Rosenfeld PJ, Brown DM, Heier JS, et al. MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration

Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
New England Journal of Medicine (Impact Factor: 55.87). 10/2006; 355(14):1419-31. DOI: 10.1056/NEJMoa054481
Source: PubMed


Ranibizumab--a recombinant, humanized, monoclonal antibody Fab that neutralizes all active forms of vascular endothelial growth factor A--has been evaluated for the treatment of neovascular age-related macular degeneration.
In this multicenter, 2-year, double-blind, sham-controlled study, we randomly assigned patients with age-related macular degeneration with either minimally classic or occult (with no classic lesions) choroidal neovascularization to receive 24 monthly intravitreal injections of ranibizumab (either 0.3 mg or 0.5 mg) or sham injections. The primary end point was the proportion of patients losing fewer than 15 letters from baseline visual acuity at 12 months.
We enrolled 716 patients in the study. At 12 months, 94.5% of the group given 0.3 mg of ranibizumab and 94.6% of those given 0.5 mg lost fewer than 15 letters, as compared with 62.2% of patients receiving sham injections (P<0.001 for both comparisons). Visual acuity improved by 15 or more letters in 24.8% of the 0.3-mg group and 33.8% of the 0.5-mg group, as compared with 5.0% of the sham-injection group (P<0.001 for both doses). Mean increases in visual acuity were 6.5 letters in the 0.3-mg group and 7.2 letters in the 0.5-mg group, as compared with a decrease of 10.4 letters in the sham-injection group (P<0.001 for both comparisons). The benefit in visual acuity was maintained at 24 months. During 24 months, presumed endophthalmitis was identified in five patients (1.0%) and serious uveitis in six patients (1.3%) given ranibizumab.
Intravitreal administration of ranibizumab for 2 years prevented vision loss and improved mean visual acuity, with low rates of serious adverse events, in patients with minimally classic or occult (with no classic lesions) choroidal neovascularization secondary to age-related macular degeneration. ( number, NCT00056836 [].).

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Available from: David M Brown, Jan 28, 2016
    • "The anti-VEGF had stronger effects on bone healing than Ranibizumab . This observation was expected because the anti-VEGF used in this study was rat specific; whereas, Ranibizumab is human specific (Rosenfeld et al. 2006, Lowe et al. 2007, Lu & Adelman 2009, Mitchell 2011, Schmucker et al. 2012). Nevertheless, Ranibizumab still had a negative effect on bone healing and osseointegration in our study, probably due to the similarity in structure between rodent and human VEGF (Carmeliet et al. 1999). "
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    ABSTRACT: To assess the effect of anti-vascular endothelial growth factors on bone healing (defect volume) and implant osseointegration (bone-implant-contact percent) in rat tibia. In Sprague Dawley rats (n=36), a unicortical defect was created in the right tibia and a titanium implant was placed in the left tibia of each rat. Rats were assigned into 3 groups and received either anti-vascular endothelial growth factor neutralizing antibody, Ranibizumab or saline (control). Two weeks following surgery, rats were euthanized and bone samples were retrieved. Bone healing and osseointegration were assessed using micro-CT and histomorphometry. One-way ANOVA followed by the Tukey's test was used for data analyses. The volume of the bone defects in the anti-VEGF group (2.48 ± 0.33 mm(3) ) was larger (p=0.026) than in the controls (2.11 ± 0.36 mm(3) ) as measured by μ-CT. Bone-implant contact percent in the anti-VEGF (19.9 ± 9.4%) and Ranibizumab (21.7 ± 9.2%) groups were lower (p<0.00) than in the control group (41.8 ± 12.4%). The results of this study suggest that drugs that inhibit the activity of vascular endothelial growth factor (i.e. anti-VEGF) may hinder bone healing and implant osseointegration in rat tibiae. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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    • ". For ranibizumab, the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration (ANCHOR) and Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration (MARINA) study groups report presumed endophthalmitis in 1.0–1.4% of patients and serious uveitis in 0.7–1.3% [56] [58] "
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    ABSTRACT: Age-related macular degeneration (AMD) is the leading cause of substantial and irreversible vision loss amongst elderly populations in industrialized countries. The advanced neovascular (or "wet") form of the disease is responsible for severe and aggressive loss of central vision. Current treatments aim to seal off leaky blood vessels via laser therapy or to suppress vessel leakage and neovascular growth through intraocular injections of antibodies that target vascular endothelial growth factor (VEGF). However, the long-term success of anti-VEGF therapy can be hampered by limitations such as low or variable efficacy, high frequency of administration (usually monthly), potentially serious side effects, and, most importantly, loss of efficacy with prolonged treatment. Gene transfer of endogenous antiangiogenic proteins is an alternative approach that has the potential to provide long-term suppression of neovascularization and/or excessive vascular leakage in the eye. Preclinical studies of gene transfer in a large animal model have provided impressive preliminary results with a number of transgenes. In addition, a clinical trial in patients suffering from advanced neovascular AMD has provided proof-of-concept for successful gene transfer. In this mini review, we summarize current theories pertaining to the application of gene therapy for neovascular AMD and the potential benefits when used in conjunction with endogenous antiangiogenic proteins.
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    • "Bevacizumab is a humanized monoclonal antibody to VEGF inhibiting VEGF-receptor interaction (Gunther and Altaweel, 2009). Ranibizumab is a recombinant humanized fraction of anti-VEGF antibody that binds to all VEGF isoforms (Rosenfeld et al., 2006). Aflibercept, known as VEGF Trap, is a fusion protein that consists of VEGF receptor-binding sequences fused to a segment of a human antibody backbone (Stewart, 2012a). "
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    ABSTRACT: Natural products are characterized by high chemical diversity and biochemical specificity; therefore, they are appealing as lead compounds for drug discovery. Given the importance of angiogenesis to many pathologies, numerous natural products have been explored as potential anti-angiogenic drugs. Ocular angiogenesis underlies blinding eye diseases such as retinopathy of prematurity (ROP) in children, proliferative diabetic retinopathy (DR) in adults of working age, and age-related macular degeneration (AMD) in the elderly. Despite the presence of effective therapy in many cases, these diseases are still a significant health burden. Anti-VEGF biologics are the standard of care, but may cause ocular or systemic side effects after intraocular administration and patients may be refractory. Many anti-angiogenic compounds inhibit tumor growth and metastasis alone or in combination therapy, but a more select subset of them has been tested in the context of ocular neovascular diseases. Here, we review the promise of natural products as anti-angiogenic agents, with a specific focus on retinal and choroidal neovascularization. The multifunctional curcumin and the chalcone isoliquiritigenin have demonstrated promising anti-angiogenic effects in mouse models of DR and choroidal neovascularization (CNV) respectively. The homoisoflavanone cremastranone and the flavonoid deguelin have been shown to inhibit ocular neovascularization in more than one disease model. The isoflavone genistein and the flavone apigenin on the other hand are showing potential in the prevention of retinal and choroidal angiogenesis with long-term administration. Many other products with anti-angiogenic potential in vitro such as the lactone withaferin A, the flavonol quercetin, and the stilbenoid combretastatin A4 are awaiting investigation in different ocular disease-relevant animal models. These natural products may serve as lead compounds for the design of more specific, efficacious, and affordable drugs with minimal side effects.
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