Intravitreal Gene Therapy vs. Natural History in Patients With Leber Hereditary Optic Neuropathy Carrying the m.11778G>A <i>ND4</i> Mutation: Systematic Review and Indirect Comparison.

Objective: This work aimed to compare the evolution of visual outcomes in Leber hereditary optic neuropathy (LHON) patients treated with intravitreal gene therapy to the spontaneous evolution in prior natural history (NH) studies. Design: A combined analysis of two phase three randomized, double-masked, sham-controlled studies (REVERSE and RESCUE) and their joint long-term extension trial (CLIN06) evaluated the efficacy of rAAV2/2-ND4 vs. 11 pooled NH studies used as an external control. Subjects: The LHON subjects carried the m.11778G>A ND4 mutation and were aged ≥15 years at onset of vision loss. Methods: A total of 76 subjects received a single intravitreal rAAV2/2-ND4 injection in one eye and sham injection in the fellow eye within 1 year after vision loss in REVERSE and RESCUE. Both eyes were considered as treated due to the rAAV2/2-ND4 treatment efficacy observed in the contralateral eyes. Best corrected visual acuity (BCVA) from REVERSE, RESCUE, and CLIN06 up to 4.3 years after vision loss was compared to the visual acuity of 208 NH subjects matched for age and ND4 genotype. The NH subjects were from a LHON registry (REALITY) and from 10 NH studies. A locally estimated scatterplot smoothing (LOESS), non-parametric, local regression model was used to modelize visual acuity curves over time, and linear mixed model was used for statistical inferences. Main Outcome Measures: The main outcome measure was evolution of visual acuity from 12 months after vision loss, when REVERSE and RESCUE patients had been treated with rAAV2/2-ND4. Results: The LOESS curves showed that the BCVA of the treated patients progressively improved from month 12 to 52 after vision loss. At month 48, there was a statistically and clinically relevant difference in visual acuity of -0.33 logarithm of the minimal angle of resolution (LogMAR) (16.5 ETDRS letters equivalent) in favor of treated eyes vs. NH eyes (p p p Conclusions: The m.11778G>A LHON patients treated with rAAV2/2-ND4 exhibited an improvement of visual acuity over more than 4 years after vision loss to a degree not demonstrated in NH studies. Clinical Trial Registration: NCT02652767, NCT02652780, NCT03406104, and NCT03295071

Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset.

PURPOSE: To evaluate the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON). DESIGN: RESCUE is a multicenter, randomized, double-masked, sham-controlled, phase 3 clinical trial. PARTICIPANTS: Subjects with the m.11778G>A mitochondrial DNA mutation and vision loss ≤6 months from onset in 1 or both eyes were included. METHODS: Each subject's right eye was randomly assigned (1:1) to treatment with rAAV2/2-ND4 (single injection of 9 × 1010 viral genomes in 90 μl) or to sham injection. The left eye received the treatment not allocated to the right eye. MAIN OUTCOME MEASURES: The primary end point was the difference of the change from baseline in best-corrected visual acuity (BCVA) between rAAV2/2-ND4-treated and sham-treated eyes at week 48. Other outcome measures included contrast sensitivity, Humphrey visual field perimetry, retinal anatomic measures, and quality of life. Follow-up extended to week 96. RESULTS: Efficacy analysis included 38 subjects. Mean age was 36.8 years, and 82% were male. Mean duration of vision loss at time of treatment was 3.6 months and 3.9 months in the rAAV2/2-ND4-treated eyes and sham-treated eyes, respectively. Mean baseline logarithm of the minimum angle of resolution (logMAR) BCVA (standard deviation) was 1.31 (0.52) in rAAV2/2-ND4-treated eyes and 1.26 (0.62) in sham-treated eyes, with a range from -0.20 to 2.51. At week 48, the difference of the change in BCVA from baseline between rAAV2/2-ND4-treated and sham-treated eyes was -0.01 logMAR (P = 0.89); the primary end point of a -0.3 logMAR (15-letter) difference was not met. The mean BCVA for both groups deteriorated over the initial weeks, reaching the worst levels at week 24, followed by a plateau phase until week 48, and then an improvement of +10 and +9 Early Treatment Diabetic Retinopathy Study letters equivalent from the plateau level in the rAAV2/2-ND4-treated and sham-treated eyes, respectively. CONCLUSIONS: At 96 weeks after unilateral injection of rAAV2/2-ND4, LHON subjects carrying the m.11778G>A mutation treated within 6 months after vision loss achieved comparable visual outcomes in the injected and uninjected eyes

