Treatment of Exudative Age-Related Macular Degeneration with a Designed Ankyrin Repeat Protein that Binds Vascular Endothelial Growth Factor: a Phase I/II Study

PURPOSE: To evaluate the safety, tolerability and bioactivity of ascending doses of MP0112, a designed ankyrin repeat protein (DARPin) that binds with high affinity to vascular endothelial growth factor-A (VEGF-A), in treatment-naive patients with exudative age-related macular degeneration (AMD). DESIGN: Phase I/II, open-label, multicenter, dose-escalation study. METHODS: Patients were to receive a single intravitreal injection of MP0112 at doses ranging from 0.04 to 3.6 mg and be monitored for 16 weeks for safety, efficacy, pharmacokinetics, and dose response. RESULTS: Altogether, 32 patients received a single injection of MP0112. The maximum tolerated dose was 1.0 mg because of a case of endophthalmitis in the 2.0 mg cohort. Drug-related adverse events were reported by 13 (41%) of 32 patients; they included ocular inflammation in 11 patients (7 mild, 4 moderate in severity). Visual acuity scores were stable or improved compared with baseline for >= 4 weeks following injection; both retinal thickness and fluorescein angiography leakage decreased in a dose-dependent manner. Rescue therapy was administered to 20 (91%) of 22 patients who received 0.04-0.4 mg MP0112 compared with 4 of 10 (40%) patients who received 1.0 or 2.0 mg. Of patients in the higher-dose cohorts who did not require rescue treatment, 83% (5/6) maintained reductions in central retinal thickness through week 16. CONCLUSIONS: A single injection of 1.0 or 2.0 mg MP0112 resulted in mean decreases in retinal thickness and leakage area despite ocular inflammation. larger-scale studies are warranted to confirm these observations. (C) 2014 The Authors. Published by Elsevier Inc. All rights reserved. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).PURPOSE: To evaluate the safety, tolerability and bioactivity of ascending doses of MP0112, a designed ankyrin repeat protein (DARPin) that binds with high affinity to vascular endothelial growth factor-A (VEGF-A), in treatment-naive patients with exudative age-related macular degeneration (AMD). DESIGN: Phase I/II, open-label, multicenter, dose-escalation study. METHODS: Patients were to receive a single intravitreal injection of MP0112 at doses ranging from 0.04 to 3.6 mg and be monitored for 16 weeks for safety, efficacy, pharmacokinetics, and dose response. RESULTS: Altogether, 32 patients received a single injection of MP0112. The maximum tolerated dose was 1.0 mg because of a case of endophthalmitis in the 2.0 mg cohort. Drug-related adverse events were reported by 13 (41%) of 32 patients; they included ocular inflammation in 11 patients (7 mild, 4 moderate in severity). Visual acuity scores were stable or improved compared with baseline for >= 4 weeks following injection; both retinal thickness and fluorescein angiography leakage decreased in a dose-dependent manner. Rescue therapy was administered to 20 (91%) of 22 patients who received 0.04-0.4 mg MP0112 compared with 4 of 10 (40%) patients who received 1.0 or 2.0 mg. Of patients in the higher-dose cohorts who did not require rescue treatment, 83% (5/6) maintained reductions in central retinal thickness through week 16. CONCLUSIONS: A single injection of 1.0 or 2.0 mg MP0112 resulted in mean decreases in retinal thickness and leakage area despite ocular inflammation. larger-scale studies are warranted to confirm these observations. (C) 2014 The Authors. Published by Elsevier Inc. All rights reserved. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/)

