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1.
Lancet ; 402(10411): 1449-1458, 2023 Oct 21.
Artículo en Inglés | MEDLINE | ID: mdl-37696275

RESUMEN

BACKGROUND: Geographic atrophy is an advanced form of dry age-related macular degeneration that can lead to irreversible vision loss and high burden of disease. We aimed to assess efficacy and safety of avacincaptad pegol 2 mg in reducing geographic atrophy lesion growth. METHODS: GATHER2 is a randomised, double-masked, sham-controlled, 24-month, phase 3 trial across 205 retina clinics, research hospitals, and academic institutions globally. To be eligible, patients had to be aged 50 years or older with non-centrepoint-involving geographic atrophy and best corrected visual acuity between 20/25 and 20/320 in the study eye. Eligible patients were randomly assigned (1:1) to monthly avacincaptad pegol 2 mg administered as a 100 µL intravitreal injection or sham for the first 12 months. Randomisation was performed using an interactive response technology system with stratification by factors known to be of prognostic importance in age-related macular degeneration. Patients, investigators, study centre staff, sponsor personnel, and data analysts were masked to treatment allocation. The primary endpoint was geographic atrophy lesion size measured by fundus autofluorescence at baseline, month 6, and month 12. Efficacy and safety analyses were done in the modified intention-to-treat and safety populations, respectively. This trial is registered with ClinicalTrials.gov, NCT04435366. FINDINGS: Between June 22, 2020, and July 23, 2021, 1422 patients were screened for eligibility, of whom 448 were enrolled and randomly assigned to avacincaptad pegol 2 mg (n=225) or sham (n=223). One patient in the sham group did not receive study treatment and was excluded from analyses. There were 154 (68%) female patients and 71 (32%) male patients in the avacincaptad pegol 2 mg group, and 156 (70%) female patients and 66 (30%) male patients in the sham group. From baseline to month 12, the mean rate of square-root-transformed geographic atrophy area growth was 0·336 mm/year (SE 0·032) with avacincaptad pegol 2 mg and 0·392 mm/year (0·033) with sham, a difference in growth of 0·056 mm/year (95% CI 0·016-0·096; p=0·0064), representing a 14% difference between the avacincaptad pegol 2 mg group and the sham group. Ocular treatment-emergent adverse events in the study eye occurred in 110 (49%) patients in the avacincaptad pegol 2 mg group and 83 (37%) in the sham group. There were no endophthalmitis, intraocular inflammation, or ischaemic optic neuropathy events over 12 months. To month 12, macular neovascularisation in the study eye occurred in 15 (7%) patients in the avacincaptad pegol 2 mg group and nine (4%) in the sham group, with exudative macular neovascularisation occurring in 11 (5%) in the avacincaptad pegol 2 mg group and seven (3%) in the sham group. INTERPRETATION: Monthly avacincaptad pegol 2 mg was well tolerated and showed significantly slower geographic atrophy growth over 12 months than sham treatment, suggesting that avacincaptad pegol might slow disease progression and potentially change the trajectory of disease for patients with geographic atrophy. FUNDING: Iveric Bio, An Astellas Company.

2.
Ophthalmology ; 131(8): 950-960, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38280653

RESUMEN

PURPOSE: To evaluate the 24-week efficacy and safety of the dual angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF)-A inhibitor faricimab versus aflibercept in patients with vein occlusion. DESIGN: Phase 3, global, randomized, double-masked, active comparator-controlled trials: BALATON/COMINO (ClincalTrials.gov identifiers: NCT04740905/NCT04740931; sites: 149/192). PARTICIPANTS: Patients with treatment-naïve foveal center-involved macular edema resulting from branch (BALATON) or central or hemiretinal (COMINO) RVO. METHODS: Patients were randomized 1:1 to faricimab 6.0 mg or aflibercept 2.0 mg every 4 weeks for 24 weeks. MAIN OUTCOME MEASURES: Primary end point: change in best-corrected visual acuity (BCVA) from baseline to week 24. Efficacy analyses included patients in the intention-to-treat population. Safety analyses included patients who received ≥ 1 doses of study drug. RESULTS: Enrollment: BALATON, n = 553; COMINO, n = 729. The BCVA gains from the baseline to week 24 with faricimab were noninferior versus aflibercept in BALATON (adjusted mean change, +16.9 letters [95.03% confidence interval (CI), 15.7-18.1 letters] vs. +17.5 letters [95.03% CI, 16.3-18.6 letters]) and COMINO (+16.9 letters [95.03% CI, 15.4-18.3 letters] vs. +17.3 letters [95.03% CI, 15.9-18.8 letters]). Adjusted mean central subfield thickness reductions from the baseline were comparable for faricimab and aflibercept at week 24 in BALATON (-311.4 µm [95.03% CI, -316.4 to -306.4 µm] and -304.4 µm [95.03% CI, -309.3 to -299.4 µm]) and COMINO (-461.6 µm [95.03% CI, -471.4 to -451.9 µm] and -448.8 µm [95.03% CI, -458.6 to -439.0 µm]). A greater proportion of patients in the faricimab versus aflibercept arm achieved absence of fluorescein angiography-based macular leakage at week 24 in BALATON (33.6% vs. 21.0%; nominal P = 0.0023) and COMINO (44.4% vs. 30.0%; nominal P = 0.0002). Faricimab was well tolerated, with an acceptable safety profile comparable with aflibercept. The incidence of ocular adverse events was similar between patients receiving faricimab (16.3% [n = 45] and 23.0% [n = 84] in BALATON and COMINO, respectively) and aflibercept (20.4% [n = 56] and 27.7% [n = 100], respectively). CONCLUSIONS: These findings demonstrate the efficacy and safety of faricimab, a dual Ang-2/VEGF-A inhibitor, in patients with macular edema secondary to retinal vein occlusion. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.