Indirect Comparison of Lenadogene Nolparvovec Gene Therapy Versus Natural History in Patients with Leber Hereditary Optic Neuropathy Carrying the m.11778G\u3eA MT-ND4 Mutation

INTRODUCTION: Lenadogene nolparvovec is a promising novel gene therapy for patients with Leber hereditary optic neuropathy (LHON) carrying the m.11778G\u3eA ND4 mutation (MT-ND4). A previous pooled analysis of phase 3 studies showed an improvement in visual acuity of patients injected with lenadogene nolparvovec compared to natural history. Here, we report updated results by incorporating data from the latest phase 3 trial REFLECT in the pool, increasing the number of treated patients from 76 to 174. METHODS: The visual acuity of 174 MT-ND4-carrying patients with LHON injected in one or both eyes with lenadogene nolparvovec from four pooled phase 3 studies (REVERSE, RESCUE and their long-term extension trial RESTORE; and REFLECT trial) was compared to the spontaneous evolution of an external control group of 208 matched patients from 11 natural history studies. RESULTS: Treated patients showed a clinically relevant and sustained improvement in their visual acuity when compared to natural history. Mean improvement versus natural history was - 0.30 logMAR (+ 15 ETDRS letters equivalent) at last observation (P \u3c 0.01) with a maximal follow-up of 3.9 years after injection. Most treated eyes were on-chart as compared to less than half of natural history eyes at 48 months after vision loss (89.6% versus 48.1%; P \u3c 0.01) and at last observation (76.1% versus 44.4%; P \u3c 0.01). When we adjusted for covariates of interest (gender, age of onset, ethnicity, and duration of follow-up), the estimated mean gain was - 0.43 logMAR (+ 21.5 ETDRS letters equivalent) versus natural history at last observation (P \u3c 0.0001). Treatment effect was consistent across all phase 3 clinical trials. Analyses from REFLECT suggest a larger treatment effect in patients receiving bilateral injection compared to unilateral injection. CONCLUSION: The efficacy of lenadogene nolparvovec in improving visual acuity in MT-ND4 LHON was confirmed in a large cohort of patients, compared to the spontaneous natural history decline. Bilateral injection of gene therapy may offer added benefits over unilateral injection. TRIAL REGISTRATION NUMBERS: NCT02652780 (REVERSE); NCT02652767 (RESCUE); NCT03406104 (RESTORE); NCT03293524 (REFLECT); NCT03295071 (REALITY)

Prolifération de précurseurs médullaires en culture chez des patients atteints d'occlusion veineuse rétinienne (a propos de 11 cas)