Central retinal vein occlusion in young population: risk factors and outcomes

ObjectiveTo evaluate the risk factors and outcomes of central retinal vein occlusion (CRVO) in young patients (< 40 years).MethodsIn this retrospective monocentric case series, we included young patients (<40 years) with CRVO. Patients’ medical files were analyzed focusing on demographic characteristics, suspected risk factors, ophthalmic work-up, visual acuity (VA), treatment, and outcomes.ResultsA total of 54 eyes of 52 patients were included. Central retinal vein occlusion was considered idiopathic in 13 patients (25%). The main risk factors identified were ocular hypertension (20.4%), inflammation (20.4%), high blood pressure (14.8%), and coagulation abnormality (11.1%). Final VA was lower in patients with high blood pressure and inflammation when compared to patients with no risk factor (p = 0.03 and 0.04, respectively). Intravitreal injections were needed in 23 eyes (42.6%) and 19 eyes (35.2%) received panretinal photocoagulation treatment.ConclusionCentral retinal vein occlusion is frequently associated with risk factors in young patients (75% of patients). In addition to the usual factors found in older patients, such as ocular hypertension and high blood pressure, coagulation abnormality and inflammation were also among the risk factors identified. Young patients with CRVO should be evaluated for the presence of risk factors and patients with high blood pressure or inflammatory findings should be followed carefully since they have a worse outcome

PREVALENCE OF RETICULAR PSEUDODRUSEN IN AGE-RELATED MACULAR DEGENERATION USING MULTIMODAL IMAGING

International audiencePurpose:To determine the rate of reticular pseudodrusen (RPD) in age-related macular degeneration using multimodal imaging, including color fundus photography, the blue channel image of fundus photography, infrared reflectance, fundus autofluorescence, multicolor imaging, and spectral domain optical coherence tomography, as well as to compare the sensitivities and specificities of these modalities for detecting RPD.Methods:This prospective study included 243 eyes from 125 consecutive patients with age-related macular degeneration. They underwent fundus examination including color fundus photography, blue channel, infrared reflectance, fundus autofluorescence, multicolor imaging, and spectral domain optical coherence tomography in both eyes. To be considered as having RPD, eyes had to have reticular patterns on spectral domain optical coherence tomography in a large studied cube of 30 degrees x 25 degrees or on infrared reflectance with at least one other examination.Results:The mean age of the 125 patients was 81.1 years (8.1). Eighty-six patients (68.8%) were diagnosed with RPD. Spectral domain optical coherence tomography, infrared reflectance, and multicolor imaging had the highest sensitivity (99.3, 84.6, and 87.1%, respectively) and specificity (100%). The color fundus photography, blue channel, and fundus autofluorescence had lower sensitivity to detect RPD.Conclusion:Reticular pseudodrusen is frequently associated with soft drusen in patients with age-related macular degeneration. As RPD may be rarely located only in the perifoveal area, spectral domain optical coherence tomography with a larger cube (30 x 25 degrees) than that usually used (20 x 20 degrees) had the highest sensitivity and specificity to detect RPD and is recommended to optimize the rate of detection

COVID-19 Associated Choroidopathy

International audienceThe aim of the study is to report on the indocyanine green angiography (ICGA) and OCT findings in patients hospitalized for severe COVID infection. In this observational prospective monocentric cohort study, we included patients hospitalized for severe COVID infection. The main outcomes were ICGA and OCT findings. A total of 14 patients with a mean age of 58.2 ± 11.4 years and a male predominance (9/14 patients; 64%) were included. The main ICGA findings included hypofluorescent spots in 19 eyes (68%), intervortex shunts in 10 eyes (36%), and characteristic “hemangioma-like” lesions in five eyes (18%). “Hemangioma-like” lesions were both unique and unilateral, and showed no washout on the late phase of the angiogram. The main OCT findings included focal choroidal thickening in seven eyes (25%), caverns in six eyes (21%) and paracentral acute middle maculopathy lesions in one eye (4%). All patients hospitalized for severe COVID infection had anomalies on ICGA and OCT. Lesions to both retinal and choroidal vasculature were found. These anomalies could be secondary to vascular involvement related directly or indirectly to the SARS-CoV2 virus

Ranibizumab versus Bevacizumab for Neovascular Age-related Macular Degeneration: Results from the GEFAL Noninferiority Randomized Trial

