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      EFFICACY AND SAFETY OF RANIBIZUMAB FOR THE TREATMENT OF CHOROIDAL NEOVASCULARIZATION DUE TO UNCOMMON CAUSE : Twelve-Month Results of the MINERVA Study

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          Abstract

          Supplemental Digital Content is Available in the Text.

          Ranibizumab was effective in treating choroidal neovascularization of various etiologies, with a treatment effect of +9.9 letters versus sham at Month 2 and a mean gain of 11.0 letters from baseline to Month 12. The beneficial effects of ranibizumab were observed across all etiology subgroups.

          Abstract

          Purpose:

          To evaluate the efficacy and safety of ranibizumab 0.5 mg in adult patients with choroidal neovascularization because of an uncommon cause enrolled in the 12-month MINERVA study.

          Methods:

          In this Phase III, double-masked study, adult (≥18 years) patients (N = 178) were randomized 2:1 to receive either ranibizumab (n = 119) or sham (n = 59) at baseline and, if needed, at Month 1 and open-label individualized ranibizumab from Month 2. Best-corrected visual acuity change from baseline to Month 2 (primary endpoint) and Month 12, treatment exposure, and safety over 12 months were reported. Subgroup analysis was conducted on five predefined choroidal neovascularization etiologies (angioid streak, postinflammatory, central serous chorioretinopathy, idiopathic, and miscellaneous).

          Results:

          Ranibizumab showed superior efficacy versus sham from baseline to Month 2 (adjusted least-squares mean best-corrected visual acuity: +9.5 vs. −0.4 letters; P < 0.001). At Month 12, the mean best-corrected visual acuity change was +11.0 letters (ranibizumab) and +9.3 letters (sham). Across the 5 subgroups, the treatment effect ranged from +5.0 to +14.6 letters. The mean number of ranibizumab injections was 5.8 (ranibizumab arm) with no new ocular or nonocular adverse events.

          Conclusion:

          Ranibizumab 0.5 mg resulted in clinically significant treatment effect versus sham at Month 2. Overall, ranibizumab was effective in treating choroidal neovascularization of various etiologies with no new safety findings.

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          Most cited references53

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          Central serous chorioretinopathy: Recent findings and new physiopathology hypothesis.

          Central serous chorioretinopathy (CSCR) is a major cause of vision threat among middle-aged male individuals. Multimodal imaging led to the description of a wide range of CSCR manifestations, and highlighted the contribution of the choroid and pigment epithelium in CSCR pathogenesis. However, the exact molecular mechanisms of CSCR have remained uncertain. The aim of this review is to recapitulate the clinical understanding of CSCR, with an emphasis on the most recent findings on epidemiology, risk factors, clinical and imaging diagnosis, and treatments options. It also gives an overview of the novel mineralocorticoid pathway hypothesis, from animal data to clinical evidences of the biological efficacy of oral mineralocorticoid antagonists in acute and chronic CSCR patients. In rodents, activation of the mineralocorticoid pathway in ocular cells either by intravitreous injection of its specific ligand, aldosterone, or by over-expression of the receptor specifically in the vascular endothelium, induced ocular phenotypes carrying many features of acute CSCR. Molecular mechanisms include expression of the calcium-dependent potassium channel (KCa2.3) in the endothelium of choroidal vessels, inducing subsequent vasodilation. Inappropriate or over-activation of the mineralocorticoid receptor in ocular cells and other tissues (such as brain, vessels) could link CSCR with the known co-morbidities observed in CSCR patients, including hypertension, coronary disease and psychological stress.
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            Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration.

            Angiogenesis is a key aspect of the wet form of age-related neovascular (AMD), the leading cause of blindness in the elderly population. Substantial evidence indicated that vascular endothelial growth factor (VEGF)-A is a major mediator of angiogenesis and vascular leakage in wet AMD. VEGF-A is the prototype member of a gene family that includes also PlGF, VEGF-B, VEGF-C, VEGF-D and the orf virus-encoded VEGF-E. Several isoforms of VEGF-A can be generated due to alternative mRNA splicing. Various VEGF inhibitors have been clinically developed. Among these, ranibizumab is a high affinity recombinant Fab that neutralizes all isoforms of VEGF-A. The article briefly reviews the biology of VEGF and then focuses on the path that led to clinical development of ranibizumab. The safety and efficacy of ranibizumab in the treatment of neovascular AMD have been evaluated in two large phase III, multicenter, randomized, double-masked, controlled pivotal trials in different neovascular AMD patient populations. Combined, the trial results indicate that ranibizumab results not only in a slowing down of vision loss but also in a significant proportion of patients experiencing a clinically meaningful vision gain. The visual acuity benefit over control was observed regardless of CNV lesion type. Furthermore, the benefit was associated with a low rate of serious adverse events. Ranibizumab represents a novel therapy that, for the first time, appears to have the potential to enable many AMD patients to obtain a meaningful and sustained gain of vision. On June 30 2006, ranibizumab was approved by the US Food and Drug Administration for the treatment of wet AMD.
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              Safety and efficacy of a flexible dosing regimen of ranibizumab in neovascular age-related macular degeneration: the SUSTAIN study.