1) Introduction : les occlusions veiuneuses (occlusion de la veine centrale et occlusion de branche) sont des atteintes vasculaires rétiniennes fréquentes, avec un pronostic visuel souvent réservé. Malgré cela, le mécanisme physiopathologique responsable de l'obstruction n'est encore que partiellement compris. Certains facteurs de risque, comme l'hypertension artérielle et l'hypertonie occulaire semblent clairement associés à la survenue d'une occlusion veineuse rétiennne (OVR). D'autres facteurs de risque de thrombophilie sont probablement impliqués dans cette pathologie multifactorielle, notamment chez les sujet jeunes. 2) Objectif : Rapporter les résultats de myélogrammes avec culture des progéniteurs hématopoïétiques au cours des OVR. 3) Patients et méthodes : Depuis janvier 2001, 14 patients d'OVR vus au CHNO des XV-XX ont bénéficié, outre d'un bilan standard, d'un myélogramme avec mise en culture des progéniteurs hématopoïétiques. L'indication était portée sur le jeune âge du patient, l'absence de facteur de risque évident, ou une OVR récidivante. 4) Résultats : Il a été mis en évidence chez les 11 patients la présence de pousse spontanée de progéniteurs hématopoïétiques (érythroblastiques chez 6 patients, les deux chez 1 patient). Cette anomalie n'est jamais retrouvée dans une population normale sain, ni en cas de polyglobulie ou thrombocytose secondaires. Deux patients avaient une thrombocytose; les autres n'avaient aucune anomalie de la numération-formule sanguine ni du volume globulaire total. Il n'y avait pas de particularité clinique de l'OVR associée à cette anomalie. 5) Conclusion : Cette étude préliminaire suggère une association entre OVR et syndrome myéloprolitératif, occulte le plus souvent, dont l'intérêt pathogénique et thérapeutique reste à déterminer. Un suivi prolongé de ces patients est nécessaire pour déterminer leur pronostic visuel et hématologique. Ces résultats demandent à être confirmés par une étude plus vatse avec témoins, avec des critères d'inclusion précis.PARIS7-Villemin (751102101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Venous Nicking Without Arteriovenous Contact: The role of the arteriolar microenvironment in arteriovenous nickings

International audienceArteriovenous nickings (AVNs) in the retina are the cause of retinal vein occlusions and are also surrogates of cerebrovascular aging. The prevalent mechanistic model of AVNs stating that arteries crush veins remains somewhat unchallenged despite the lack of evidence other than fundus photographs. Here, we observed that venous nicking may be observed in the absence of physical contact with an arteriole.This observational study, conducted from January 2013 to September 2014, included 7 patients showing remodeling of a venous segment close to a retinal arteriole without arteriovenous overlap were imaged by adaptive optics imaging. Affected venous segments showed a variable association of nicking, narrowing, deviation, and opacification. Venous segments were deviated toward the arterioles in 6 of the 7 cases. The degree of venous narrowing ranged from 40% to 77%, while at these sites, the width of the intervascular space ranged from 16 μm to 42 μm. Similar features were identified in typical AVNs.Arteriovenous nickings do not necessarily involve an arteriovenous compression. Instead, the topology of venous changes suggests a retractile process originating in the intervascular space. These findings have important implications for the understanding of retinal vein occlusions and of cerebrovascular aging

Real-world outcomes of ranibizumab treatment in French patients with visual impairment due to Macular Edema secondary to Retinal Vein Occlusion: 24-month results from the BOREAL-RVO study.