International audienceObjective: To evaluate the relative efficacy and safety profile of bevacizumab versus ranibizumab intravitreal injections for the treatment of neovascular age-related macular degeneration (AMD). Design: Multicenter, prospective, noninferiority, double-masked, randomized clinical trial performed in 38 French ophthalmology centers. The noninferiority limit was 5 letters. Participants: Patients aged >= 50 years were eligible if they presented with subfoveal neovascular AMD, with best-corrected visual acuity (BVCA) in the study eye of between 20/32 and 20/320 measured on the Early Treatment of Diabetic Retinopathy Study chart and a lesion area of less than 12 optic disc areas (DA). Methods: Patients were randomly assigned to intravitreal administration of bevacizumab (1.25 mg) or ranibizumab (0.50 mg). Hospital pharmacies were responsible for preparing, blinding, and dispensing treatments. Patients were followed for 1 year, with a loading dose of 3 monthly intravitreal injections, followed by an asneeded regimen (1 injection in case of active disease) for the remaining 9 months with monthly follow-up. Main Outcome Measures: Mean change in visual acuity at 1 year. Results: Between June 2009 and November 2011, 501 patients were randomized. In the per protocol analysis, bevacizumab was noninferior to ranibizumab (bevacizumab minus ranibizumab +1.89 letters; 95% confidence interval [CI], -1.16 to +4.93, P< 0.0001). The intention-to-treat analysis was concordant. The mean number of injections was 6.8 in the bevacizumab group and 6.5 in the ranibizumab group (P=0.39). Both drugs reduced the central subfield macular thickness, with a mean decrease of 95 mm for bevacizumab and 107 mm for ranibizumab (P=0.27). There were no significant differences in the presence of subretinal or intraretinal fluid at final evaluation, dye leakage on angiogram, or change in choroidal neovascular area. The proportion of patients with serious adverse events was 12.6% in the bevacizumab group and 12.1% in the ranibizumab group (P=0.88). The proportion of patients with serious systemic or ocular adverse events was similar in both groups. Conclusions: Bevacizumab was noninferior to ranibizumab for visual acuity at 1 year with similar safety profiles. Ranibizumab tended to have a better anatomic outcome. The results are similar to those of previous head-to-head studies. (C) 2013 by the American Academy of Ophthalmology

Ranibizumab versus Bevacizumab for Neovascular Age-related Macular Degeneration: Results from the GEFAL Noninferiority Randomized Trial.

OBJECTIVE: To evaluate the relative efficacy and safety profile of bevacizumab versus ranibizumab intravitreal injections for the treatment of neovascular age-related macular degeneration (AMD). DESIGN: Multicenter, prospective, noninferiority, double-masked, randomized clinical trial performed in 38 French ophthalmology centers. The noninferiority limit was 5 letters. PARTICIPANTS: Patients aged ≥50 years were eligible if they presented with subfoveal neovascular AMD, with best-corrected visual acuity (BVCA) in the study eye of between 20/32 and 20/320 measured on the Early Treatment of Diabetic Retinopathy Study chart and a lesion area of less than 12 optic disc areas (DA). METHODS: Patients were randomly assigned to intravitreal administration of bevacizumab (1.25 mg) or ranibizumab (0.50 mg). Hospital pharmacies were responsible for preparing, blinding, and dispensing treatments. Patients were followed for 1 year, with a loading dose of 3 monthly intravitreal injections, followed by an as-needed regimen (1 injection in case of active disease) for the remaining 9 months with monthly follow-up. MAIN OUTCOME MEASURES: Mean change in visual acuity at 1 year. RESULTS: Between June 2009 and November 2011, 501 patients were randomized. In the per protocol analysis, bevacizumab was noninferior to ranibizumab (bevacizumab minus ranibizumab +1.89 letters; 95% confidence interval [CI], -1.16 to +4.93, P &lt; 0.0001). The intention-to-treat analysis was concordant. The mean number of injections was 6.8 in the bevacizumab group and 6.5 in the ranibizumab group (P = 0.39). Both drugs reduced the central subfield macular thickness, with a mean decrease of 95 μm for bevacizumab and 107 μm for ranibizumab (P = 0.27). There were no significant differences in the presence of subretinal or intraretinal fluid at final evaluation, dye leakage on angiogram, or change in choroidal neovascular area. The proportion of patients with serious adverse events was 12.6% in the bevacizumab group and 12.1% in the ranibizumab group (P = 0.88). The proportion of patients with serious systemic or ocular adverse events was similar in both groups. CONCLUSIONS: Bevacizumab was noninferior to ranibizumab for visual acuity at 1 year with similar safety profiles. Ranibizumab tended to have a better anatomic outcome. The results are similar to those of previous head-to-head studies. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references