Asunto(s)
Inhibidores de la Angiogénesis , Inyecciones Intravítreas , Edema Macular , Receptores de Factores de Crecimiento Endotelial Vascular , Proteínas Recombinantes de Fusión , Oclusión de la Vena Retiniana , Tomografía de Coherencia Óptica , Factor A de Crecimiento Endotelial Vascular , Agudeza Visual , Humanos , Edema Macular/tratamiento farmacológico , Edema Macular/etiología , Edema Macular/fisiopatología , Edema Macular/diagnóstico , Oclusión de la Vena Retiniana/tratamiento farmacológico , Oclusión de la Vena Retiniana/complicaciones , Oclusión de la Vena Retiniana/diagnóstico , Oclusión de la Vena Retiniana/fisiopatología , Agudeza Visual/fisiología , Proteínas Recombinantes de Fusión/uso terapéutico , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/efectos adversos , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Masculino , Femenino , Método Doble Ciego , Inhibidores de la Angiogénesis/uso terapéutico , Inhibidores de la Angiogénesis/efectos adversos , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Persona de Mediana Edad , Anciano , Resultado del Tratamiento , Angiopoyetina 2/antagonistas & inhibidores
3.
Ophthalmology ; 131(8): 914-926, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38382813

RESUMEN

PURPOSE: To evaluate 2-year efficacy, durability, and safety of the bispecific antibody faricimab, which inhibits both angiopoietin-2 and VEGF-A. DESIGN: TENAYA (ClinicalTrials.gov identifier, NCT03823287) and LUCERNE (ClinicalTrials.gov identifier, NCT03823300) were identically designed, randomized, double-masked, active comparator-controlled phase 3 noninferiority trials. PARTICIPANTS: Treatment-naive patients with neovascular age-related macular degeneration (nAMD) 50 years of age or older. METHODS: Patients were randomized (1:1) to intravitreal faricimab 6.0 mg up to every 16 weeks (Q16W) or aflibercept 2.0 mg every 8 weeks (Q8W). Faricimab fixed dosing based on protocol-defined disease activity at weeks 20 and 24 up to week 60, followed up to week 108 by a treat-and-extend personalized treatment interval regimen. MAIN OUTCOME MEASURES: Efficacy analyses included change in best-corrected visual acuity (BCVA) from baseline at 2 years (averaged over weeks 104, 108, and 112) and proportion of patients receiving Q16W, every 12 weeks (Q12W), and Q8W dosing at week 112 in the intention-to-treat population. Safety analyses included ocular adverse events (AEs) in the study eye through study end at week 112. RESULTS: Of 1326 patients treated across TENAYA/LUCERNE, 1113 (83.9%) completed treatment (n = 555 faricimab; n = 558 aflibercept). The BCVA change from baseline at 2 years was comparable between faricimab and aflibercept groups in TENAYA (adjusted mean change, +3.7 letters [95% confidence interval (CI), +2.1 to +5.4] and +3.3 letters [95% CI, +1.7 to +4.9], respectively; mean difference, +0.4 letters [95% CI, -1.9 to +2.8]) and LUCERNE (adjusted mean change, +5.0 letters [95% CI, +3.4 to +6.6] and +5.2 letters [95% CI, +3.6 to +6.8], respectively; mean difference, -0.2 letters [95% CI, -2.4 to +2.1]). At week 112 in TENAYA and LUCERNE, 59.0% and 66.9%, respectively, achieved Q16W faricimab dosing, increasing from year 1, and 74.1% and 81.2%, achieved Q12W or longer dosing. Ocular AEs in the study eye were comparable between faricimab and aflibercept groups in TENAYA (55.0% and 56.5% of patients, respectively) and LUCERNE (52.9% and 47.5% of patients, respectively) through week 112. CONCLUSIONS: Treat-and-extend faricimab treatment based on nAMD disease activity maintained vision gains through year 2, with most patients achieving extended dosing intervals. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.


Asunto(s)
Inhibidores de la Angiogénesis , Angiopoyetina 2 , Anticuerpos Biespecíficos , Inyecciones Intravítreas , Receptores de Factores de Crecimiento Endotelial Vascular , Proteínas Recombinantes de Fusión , Factor A de Crecimiento Endotelial Vascular , Agudeza Visual , Degeneración Macular Húmeda , Humanos , Masculino , Femenino , Agudeza Visual/fisiología , Método Doble Ciego , Anticuerpos Biespecíficos/administración & dosificación , Anticuerpos Biespecíficos/efectos adversos , Anticuerpos Biespecíficos/uso terapéutico , Anciano , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Persona de Mediana Edad , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/uso terapéutico , Proteínas Recombinantes de Fusión/efectos adversos , Degeneración Macular Húmeda/tratamiento farmacológico , Degeneración Macular Húmeda/fisiopatología , Degeneración Macular Húmeda/diagnóstico , Receptores de Factores de Crecimiento Endotelial Vascular/administración & dosificación , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Angiopoyetina 2/antagonistas & inhibidores , Resultado del Tratamiento , Tomografía de Coherencia Óptica , Estudios de Seguimiento , Anciano de 80 o más Años , Angiografía con Fluoresceína , Relación Dosis-Respuesta a Droga
4.
Artículo en Inglés | MEDLINE | ID: mdl-38668853

RESUMEN

BACKGROUND: Intraocular dexamethasone implant (DEXi) is an efficient treatment for diabetic macular edema (DME). However, it may be unavailable or contraindicated. Triamcinolone acetonide is another corticosteroid that has proved to be safe and effective in treating macular edema complicating various diseases including diabetes. The purpose of this study is to evaluate the outcomes of a switch from DEXi to subtenon triamcinolone acetonide (STTA) and back, in eyes with DME. METHODS: Retrospective study. DME eyes that had been treated with DEXi and switched to STTA between October 2018 and February 2019 (stock shortage of DEXi) were included. The functional and anatomical outcomes of the switch and switch-back were studied. RESULTS: 26 eyes of 17 patients (mean age 67.1 ± 8.2 years) were considered. The mean baseline visual acuity (VA) was 0.35 ± 0.17 decimals remaining stable after DEXi, STTA and switch-back to DEXi. The mean central macular thickness (CMT) was 492.7 ± 32.8 µm initially, decreasing to 294.3 ± 133.4 µm after DEXi, 369.9 ± 182.3 µm after STTA and 297.6 ± 72.0 µm after switching back to DEXi (all p < 0.05 versus baseline). Compared to baseline, the CMT reduction was numerically better after DEXi and switching back to DEXi than after STTA (mean reduction: -200.4 µm, -167.7 µm, and -95.08 µm respectively, p = 0.13). Intraocular pressure was comparable after DEXi and STTA. CONCLUSION: DEXi is the steroid of choice in DME. However, STTA can be a cost-effective alternative when DEXi is unavailable or contraindicated. This study suggests that STTA may be used in the context of a step therapy in DME.