International audienceIntroduction: Information about real-world ranibizumab use is needed to optimize treatment of macular edema secondary to retinal vein occlusion (RVO). The BOREAL-RVO study assessed treatment use, effectiveness and safety of 24-month treatment with ranibizumab 0.5 mg in patients with visual impairment due to macular edema secondary to RVO in a real-world setting. Methods: This was a multicenter, post-authorization, observational study in France, including patients starting ranibizumab for RVO. Primary endpoint was mean change from baseline in best-corrected visual acuity (BCVA) at Month 6. Secondary endpoints were mean changes from baseline in BCVA at Month 24 and central retinal thickness (CRT) at Months 6 and 24, and treatment use in real-world setting. Results: 226 branch RVO (BRVO) and 196 central RVO (CRVO) patients were enrolled; 71.7% and 70.9% completed the 24-month follow-up, respectively. In BRVO, mean (SD) baseline BCVA was 55.2 (18.7) letters, with gains of 14.3 (13.7), 14.1 (16.5), 13.0 (17.5) and 11.4 (20.1) letters at Months 3, 6, 12 and 24. In CRVO, mean (SD) baseline BCVA was 40.4 (25.6) letters, with gains of 16.0 (21.2), 9.5 (25.4), 9.2 (27.7) and 8.3 (23.8) letters at Months 3, 6, 12 and 24. At Month 24, 52% of BRVO and 41% of CRVO patients had gains of 15 or more letters. In BRVO, mean (SD) CRT values at baseline and Months 3, 6, 12 and 24 were 550 (175), 315 (104), 343 (122), 335 (137) and 340 (105) μm. In CRVO, mean (SD) CRT values at baseline and Months 3, 6, 12 and 24 were 643 (217), 327 (152), 400 (203), 379 (175) and 348 (161) μm. On average, BRVO patients had 3.8 injections for 6.9 visits by Month 6, and 7.2 injections for 19.7 visits by Month 24. CRVO patients had 2.7 injections for 4.2 visits by Month 6, and 7.1 injections for 21.1 visits by Month 24. Factors predictive of better BCVA gain at Month 6 were age under 60 at baseline, lower baseline BCVA and BCVA gain at Month 3. There were no new safety findings. Conclusion: Major improvements in BCVA and CRT were observed at Month 3 after the induction phase, and then was sustained up to Month 24, with a slight decrease, probably due to under-treatment. This study demonstrated ranibizumab to be a safe and effective treatment for BRVO and CRVO in the real-world setting, although more regular or pro-active treatment could further improve outcomes

Management of diabetic macular edema with visual impairment in real-life practice in France: findings from the cross-sectional BOREAL DME study

Purpose: Diabetic macular edema (DME) is the leading cause of visual impairment (VI) in patients with diabetes. With the introduction of anti-vascular endothelial growth factor (anti-VEGF) agents, management of DME has evolved. The aim of this study was to identify the routine practice for the management of patients with VI due to DME (best-corrected visual acuity [BCVA] ≤ 20/40) in France in 2014. Methods: The cross-sectional, observational BOREAL DME study was conducted in a real-life practice in France on request of health authority. The study included patients with Type 1 or 2 diabetes aged ≥ 18 years who had a reduction in BCVA due to DME ( ≤ 20/40) irrespective of treatment prescribed at inclusion (including monitoring alone). The following medical data were collected from patients’ medical files: general patient characteristics, disease characteristics (including diabetes and DME), previous treatment for VI due to DME, and treatment prescribed at inclusion. Results: Of the 1023 screened patients, 918 were included in the study (Figure 1). The mean age of the patients was 67.0 years with an average 18.9 years of diabetes; 53.1% were male and 67.3% had bilateral DME (Table 1). For this analysis we included 1321 eyes with VI due to DME (BCVA ≤ 20/40; Figure 1). The majority of eyes (64.6%) had received prior treatment for reduction in BCVA due to DME. In the analyzed eyes, anti-VEGF (49.6%) was the most frequently prescribed treatment at inclusion followed by monitoring alone (41.1%). 65.9% of eyes with monitoring alone had received prior treatment. Corticosteroids were prescribed for 6.5% of eyes, while only 2.2% of eyes received laser. The mean BCVA and central retinal thickness were 53.5 letters and 415 μ m, respectively. Overall, 57.8% of eyes presented non-proliferative DR. In the treatment naïve eyes (n=459), 50.5% received ranibizumab, 40.5% had monitoring alone, and 3.9% each received laser and corticosteroids, respectively. Conclusions: The BOREAL DME study findings suggest that, in real-life practice in France, anti-VEGFs, primarily ranibizumab 0.5 mg, are the primary treatment for VI due to DME, followed by monitoring alone in 2014. Macular laser is currently rarely used in the French population

Management of diabetic macular edema with visual impairment in real-life practice in France: findings from the cross-sectional BOREAL DME study

