Ranibizumab for age-related macular degeneration
ABSTRACT INTRODUCTION: Age-related macular degeneration (AMD) is the leading cause of blindness in patients over 50 years in the developed world. The wet form of AMD is responsible for the majority of severe vision loss. VEGF-A is a key component in the development of wet AMD. Ranibizumab is an anti-VEGF agent that has established itself as the gold standard in the treatment of neovascular AMD. Herein, we review the pharmacology, pharmacokinetics, efficacy and safety of ranibizumab. AREAS COVERED: Since its approval in 2006, ranibizumab has revolutionized the treatment of wet AMD. In two pivotal Phase III trials, MARINA and ANCHOR, ranibizumab (0.5 mg) prevented moderate visual loss in 90 and 96% of patients, respectively, and improved vision by 15 letters or more in 33 and 40% of patients, respectively. Fixed monthly dosing regimens were compared with quarterly dosing regimens in PIER and EXCITE studies and support the superiority of fixed monthly dosing. The CATT trial revealed that bevacizumab was not inferior to ranibizumab when dosed monthly. As-needed treatment regimens of ranibizumab were also found to be non-inferior to monthly ranibizumab after 1 year of follow-up. EXPERT OPINION: Ranibizumab has positively altered the treatment of wet AMD and offers hope for millions of patients.
- SourceAvailable from: Christophe Klein
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- "Whether anti-VEGF drugs commonly used in ocular conditions associated with VEGF increase could modulate retinal microglia and macrophage activation has not been examined. Anti-VEGF drugs are routinely used in treating wet AMD to reduce deleterious consequences of choroidal neovascularization [29-31]. In other ocular diseases, anti-VEGF drugs efficiently reduced macular edema secondary to vein occlusion  and diabetic retinopathy [33,34]. "
ABSTRACT: Purpose To evaluate whether anti-vascular endothelial growth factor (VEGF) neutralizing antibodies injected in the vitreous of rat eyes influence retinal microglia and macrophage activation. To dissociate the effect of anti-VEGF on microglia and macrophages subsequent to its antiangiogenic effect, we chose a model of acute intraocular inflammation. Methods Lewis rats were challenged with systemic lipopolysaccharide (LPS) injection and concomitantly received 5 µl of rat anti-VEGF-neutralizing antibody (1.5 mg/ml) in the vitreous. Rat immunoglobulin G (IgG) isotype was used as the control. The effect of anti-VEGF was evaluated at 24 and 48 h clinically (uveitis scores), biologically (cytokine multiplex analysis in ocular media), and histologically (inflammatory cell counts on eye sections). Microglia and macrophages were immunodetected with ionized calcium-binding adaptor molecule 1 (IBA1) staining and counted based on their differential shapes (round amoeboid or ramified dendritiform) on sections and flatmounted retinas using confocal imaging and automatic quantification. Activation of microglia was also evaluated with inducible nitric oxide synthase (iNOS) and IBA1 coimmunostaining. Coimmunolocalization of VEGF receptor 1 and 2 (VEGF-R1 and R2) with IBA1 was performed on eye sections with or without anti-VEGF treatment. Results Neutralizing rat anti-VEGF antibodies significantly decreased ocular VEGF levels but did not decrease the endotoxin-induced uveitis (EIU) clinical score or the number of infiltrating cells and cytokines in ocular media (interleukin [IL]-1β, IL-6, tumor necrosis factor [TNF]-α, and monocyte chemoattractant protein [MCP]-1). Eyes treated with anti-VEGF showed a significantly decreased number of activated microglia and macrophages in the retina and the choroid and decreased iNOS-positive microglia. IBA1-positive cells expressed VEGF-R1 and R2 in the inflamed retina. Conclusions Microglia and macrophages expressed VEGF receptors, and intravitreous anti-VEGF influenced the microglia and macrophage activation state. Taking into account that anti-VEGF drugs are repeatedly injected in the vitreous of patients with retinal diseases, part of their effects could result from unsuspected modulation of the microglia activation state. This should be further studied in other ocular pathogenic conditions and human pathology.Molecular vision 06/2014; 20:908-20. · 1.99 Impact Factor