              To evaluate the safety and efficacy of individualized ranibizumab treatment in patients with neovascular age-related macular degeneration. Twelve-month, phase III, multicenter, open-label, single-arm study. A total of 513 ranibizumab-naïve SUSTAIN patients. Three initial monthly injections of ranibizumab (0.3 mg) and thereafter pro re nata (PRN) retreatment for 9 months based on prespecified retreatment criteria. Patients switched to 0.5 mg ranibizumab after approval in Europe. Frequency of adverse events (AEs), monthly change of best-corrected visual acuity (BCVA) and central retinal thickness (CRT) from baseline, the time to first re-treatment, and the number of treatments were assessed. A total of 249 patients (48.5%) reported ocular AEs, and 8 (1.5%) deaths, 5 (1.2%) patients with ocular serious AEs of the study eye (retinal hemorrhage, cataract, retinal pigment epithelial tear, reduced visual acuity [VA], vitreous hemorrhage), and 19 (3.7%) patients with arteriothromboembolic events were observed. Most frequent AEs in the study eye were reduced VA (18.5%), retinal hemorrhage (7.2%), increased intraocular pressure (7.0%), and conjunctival hemorrhage (5.5%). The average number of re-treatments from months 3 to 11 was 2.7. Mean best-corrected visual acuity increased steadily from baseline to month 3 to reach +5.8 letters, decreased slightly from month 3 to 6, and remained stable from month 6 to 12, reaching +3.6 at month 12. Mean change in CRT was -101.1 μm from baseline to month 3 and -91.5 μm from baseline to month 12. The safety results are comparable to the favorable tolerability profile of ranibizumab observed in previous pivotal clinical studies; individualized treatment with less than monthly re-treatments shows a similar safety profile as observed in previous randomized clinical trials with monthly ranibizumab treatment. Efficacy outcomes were achieved with a low average number of re-treatments. Visual acuity in SUSTAIN patients with individualized re-treatment based on VA/optical coherence tomography assessment reached on average a maximum after the first 3 monthly injections, decreased slightly under PRN during the next 2 to 3 months, and was then sustained throughout the treatment period. Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Retina
                Retina (Philadelphia, Pa.)
                retina
                Retina (Philadelphia, Pa.)
                Retina
                0275-004X
                1539-2864
                August 2018
                12 July 2017
                : 38
                : 8
                : 1464-1477
                Affiliations
                [* ]Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Eye Hospital, Kowloon, Hong Kong, SAR;
                []Department of Biomedical and Clinical Science Luigi Sacco, Luigi Sacco Hospital, University of Milan, Milan, Italy;
                []Department of Medical and Biological Sciences Ophthalmology, University of Udine, Udine, Italy;
                [§ ]Istituto Europeo di Microchirurgia Oculare (IEMO), Udine, Italy;
                []Department of Ophthalmology, University of Bonn, Bonn, Germany;
                [** ]Novartis Pharmaceuticals Corporation, East Hanover, New Jersey;
                [†† ]Novartis Pharma AG, Basel, Switzerland;
                [‡‡ ]Sigma Statistical Services, Balmullo, St Andrews, Scotland, United Kingdom; and
                [§§ ]NIHR Biomedical Centre for Research in Ophthalmology, Moorfields Eye Hospital, London, United Kingdom.
                Author notes
                Reprint requests: Timothy Y. Y. Lai, MD, FRCOphth, Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, 3/F Hong Kong Eye Hospital, 147K Argyle Street, Kowloon, Hong Kong, SAR; e-mail: tyylai@ 123456cuhk.edu.hk
                Article
                Retina-216-1446 00003
                10.1097/IAE.0000000000001744
                6086222
                28704254
                14af8bb0-6dcc-49f3-a895-171984f24cbb
                Copyright @ 2017

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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                Original Study
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                anti–vascular endothelial growth factor,choroidal neovascularization,choroidal neovascularization etiologies,angioid streak,uveitis,central serous chorioretinopathy,idiopathic,phase iii,ranibizumab,randomized

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