Ranibizumab versus Bevacizumab for Neovascular Age-related Macular Degeneration: Results from the GEFAL Noninferiority Randomized Trial

International audienceObjective: To evaluate the relative efficacy and safety profile of bevacizumab versus ranibizumab intravitreal injections for the treatment of neovascular age-related macular degeneration (AMD). Design: Multicenter, prospective, noninferiority, double-masked, randomized clinical trial performed in 38 French ophthalmology centers. The noninferiority limit was 5 letters. Participants: Patients aged >= 50 years were eligible if they presented with subfoveal neovascular AMD, with best-corrected visual acuity (BVCA) in the study eye of between 20/32 and 20/320 measured on the Early Treatment of Diabetic Retinopathy Study chart and a lesion area of less than 12 optic disc areas (DA). Methods: Patients were randomly assigned to intravitreal administration of bevacizumab (1.25 mg) or ranibizumab (0.50 mg). Hospital pharmacies were responsible for preparing, blinding, and dispensing treatments. Patients were followed for 1 year, with a loading dose of 3 monthly intravitreal injections, followed by an asneeded regimen (1 injection in case of active disease) for the remaining 9 months with monthly follow-up. Main Outcome Measures: Mean change in visual acuity at 1 year. Results: Between June 2009 and November 2011, 501 patients were randomized. In the per protocol analysis, bevacizumab was noninferior to ranibizumab (bevacizumab minus ranibizumab +1.89 letters; 95% confidence interval [CI], -1.16 to +4.93, P< 0.0001). The intention-to-treat analysis was concordant. The mean number of injections was 6.8 in the bevacizumab group and 6.5 in the ranibizumab group (P=0.39). Both drugs reduced the central subfield macular thickness, with a mean decrease of 95 mm for bevacizumab and 107 mm for ranibizumab (P=0.27). There were no significant differences in the presence of subretinal or intraretinal fluid at final evaluation, dye leakage on angiogram, or change in choroidal neovascular area. The proportion of patients with serious adverse events was 12.6% in the bevacizumab group and 12.1% in the ranibizumab group (P=0.88). The proportion of patients with serious systemic or ocular adverse events was similar in both groups. Conclusions: Bevacizumab was noninferior to ranibizumab for visual acuity at 1 year with similar safety profiles. Ranibizumab tended to have a better anatomic outcome. The results are similar to those of previous head-to-head studies. (C) 2013 by the American Academy of Ophthalmology

Real Life of Aflibercept In FraNce: oBservatiOnal study in Wet AMD: the RAINBOW study