5.
Retina ; 44(7): 1217-1223, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38900579

RESUMEN

PURPOSE: To describe the progression from outer retinal neovascularization (ORNV) to exudative subretinal new vessels (SRNVs) in idiopathic macular telangiectasia type 2. METHODS: A total of 135 patients (270 eyes) imaged with optical coherence tomography angiography were included. MAIN OUTCOME MEASURES: Ellipsoid zone loss, outer retinal hyperreflectivity, ORNV, and SRNVs. Outer retinal neovascularization was defined as a flow signal passing through the outer plexiform layer, with or without vertical linear outer retinal hyperreflectivity on the optical coherence tomography B-scan. Subretinal new vessels were defined as an abnormal capillary network with a peripheral anastomotic arcade seen on en face optical coherence tomography angiography and a convex hyperreflectivity at the retinal pigment epithelium. RESULTS: Subretinal new vessels were observed in 38/270 eyes (14%). Subretinal new vessels were at a fibrotic stage in 24/38 eyes and at an exudative stage in 6/38 eyes, and a progression from ORNV to SRNVs was documented in 8/38 eyes. All cases showed an ellipsoid zone loss. In seven eyes (2.5%), SRNVs were also associated with subepithelial neovascularization. No retinochoroidal anastomosis was detected. The visual acuity dropped when SRNVs were present. CONCLUSION: In this case series, SRNVs were found in 14% of eyes. In all cases, they were associated with an ellipsoid zone loss and with outer retinal hyperreflectivity. A progression from ORNV to SRNVs was observed.


Asunto(s)
Angiografía con Fluoresceína , Neovascularización Retiniana , Telangiectasia Retiniana , Vasos Retinianos , Tomografía de Coherencia Óptica , Agudeza Visual , Humanos , Tomografía de Coherencia Óptica/métodos , Femenino , Masculino , Neovascularización Retiniana/diagnóstico , Neovascularización Retiniana/etiología , Angiografía con Fluoresceína/métodos , Anciano , Persona de Mediana Edad , Telangiectasia Retiniana/diagnóstico , Telangiectasia Retiniana/complicaciones , Vasos Retinianos/patología , Vasos Retinianos/diagnóstico por imagen , Estudios Retrospectivos , Fondo de Ojo , Progresión de la Enfermedad , Epitelio Pigmentado de la Retina/patología , Anciano de 80 o más Años , Adulto
6.
Retina ; 44(1): 10-19, 2024 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-37824807

RESUMEN

PURPOSE: To evaluate the impact of pigment epithelial detachment (PED) thickness (i.e., height) and thickness variability on best-corrected visual acuity outcomes in patients with neovascular age-related macular degeneration in the Phase 3 HAWK and HARRIER trials. METHODS: Optical coherence tomography images from the pooled brolucizumab 6 mg and aflibercept 2 mg arms were analyzed for the maximum PED thickness across the macula at baseline through to week 96. Best-corrected visual acuity outcomes were compared in patients with different PED thickness and variability cut-off thresholds. RESULTS: Greater PED thickness at baseline or at week 12 was associated with lower mean best-corrected visual acuity gain from baseline to week 96 (baseline PED ≥200 µ m: +4.6 letters; <200 µ m: +7.0 letters; week 12 PED ≥100 µ m: +5.6 letters; <100 µ m: +6.6 letters). Eyes with the largest PED thickness variability from week 12 through week 96 gained fewer letters from baseline at week 96 (≥33 µ m: +3.3 letters; <9 µ m: +6.2 letters). Furthermore, increased PED thickness at week 48 was associated with higher prevalence of intraretinal and subretinal fluid. CONCLUSION: In this treatment-agnostic analysis, greater PED thickness and PED thickness variability were associated with poorer visual outcomes in patients with neovascular age-related macular degeneration and greater neovascular activity.


Asunto(s)
Degeneración Macular , Desprendimiento de Retina , Degeneración Macular Húmeda , Humanos , Inhibidores de la Angiogénesis/uso terapéutico , Epitelio Pigmentado de la Retina , Agudeza Visual , Inyecciones Intravítreas , Desprendimiento de Retina/diagnóstico , Desprendimiento de Retina/tratamiento farmacológico , Desprendimiento de Retina/etiología , Tomografía de Coherencia Óptica/métodos , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Degeneración Macular/tratamiento farmacológico , Proteínas Recombinantes de Fusión/uso terapéutico , Degeneración Macular Húmeda/complicaciones , Degeneración Macular Húmeda/diagnóstico , Degeneración Macular Húmeda/tratamiento farmacológico
7.
Int Ophthalmol ; 44(1): 66, 2024 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-38347237

RESUMEN

PURPOSE: The incidence of retinal displacement after rhegmatogenous retinal detachment (RRD) surgery is variable and its clinical consequences are unclear. The aim of this study was to assess the incidence and clinical features of retinal displacement after RRD surgery by using ultra-widefield (UWF) imaging. METHODS: Retrospective observational study including all consecutive patients who underwent RRD surgery at the Rothschild Foundation Hospital. Postoperative data included the visual acuity and symptoms of visual impairment. Macular retinal displacement occurrence and its features were assessed and measured by using the autofluorescence images. RESULTS: A total of 123 eyes were included. UWF fundus autofluorescence revealed the presence of macular retinal displacement in 14 (11%) eyes. All displacements were inferior, with a mean angle of 3.8°. Patients with and without macular displacement did not differ in postoperative visual acuity. The retinal detachment extent and preoperative macular involvement were not significantly associated with the occurrence of retinal displacement. CONCLUSION: In this representative cohort of eyes that underwent RRD surgery with systematic screening for postoperative retinal displacement by UWF fundus autofluorescence, 11% of eyes experienced an inferior retinal shift. As in other cohorts, the presence of metamorphopsia was not associated with the occurrence of retinal shift.


