemia-induced downregulation of PEDF as a mechanism for such modulation.