PurposeThe Rainbow study was implemented to collect real-life data on 600 patients with naïve wet AMD (wAMD) for whom treatment with aflibercept was initiated as first-line therapy. This large real life study with aflibercept will allow evaluating whether results of the VIEW Studies could be transposable in real-life conditions in France. MethodsRainbow is a retrospective and prospective observational study of 600 consecutive patients with wAMD included by a sample of 60 investigators selected with respect to activity and geography criteria, representative of French ophthalmologists. Patients have to be treated as part of the routine clinical practice in France. Any decisions on diagnostic and treatment-related procedures have to be made at the discretion of the investigator according to his/her medical practice. Patients will have a 48-month follow-up period during which routine visits will be considered as part of the study. Recorded data are: demographic data of patients, type of choroidal neovascularization (CNV), tools used for initial diagnosis of CNV, i.e. SD-OCT, and/or fluorescein angiography (FA) and/or indocyanine green angiography (ICGA), changes in ETDRS visual acuity, changes in central retinal thickness (CRT) measured with SD-OCT, number of intravitreal injection performed with aflibercept or with other anti-VEGF agents. ResultsRecruitment is ongoing, with an inclusion rate better than expected. At the time of submission of this abstract, the baseline characteristics showed a mean BCVA of 54.14 ± 17.71 letters, mean CRT of 383.50 ± 122.47 µm. Most patients were female (63.20%), their mean age was 81.27 ± 7.20 years. The tools used for initial diagnosis were SD-OCT (90.91%), FA (74.42%), ICGA (52.5%). Subtypes of CNV were: classic or minimally classic (37.50%), occult (20.83%), RAP (12.50%). Given retrospective/prospective study design, 3-and 6-month results should be available for most patients in April 2015. ConclusionsData collected in the real life are important to be compared with results of randomized clinical trials. The Rainbow study will be the first observational study to analyze results of aflibercept used in the real-life as first-line therapy in naïve wAMD in France. Results will also provide information on the practices for the monitoring and re-treatment strategy with aflibercept

Martinique Crinkled Retinal Pigment Epitheliopathy

International audiencePURPOSE:To reappraise the autosomal dominant Martinique crinkled retinal pigment epitheliopathy (MCRPE) in light of the knowledge of its associated mutated gene mitogen-activated protein kinase-activated protein kinase 3 (MAPKAPK3), an actor in the p38 mitogen-activated protein kinase pathway.DESIGN:Clinical and molecular study.PARTICIPANTS:A total of 45 patients from 3 generations belonging to a family originating from Martinique with an autosomal dominant MCRPE were examined.METHODS:Best-corrected visual acuity, fundus photographs, and spectral-domain optical coherence tomography (SD OCT) of all clinically affected patients and carriers for the causal mutation were reviewed at the initial visit and 4 years later for 10 of them. Histologic retinal lesions of Mapkapk3(-/-) mice were compared with those of the human disease.MAIN OUTCOME MEASURES:The MCRPE natural history in view of MAPKAPK3 function and Mapkapk3(-/-) mouse retinal lesions.RESULTS:Eighteen patients had the c.518T>C mutation. One heterozygous woman aged 20 years was asymptomatic with normal fundus and SD OCT (stage 0). All c.518T>C heterozygous patients older than 30 years of age had the characteristic dried-out soil fundus pattern (stages 1 and 2). Complications (stage 3) were observed in 7 cases, including polypoidal choroidal vasculopathy (PCV) and macular fibrosis or atrophy. One patient was homozygous and had a form with severe Bruch's membrane (BM) thickening and macular exudation with a dried-out soil pattern in the peripheral retina. The oldest heterozygous patient, who was legally blind, had peripheral nummular pigmentary changes (stage 4). After 4 years, visual acuity was unchanged in 6 of 10 patients. The dried-out soil elementary lesions radically enlarged in patients with a preferential macular extension and confluence. These findings are in line with the progressive thickening of BM noted with age in the mouse model. During follow-up, there was no occurrence of PCV.CONCLUSIONS:MCRPE is an autosomal dominant, fully penetrant retinal dystrophy with a preclinical stage, an onset after the age of 30 years, and a preserved visual acuity until occurrence of macular complications. The natural history of MCRPE is in relation to the role of MAPKAPK3 in BM modeling, vascular endothelial growth factor activity, retinal pigment epithelial responses to aging, and oxidative stress