Asunto(s)
Desprendimiento de Retina , Enfermedades de la Retina , Humanos , Desprendimiento de Retina/diagnóstico , Desprendimiento de Retina/epidemiología , Desprendimiento de Retina/cirugía , Incidencia , Vitrectomía/efectos adversos , Enfermedades de la Retina/diagnóstico , Retina , Estudios Retrospectivos
8.
Lancet ; 399(10326): 741-755, 2022 02 19.
Artículo en Inglés | MEDLINE | ID: mdl-35085503

RESUMEN

BACKGROUND: To reduce treatment burden and optimise patient outcomes in diabetic macular oedema, we present 1-year results from two phase 3 trials of faricimab, a novel angiopoietin-2 and vascular endothelial growth factor-A bispecific antibody. METHODS: YOSEMITE and RHINE were randomised, double-masked, non-inferiority trials across 353 sites worldwide. Adults with vision loss due to centre-involving diabetic macular oedema were randomly assigned (1:1:1) to intravitreal faricimab 6·0 mg every 8 weeks, faricimab 6·0 mg per personalised treatment interval (PTI), or aflibercept 2·0 mg every 8 weeks up to week 100. PTI dosing intervals were extended, maintained, or reduced (every 4 weeks up to every 16 weeks) based on disease activity at active dosing visits. The primary endpoint was mean change in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Efficacy analyses included the intention-to-treat population (non-inferiority margin 4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); safety analyses included patients with at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (YOSEMITE NCT03622580 and RHINE NCT03622593). FINDINGS: 3247 patients were screened for eligibility in YOSEMITE (n=1532) and RHINE (n=1715). After exclusions, 940 patients were enrolled into YOSEMITE between Sept 5, 2018, and Sept 19, 2019, and 951 patients were enrolled into RHINE between Oct 9, 2018, and Sept 20, 2019. These 1891 patients were randomly assigned to faricimab every 8 weeks (YOSEMITE n=315, RHINE n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Non-inferiority for the primary endpoint was achieved with faricimab every 8 weeks (adjusted mean vs aflibercept every 8 weeks in YOSEMITE 10·7 ETDRS letters [97·52% CI 9·4 to 12·0] vs 10·9 ETDRS letters [9·6 to 12·2], difference -0·2 ETDRS letters [-2·0 to 1·6]; RHINE 11·8 ETDRS letters [10·6 to 13·0] vs 10·3 ETDRS letters [9·1 to 11·4] letters, difference 1·5 ETDRS letters [-0·1 to 3·2]) and faricimab PTI (YOSEMITE 11·6 ETDRS letters [10·3 to 12·9], difference 0·7 ETDRS letters [-1·1 to 2·5]; RHINE 10·8 ETDRS letters [9·6 to 11·9], difference 0·5 ETDRS letters [-1·1 to 2·1]). Incidence of ocular adverse events was comparable between faricimab every 8 weeks (YOSEMITE n=98 [31%], RHINE n=137 [43%]), faricimab PTI (n=106 [34%], n=119 [37%]), and aflibercept every 8 weeks (n=102 [33%], n=113 [36%]). INTERPRETATION: Robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for faricimab to extend the durability of treatment for patients with diabetic macular oedema. FUNDING: F Hoffmann-La Roche.


Asunto(s)
Inhibidores de la Angiogénesis/administración & dosificación , Anticuerpos Biespecíficos/administración & dosificación , Retinopatía Diabética/tratamiento farmacológico , Edema/tratamiento farmacológico , Anciano , Inhibidores de la Angiogénesis/efectos adversos , Angiopoyetina 2/antagonistas & inhibidores , Anticuerpos Biespecíficos/efectos adversos , Retinopatía Diabética/diagnóstico , Método Doble Ciego , Esquema de Medicación , Edema/etiología , Femenino , Humanos , Inyecciones Intravítreas , Mácula Lútea/diagnóstico por imagen , Mácula Lútea/efectos de los fármacos , Masculino , Persona de Mediana Edad , Receptores de Factores de Crecimiento Endotelial Vascular/administración & dosificación , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/efectos adversos , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Agudeza Visual/efectos de los fármacos
9.
Ophthalmology ; 130(9): 947-957, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37088447

RESUMEN

PURPOSE: To compare the efficacy and the safety of submacular hemorrhage (SMH) management using either surgical pars plana vitrectomy (PPV) or pneumatic displacement (PD) with tissue plasminogen activator (tPA) and vascular endothelial growth factor (VEGF) inhibitor added to each arm. DESIGN: Randomized, open-label, multicenter superiority study. PARTICIPANTS: Ninety patients with neovascular age-related macular degeneration (nAMD) 50 years of age or older with recent SMH (≤ 14 days) of more than 2 optic disc areas and predominantly overlying the retinal pigment epithelium. METHODS: Patients were assigned randomly to surgery (PPV, subretinal tPA [maximum, 0.5 ml/50 µg], and 20% sulfur hexafluoride [SF6] tamponade) or PD (0.05 ml intravitreal tPA [50 µg] and 0.3 ml intravitreal pure SF6). Both groups were asked to maintain a head upright position with the face forward at 45° for 3 days after intervention and received 0.5 mg intravitreal ranibizumab at the end of the intervention, at months 1 and 2, as the loading phase, and then on a pro re nata regimen during a 6-month follow-up. MAIN OUTCOME MEASURES: The primary efficacy endpoint was mean best-corrected visual acuity (VA) change at month 3. The secondary endpoints were mean VA change at month 6, 25-item National Eye Institute Visual Function Questionnaire composite score value at months 3 and 6, number of anti-VEGF injections, and complications during the 6-month follow-up. RESULTS: Of the 90 patients randomized, 78 patients (86.7%) completed the 3-month efficacy endpoint visit. The mean VA change from baseline to month 3 in the surgery group (+16.8 letters [95% confidence interval (CI), 8.7-24.9 letters]) was not significantly superior to that in the PD group (+16.4 letters [95% CI, 7.1-25.7 letters]; adjusted difference ß, 1.9 [-11.0; 14.9]; P = 0.767). Both groups achieved similar secondary outcomes at month 6. No unexpected ocular safety concerns were observed in either group. CONCLUSIONS: Surgery did not yield superior visual gain nor additional benefit for SMH secondary to nAMD compared with PD at 3 months, with intravitreal anti-VEGF added to each arm. Both treatment strategies lead to a clinical improvement of VA without safety concerns for SMH over 6 months. Both design and results of the trial cannot be used to establish equivalence between treatments. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.