Purpose: Diabetic macular edema (DME) is the leading cause of visual impairment (VI) in patients with diabetes. With the introduction of anti-vascular endothelial growth factor (anti-VEGF) agents, management of DME has evolved. The aim of this study was to identify the routine practice for the management of patients with VI due to DME (best-corrected visual acuity [BCVA] ≤ 20/40) in France in 2014. Methods: The cross-sectional, observational BOREAL DME study was conducted in a real-life practice in France on request of health authority. The study included patients with Type 1 or 2 diabetes aged ≥ 18 years who had a reduction in BCVA due to DME ( ≤ 20/40) irrespective of treatment prescribed at inclusion (including monitoring alone). The following medical data were collected from patients’ medical files: general patient characteristics, disease characteristics (including diabetes and DME), previous treatment for VI due to DME, and treatment prescribed at inclusion. Results: Of the 1023 screened patients, 918 were included in the study (Figure 1). The mean age of the patients was 67.0 years with an average 18.9 years of diabetes; 53.1% were male and 67.3% had bilateral DME (Table 1). For this analysis we included 1321 eyes with VI due to DME (BCVA ≤ 20/40; Figure 1). The majority of eyes (64.6%) had received prior treatment for reduction in BCVA due to DME. In the analyzed eyes, anti-VEGF (49.6%) was the most frequently prescribed treatment at inclusion followed by monitoring alone (41.1%). 65.9% of eyes with monitoring alone had received prior treatment. Corticosteroids were prescribed for 6.5% of eyes, while only 2.2% of eyes received laser. The mean BCVA and central retinal thickness were 53.5 letters and 415 μ m, respectively. Overall, 57.8% of eyes presented non-proliferative DR. In the treatment naïve eyes (n=459), 50.5% received ranibizumab, 40.5% had monitoring alone, and 3.9% each received laser and corticosteroids, respectively. Conclusions: The BOREAL DME study findings suggest that, in real-life practice in France, anti-VEGFs, primarily ranibizumab 0.5 mg, are the primary treatment for VI due to DME, followed by monitoring alone in 2014. Macular laser is currently rarely used in the French population

Real-world outcomes after 36 months treatment with ranibizumab 0.5 mg in patients with visual impairment due to diabetic macular edema (BOREAL-DME)

International audienceTo assess the efficacy, safety and follow-up of 36 months treatment with ranibizumab in patients with diabetic macular edema (DME) in real life setting. Methods This is a prospective phase 4 observational study. Between December 2013 and April 2015, 84 ophthalmologists enrolled a total of 290 adult patients initiating ranibizumab for visual impairment due to diabetic macular edema (DME) and treated them according to their routine practice. The primary outcome (mean change in best-corrected visual acuity [BCVA] after 12 months) was previously reported. Here we present outcomes after 36 months of follow-up for BCVA, change in central subfield thickness (CSFT) and report how participating ophthalmologists treated DME over a 3 year period (number of visits and injections, and evolution of treatment strategy). Results Of the 290 patients enrolled, 187 (64.5%) completed the 36 months of the study (entire cohort). In the entire cohort, 97 patients were treated exclusively with ranibizumab throughout the study and 90 patients switched to other intravitreal treatments. Mean BCVA was 64.2 (20.1) letters, representing a gain of +4.1 (19.9) letters from baseline to Month 36 (M36). CSFT improved over the study, and by M36 had decreased by 127 (138) µm compared to baseline. Over the 36 months of follow-up, patients in the entire cohort paid their ophthalmologists a mean of 30.9 (12.2) visits and had a mean of 7.6 (5.2) any injections Results for quality of life questionnaires NEI-VFQ25 and HUI-3 remained stable throughout the study. Multivariate analysis on the 145 patients with evaluable BCVA data at M36 found that male gender and milder baseline DME characteristics (BCVA ≥59 and CSFT <500 µm) were predictive factors for achieving a BCVA of ≥70 letters at M36. This study did not find any new safety signals, compared to the known profile of ranibizumab. Conclusions Gains in BCVA in this real life study were lower than those observed in randomized clinical trials with ranibizumab, mainly due to under treatment. Safety analysis of ranibizumab did not yield any new safety concerns