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- "Treatments largely focuses on halting this process and include surgical resection of the neovasculature and laser photocoagulation of affected areas . Recently, a regimen of frequent intravitreal injections of angiogenesis-inhibiting anti-VEGF reagents has proven to be a very successful treatment for age-related macular degeneration ,  and shows promise for diabetic retinopathy . However, complications associated with repeated injections and potential long-term secondary effects could potentially limit the utility of anti-VEGF therapy  and the fact that a percentage of patients do not respond  highlight the need to explore new target molecules for use in treatment of angiogenic-based diseases. "
ABSTRACT: Aberrant growth of blood vessels in the eye forms the basis of many incapacitating diseases and currently the majority of patients respond to anti-angiogenic therapies based on blocking the principal angiogenic growth factor, vascular endothelial growth factor (VEGF). While highly successful, new therapeutic targets are critical for the increasing number of individuals susceptible to retina-related pathologies in our increasingly aging population. Prostate specific membrane antigen (PSMA) is a cell surface peptidase that is absent on normal tissue vasculature but is highly expressed on the neovasculature of most solid tumors, where we have previously shown to regulate angiogenic endothelial cell invasion. Because pathologic angiogenic responses are often triggered by distinct signals, we sought to determine if PSMA also contributes to the pathologic angiogenesis provoked by hypoxia of the retina, which underlies many debilitating retinopathies. Using a mouse model of oxygen-induced retinopathy, we found that while developmental angiogenesis is normal in PSMA null mice, hypoxic challenge resulted in decreased retinal vascular pathology when compared to wild type mice as assessed by avascular area and numbers of vascular tufts/glomeruli. The vessels formed in the PSMA null mice were more organized and highly perfused, suggesting a more 'normal' phenotype. Importantly, the decrease in angiogenesis was not due to an impaired hypoxic response as levels of pro-angiogenic factors are comparable; indicating that PSMA regulation of angiogenesis is independent of VEGF. Furthermore, both systemic and intravitreal administration of a PSMA inhibitor in wild type mice undergoing OIR mimicked the PSMA null phenotype resulting in improved retinal vasculature. Our data indicate that PSMA plays a VEGF-independent role in retinal angiogenesis and that the lack of or inhibition of PSMA may represent a novel therapeutic strategy for treatment of angiogenesis-based ocular diseases.PLoS ONE 11/2012; 7(7):e41285. DOI:10.1371/journal.pone.0041285 · 3.23 Impact Factor
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ABSTRACT: Hintergrund Ziel dieser retrospektiven Studie ist eine Evaluierung des Visusverlaufs vor und nach Rezidivtherapie der feuchten altersbedingten Makuladegeneration (AMD) in einer Universitätsaugenklinik mit zuweisenden niedergelassenen Augenärzten. Material und Methoden Retrospektiv wurden Daten von Patienten mit Rezidiv analysiert, die initial an unserer Klinik wegen ihrer feuchten AMD behandelt und von niedergelassenen Augenärzten nachkontrolliert worden waren. Es folgte an unserer Klinik eine erneute intravitreale Behandlung mit Ranibizumab nach demselben PrONTO-Schema wie in der Upload-Phase. Ergebnisse Der mittlere Visus aller 100 eingeschlossenen Patientenaugen betrug vor Therapiebeginn − 0,61 ± 0,33 LogMAR und verbesserte sich auf − 0,36 ± 0,24 LogMAR (p < 0,001). Die mittlere zentrale Netzhautdicke betrug vor Therapiebeginn 291,5 ± 85,3 μm und verringerte sich nach Abschluss der Therapie auf 200,1 ± 63,7 μm (p < 0,001). Zum Zeitpunkt des Rezidivs betrug der mittlere Visus − 0,63 ± 0,33 LogMAR und verbesserte sich nach Abschluss der Therapie signifikant auf − 0,52 ± 0,28 LogMAR (p < 0,001). Die mittlere Netzhautdicke betrug zum Zeitpunkt des Rezidivs 281,2 ± 94,4 μm und verringerte sich signifikant auf 202,7 ± 59,9 μm nach Abschluss der Rezidivtherapie (p < 0,001). Schlussfolgerung Die PrONTO-Wiederbehandlungskriterien scheinen bei gutem morphologischem und funktionellem Ansprechen der behandelten Patienten unter alltäglichen Bedingungen zu weit gefasst, sodass es im Fall eines Rezidivs unter diesen Bedingungen zu einer irreversiblen Verschlechterung kommt. Dementsprechend sollten die neuen Rezidivkriterien der aktuellen DOG/BVA/DOC-Empfehlung angewendet werden.Der Ophthalmologe 08/2012; 110(8). DOI:10.1007/s00347-012-2717-6 · 0.50 Impact Factor