Asunto(s)
Degeneración Macular , Activador de Tejido Plasminógeno , Humanos , Persona de Mediana Edad , Recién Nacido , Activador de Tejido Plasminógeno/uso terapéutico , Inhibidores de la Angiogénesis/uso terapéutico , Fibrinolíticos/uso terapéutico , Factor A de Crecimiento Endotelial Vascular , Ranibizumab/uso terapéutico , Hemorragia Retiniana/tratamiento farmacológico , Hemorragia Retiniana/etiología , Hemorragia Retiniana/cirugía , Degeneración Macular/complicaciones , Degeneración Macular/tratamiento farmacológico , Epitelio Pigmentado de la Retina , Inyecciones Intravítreas
10.
Retina ; 43(9): 1514-1524, 2023 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-37199396

RESUMEN

PURPOSE: To describe and quantify the abnormalities of the retinal capillary plexuses using optical coherence tomography angiography in Coats disease. METHODS: Retrospective study. Eleven eyes of 11 patients with Coats disease (9 men and two women aged 32-80 years) compared with nine fellow eyes and 11 healthy control eyes. Horizontal bands of contiguous 3 × 3 mm optical coherence tomography angiograms of the superficial vascular plexus and deep capillary complex were acquired from the optic disk to 6 mm temporal to the fovea, through areas with telangiectasia visible on fluorescein angiography in 9 cases. RESULTS: The vascular density was significantly decreased in both plexuses in eyes with Coats disease compared with normal and fellow eyes within the 6 mm temporal to the fovea (superficial vascular plexus: 21.5 vs. 29.4%, P = 0.00004 and vs. 30.3%, P = 0.00008; deep capillary complex, 16.5 vs. 23.9%, P = 0.00004 and vs. 24.7%, P = 0.00008, respectively). The fractal dimension was also significantly decreased in eyes with Coats disease (superficial vascular plexus: 1.796 vs. 1.848 P = 0.001 and vs. 1.833, P = 0.003; deep capillary complex: 1.762 vs. 1.853, P = 0.003 and vs. 1.838, P = 0.004, respectively). CONCLUSION: Retinal plexuses' vascular density was decreased in Coats disease, including in areas with no visible telangiectasia.


Asunto(s)
Telangiectasia Retiniana , Masculino , Humanos , Femenino , Telangiectasia Retiniana/diagnóstico , Estudios Retrospectivos , Vasos Retinianos , Tomografía de Coherencia Óptica/métodos , Agudeza Visual , Angiografía con Fluoresceína/métodos
11.
J Eur Acad Dermatol Venereol ; 37(5): 1056-1063, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-36732052

RESUMEN

BACKGROUND: Although ocular adverse events are frequent in AD patients treated with dupilumab, their characterization remains limited due to a lack of prospective studies with a systematic ophthalmological examination. OBJECTIVE: To examine the incidence, characteristics and risk factors of dupilumab-induced ocular adverse events. METHODS: A prospective, multicenter, and real-life study in adult AD patients treated with dupilumab. RESULTS: At baseline, 27 out of 181 patients (14.9%) had conjunctivitis. At week 16 (W16), 25 out of 27 had improved their conjunctivitis and 2 remained stable and 34 out of 181 patients (18.7%) had dupilumab-induced blepharoconjunctivitis: either de novo (n = 32) or worsening of underlying blepharoconjunctivitis (n = 2). Most events (27/34; 79.4%) were moderate. A multivariate analysis showed that head and neck AD (OR = 7.254; 95%CI [1.938-30.07]; p = 0.004), erythroderma (OR = 5.635; 95%CI [1.635-21.50]; p = 0.007) and the presence of dry eye syndrome at baseline (OR = 3.51; 95%CI [3.158-13.90]; p = 0.031) were independent factors associated with dupilumab-induced blepharoconjunctivitis. LIMITATIONS: Our follow-up period was 16 weeks and some late-onset time effects may still occur. CONCLUSION: This study showed that most dupilumab-induced blepharoconjunctivitis cases are de novo. AD severity and conjunctivitis at baseline were not found to be associated risk factors in this study.


Asunto(s)
Conjuntivitis , Dermatitis Atópica , Adulto , Humanos , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/diagnóstico , Estudios Prospectivos , Anticuerpos Monoclonales Humanizados/efectos adversos , Conjuntivitis/inducido químicamente , Conjuntivitis/epidemiología , Índice de Severidad de la Enfermedad , Resultado del Tratamiento
12.
Retina ; 42(2): 290-297, 2022 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-34620799

RESUMEN

PURPOSE: To evaluate the mean change in visual acuity at 52 weeks in patients with idiopathic choroidal neovascularization treated with aflibercept. METHODS: We conducted a prospective noncomparative open-label Phase-II trial. The dosage regimen evaluated in this study was structured into two periods: (1) from inclusion to 20 weeks: a treat-and-extend period composed of three mandatory intravitreal injections, and complementary intravitreal injections performed if needed; (2) from 21 weeks to 52 weeks: a pro re nata period composed of intravitreal injections performed only if needed. RESULTS: A total of 19 patients were included, and 16 completed the 52-week study. At baseline, the mean best corrected visual acuity was 66.56 (±20.72) letters (≈20/50 Snellen equivalent), and the mean central retinal thickness was 376.74 µm (±93.77). At 52 weeks, the mean change in the best-corrected visual acuity was +19.50 (±19.36) letters [95% confidence interval = +9.18 to +29.82]. None of the patients included lost ≥15 letters at 24 weeks or 52 weeks. The mean change in central retinal thickness was -96.78 µm (±104.29) at 24 weeks and -86.22 µm (±112.27) at 52 weeks. The mean number of intravitreal injections was 5.4 (±3.0) at 52-weeks. No ocular serious adverse events related to the treatment were reported. CONCLUSION: The present analysis shows clinically significant functional and anatomical treatment effect of aflibercept in case of idiopathic choroidal neovascularization. The treat-and-extend regimen proposed after the first injection seems adequate to treat most neovessels.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Neovascularización Coroidal/tratamiento farmacológico , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Adulto , Inhibidores de la Angiogénesis/efectos adversos , Neovascularización Coroidal/fisiopatología , Colorantes/administración & dosificación , Femenino , Angiografía con Fluoresceína , Estudios de Seguimiento , Humanos , Verde de Indocianina/administración & dosificación , Inyecciones Intravítreas , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proteínas Recombinantes de Fusión/efectos adversos , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Agudeza Visual/fisiología , Adulto Joven
13.
Ophthalmologica ; 245(4): 350-357, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34587614

RESUMEN

BACKGROUND AND PURPOSE: The aim of this study was to describe the outcomes of a switch back to anti-vascular endothelial growth factor (VEGF) in diabetic macular oedema (DME) eyes treated temporarily with a dexamethasone implant (DEXi), after an initial poor response to anti-VEGF. METHODS: The study involved a case series. RESULTS: Twenty-three eyes of 17 patients were included. All were poorly responsive to anti-VEGF and switched to a DEXi after a mean of 12 anti-VEGF injections. The mean best-corrected visual acuity (BCVA) increased from 0.25 ± 0.19 (decimals) to 0.29 ± 0.20 after switching to the DEXi (p = 0.11). BCVA remained stable (0.31 ± 0.23; p = 0.11) after switching back to anti-VEGF, one month after the last injection. The mean central macular thickness (CMT) decreased significantly from 517.0 ± 128.5 µm to 343.4 ± 118.9 µm (p < 0.001) after switching to the DEXi. In eyes receiving ≥3 anti-VEGF injections during the switch back, the CMT 1 month after the last anti-VEGF injection was significantly decreased compared to the CMT before the switch to the DEXi (mean change of - 95.55 ± 89.82 µm, p = 0.005). CONCLUSION: Switching back poorly responsive DME eyes to anti-VEGF after temporary DEXi therapy is associated with good anatomical and visual outcomes similar to those obtained with the DEXi, provided that at least 3 anti-VEGF injections are administered. The DEXi might restore retinal sensitivity to anti-VEGF.


Asunto(s)
Diabetes Mellitus , Retinopatía Diabética , Edema Macular , Inhibidores de la Angiogénesis , Bevacizumab , Dexametasona , Retinopatía Diabética/complicaciones , Retinopatía Diabética/diagnóstico , Retinopatía Diabética/tratamiento farmacológico , Humanos , Inyecciones Intravítreas , Edema Macular/diagnóstico , Edema Macular/tratamiento farmacológico , Edema Macular/etiología , Ranibizumab , Factor A de Crecimiento Endotelial Vascular , Agudeza Visual
14.
Glia ; 69(7): 1679-1693, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33683746

RESUMEN

Muller glial cells (MGCs) are responsible for the homeostatic and metabolic support of the retina. Despite the importance of MGCs in retinal disorders, reliable and accessible human cell sources to be used to model MGC-associated diseases are lacking. Although primary human MGCs (pMGCs) can be purified from post-mortem retinal tissues, the donor scarcity limits their use. To overcome this problem, we developed a protocol to generate and bank human induced pluripotent stem cell-derived MGCs (hiMGCs). Using a transcriptome analysis, we showed that the three genetically independent hiMGCs generated were homogeneous and showed phenotypic characteristics and transcriptomic profile of pMGCs. These cells expressed key MGC markers, including Vimentin, CLU, DKK3, SOX9, SOX2, S100A16, ITGB1, and CD44 and could be cultured up to passage 8. Under our culture conditions, hiMGCs and pMGCs expressed low transcript levels of RLPB1, AQP4, KCNJ1, KCJN10, and SLC1A3. Using a disease modeling approach, we showed that hiMGCs could be used to model the features of diabetic retinopathy (DR)-associated dyslipidemia. Indeed, palmitate, a major free fatty acid with elevated plasma levels in diabetic patients, induced the expression of inflammatory cytokines found in the ocular fluid of DR patients such as CXCL8 (IL-8) and ANGPTL4. Moreover, the analysis of palmitate-treated hiMGC secretome showed an upregulation of proangiogenic factors strongly related to DR, including ANG2, Endoglin, IL-1ß, CXCL8, MMP-9, PDGF-AA, and VEGF. Thus, hiMGCs could be an alternative to pMGCs and an extremely valuable tool to help to understand and model glial cell involvement in retinal disorders, including DR.


Asunto(s)
Diabetes Mellitus , Retinopatía Diabética , Células Madre Pluripotentes Inducidas , Diabetes Mellitus/metabolismo , Células Ependimogliales/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Neuroglía/metabolismo , Retina
15.
Ophthalmology ; 128(1): 89-99, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32574761

RESUMEN

PURPOSE: To report the 96-week outcomes from HAWK and HARRIER. DESIGN: Phase 3, prospective, randomized, double-masked, multicenter studies comparing efficacy and safety of brolucizumab 3 mg (HAWK only) and 6 mg with aflibercept 2 mg in eyes with neovascular age-related macular degeneration (nAMD). PARTICIPANTS: Treatment-naïve eyes with nAMD were randomized 1:1:1 to brolucizumab 3 mg (n = 358), brolucizumab 6 mg (n = 360), aflibercept 2 mg (n = 360; HAWK) or 1:1 to brolucizumab 6 mg (n = 370), aflibercept 2 mg (n = 369; HARRIER). METHODS: After 3 monthly loading doses, brolucizumab patients received every (q)-12-week (w) dosing, possibly adjusting to q8w dosing if disease activity was present at predefined disease activity assessment (DAA) visits. Aflibercept was dosed in a fixed q8w regimen. Visual and anatomic parameters were assessed throughout. Primary end point was at week 48 (48w), confirmed at 96w. MAIN OUTCOME MEASURES: Mean best-corrected visual acuity (BCVA) change from baseline, proportion of patients on an q12w regimen, retinal thickness, retinal fluid changes, and safety, all to 96w. RESULTS: Mean change (least squares [LS] mean ± standard error) in BCVA from baseline to 96w in HAWK was 5.6±0.79 Early Treatment Diabetic Retinopathy Study (ETDRS) letters for brolucizumab 3 mg, 5.90±0.78 letters for brolucizumab 6 mg, and 5.3±0.78 letters for aflibercept and in HARRIER was 6.1±0.73 letters for brolucizumab 6 mg and 6.6 ± 0.73 letters for aflibercept. Greater central subfield thickness reductions were observed with brolucizumab 6 mg versus aflibercept in HAWK (LS mean, -174.8 µm vs. -148.7 µm; 95% confidence interval for treatment difference, -46.2 to -5.9 µm; P = 0.0115) and HARRIER (LS mean, -197.7 µm vs. -155.1 µm; 95% confidence interval for treatment difference, -62.0 to -23.3 µm; P < 0.0001). The proportions of eyes with intraretinal fluid and/or subretinal fluid (IRF/SRF) at 96w in HAWK were 31% (P = 0.0688) and 24% (P = 0.0002) for brolucizumab 3 mg and 6 mg and 37% for aflibercept, whereas in HARRIER, they were 24% for brolucizumab 6 mg (P < 0.0001) and 39% for aflibercept. At 92w (last DAA), a 45.4% and 38.6% probability was observed for brolucizumab 6 mg patients of maintaining an q12w treatment regimen in HAWK and HARRIER, respectively. Brolucizumab exhibited an overall well-tolerated safety profile. CONCLUSIONS: Visual outcomes from 48w to 96w confirm the efficacy achieved at 48w. Brolucizumab demonstrated greater fluid resolution compared with aflibercept. The q12w potential for brolucizumab observed at 48w was maintained to 96w.


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Agudeza Visual , Degeneración Macular Húmeda/tratamiento farmacológico , Inhibidores de la Angiogénesis/administración & dosificación , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Quimioterapia Combinada , Estudios de Seguimiento , Mácula Lútea/patología , Estudios Prospectivos , Receptores de Factores de Crecimiento Endotelial Vascular/administración & dosificación , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Proteínas Recombinantes de Fusión/administración & dosificación , Factores de Tiempo , Tomografía de Coherencia Óptica/métodos , Resultado del Tratamiento , Degeneración Macular Húmeda/diagnóstico
16.
Ophthalmology ; 128(7): 1050-1059, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33207259

RESUMEN

PURPOSE: An independent Safety Review Committee (SRC), supported by Novartis Pharma AG, analyzed investigator-reported cases of intraocular inflammation (IOI), endophthalmitis, and retinal arterial occlusion in the phase 3 HAWK and HARRIER trials of brolucizumab versus aflibercept in neovascular age-related macular degeneration (nAMD). DESIGN: A post hoc analysis of a subset of data from two 2-year, double-masked, multicenter, active-controlled randomized phase 3 trials (NCT02307682, NCT02434328). PARTICIPANTS: Patients (N = 1817) with untreated, active choroidal neovascularization due to age-related macular degeneration in the study eye were randomized and treated in HAWK/HARRIER. The SRC reviewed data from cases of investigator-reported IOI (60/1088 brolucizumab-treated eyes; 8/729 aflibercept-treated eyes). METHODS: The SRC received details and images (color fundus photography, fluorescein angiography, and OCT) for all investigator-determined cases of IOI, retinal arterial occlusion, and endophthalmitis. Cases were reviewed in detail by ≥2 readers, then adjudicated by the SRC as a group. MAIN OUTCOME MEASURES: Within this patient subset: incidence of IOI, signs and incidence of retinal vasculitis and/or retinal vascular occlusion, and visual acuity loss; time since first brolucizumab injection to IOI event onset; and frequency of visual acuity loss after brolucizumab injection by time of first IOI event onset. RESULTS: Fifty brolucizumab-treated eyes were considered to have definite/probable drug-related events within the spectrum of IOI, retinal vasculitis, and/or vascular occlusion. On the basis of these cases, incidence of definite/probable IOI was 4.6% (IOI + vasculitis, 3.3%; IOI + vasculitis + occlusion, 2.1%). There were 8 cases (incidence 0.74%) of at least moderate visual acuity loss (≥15 ETDRS letters) in eyes with IOI (7 in eyes with IOI + vasculitis + occlusion). Of the 8 cases, 5 experienced their first IOI-related event within 3 months of the first brolucizumab injection (increasing to 7/8 within 6 months). Incidence of IOI in aflibercept-treated eyes was 1.1%, with at least moderate visual acuity loss in 0.14%. CONCLUSIONS: This analysis of IOI cases after brolucizumab injection identified signs of retinal vasculitis with or without retinal vascular occlusion and an associated risk of visual acuity loss. The findings will help physicians to evaluate the risks and benefits of brolucizumab treatment for nAMD.


Asunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Endoftalmitis/etiología , Oclusión de la Arteria Retiniana/etiología , Vasculitis Retiniana/etiología , Agudeza Visual , Degeneración Macular Húmeda/tratamiento farmacológico , Anciano , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Coroides/patología , Progresión de la Enfermedad , Método Doble Ciego , Endoftalmitis/diagnóstico , Endoftalmitis/epidemiología , Europa (Continente)/epidemiología , Femenino , Angiografía con Fluoresceína , Estudios de Seguimiento , Fondo de Ojo , Humanos , Incidencia , Inyecciones Intravítreas , Masculino , Pronóstico , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Proteínas Recombinantes de Fusión , Retina/patología , Oclusión de la Arteria Retiniana/diagnóstico , Oclusión de la Arteria Retiniana/epidemiología , Vasculitis Retiniana/diagnóstico , Vasculitis Retiniana/epidemiología , Factores de Tiempo , Estados Unidos/epidemiología , Degeneración Macular Húmeda/diagnóstico
17.
Graefes Arch Clin Exp Ophthalmol ; 259(12): 3613-3623, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34264396

RESUMEN

PURPOSE: To determine the prevalence of diabetic retinopathy (DR) and its risk factors in adult type 1 diabetes (T1D) patients METHODS: In this cross-sectional study, all T1D patients followed in the University Center for Diabetes and its Complications of Lariboisière Hospital (Paris, France) between January 2017 and February 2019 were included. Ophthalmologic and systemic data were collected from electronic records. The association between DR (and each grade) and associated factors were estimated by univariate and multivariate analyses using logistic regression models. RESULTS: A total of 1464 patients (46.2% of women, mean age: 42.2 ± 15.8 years) were included. The mean hemoglobin A1c (HbA1c) was 7.8 ± 1.7% and the mean diabetes duration was 20.5 ± 13.5 years. DR prevalence was 50.1% (47.4-52.6) and the prevalence of mild, moderate, and severe non-proliferative DR and proliferative DR was 19.1%, 9.4%, 3.9%, and 17.6%, respectively. DR was significantly associated with male gender, an older age, former and current smoking status, a higher BMI, the presence of nephropathy and neuropathy, higher HBA1c, and longer diabetes duration. Patients with HbA1c > 10% had an adjusted odds ratio (OR) of 3.25 (1.77-6.01) of having DR compared to patients with HbA1c < 6.5%. Patients with a diabetes duration > 30 years had an adjusted OR of 24.87 (14.82-42.67) higher of having DR compared to patients with a diabetes duration < 10 years. CONCLUSION: In this study, 50.1% of adult T1D patients had DR and 17.6% had proliferative DR. Diabetes duration and HbA1c were major risk factors.


Asunto(s)
Diabetes Mellitus Tipo 1 , Retinopatía Diabética , Adulto , Anciano , Estudios Transversales , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/epidemiología , Retinopatía Diabética/diagnóstico , Retinopatía Diabética/epidemiología , Femenino , Hemoglobina Glucada , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Factores de Riesgo
18.
Ophthalmologica ; 244(2): 127-132, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-32772030

RESUMEN

PURPOSE: To assess preoperative optical coherence tomography (OCT) findings of foveal-splitting retinal detachment (RD) and determine postoperative outcomes. METHODS: Consecutive patients who underwent RD surgery over a 1-year period were included. Patients diagnosed with a detachment extending to the edge of the fovea on fundus examination (i.e., macula-On/Off) underwent macular OCT scanning. Visual acuity (VA) after 1 year of macula-On/Off, macula-On, and macula-Off eyes was compared. RESULTS: A total of 85 eyes were included, 8 of which had a macula-On/Off RD. On preoperative OCT, all macula-On/Off RD eyes had foveal detachment extending beyond the foveal center over a median distance of 632 µm. Mean VA of the macula-On/Off eyes had improved from 20/160 to 20/40 at 1 year postoperatively (p = 0.035). The preoperative VA of macula-On/Off eyes was significantly better than macula-Off eyes (p = 0.032) and lower than macula-On eyes (p = 0.004). At 1 year, the VA of macula-On/Off eyes was no different from that of the macula-On eyes (p = 0.320), and tended to be better than that of the macula-Off eyes (p = 0.062). CONCLUSION: Preoperative OCT revealed a shallow RD extending beyond the foveal center in eyes with clinical foveal-splitting RD. These eyes, termed macula-On/Off RD eyes, had a preoperative VA between macula-On and macula-Off eyes, while their final VA was close to those with macula-On RD.


Asunto(s)
Mácula Lútea , Desprendimiento de Retina , Fóvea Central , Humanos , Desprendimiento de Retina/diagnóstico , Desprendimiento de Retina/cirugía , Estudios Retrospectivos , Tomografía de Coherencia Óptica , Vitrectomía
19.
Ophthalmologica ; 244(2): 93-101, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33197916

RESUMEN

BACKGROUND: Despite the success of anti-vascular endothelial growth factors (anti-VEGFs), currently, there is a need for highly effective compounds that can alleviate the burden of managing neovascular age-related macular degeneration (nAMD). PURPOSE: To review the milestones in the molecular and clinical development of brolucizumab, the first single-chain antibody fragment (scFv) designed specifically for intraocular use in humans. METHODS: In this article, we summarize the preclinical and current clinical evidence of brolucizumab administration with an overview of the other treatment regimens and additional indications under investigation. RESULTS: The unique molecular design of brolucizumab led to a low molecular weight of only 26 kDa, allowing for a concentrated molar dose of 1 intravitreal injection compared with other anti-VEGF agents. Phase I and II clinical trial outcomes validated the efficacy of brolucizumab in the treatment of nAMD with signals of a more durable treatment effect. The pivotal phase III trials, HAWK and HARRIER, which included a total of 1,817 patients, established that brolucizumab can be administered every 3 months while maintaining disease control. CONCLUSIONS: The preclinical and clinical data on brolucizumab provide evidence of sustained disease control with longer injection intervals, thus potentially reducing the treatment burden in patients with nAMD.


Asunto(s)
Inhibidores de la Angiogénesis , Degeneración Macular , Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Humanos , Inyecciones Intravítreas , Degeneración Macular/tratamiento farmacológico
20.
J Neuroinflammation ; 17(1): 1, 2020 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-31900165

RESUMEN

BACKGROUND: Age-related macular degeneration is characterized by the accumulation of subretinal macrophages and the degeneration of cones, but mainly of rods. We have previously shown that Mononuclear Phagocytes-derived IL-1ß induces rod photoreceptor cell death during experimental subretinal inflammation and in retinal explants exposed to IL-1ß but the mechanism is unknown. METHODS: Retinal explants were culture in the presence of human monocytes or IL-1ß and photoreceptor cell survival was analyzed by TUNEL labeling. Glutamate concentration and transcription levels of gene involved in the homeostasis of glutamate were analyzed in cell fractions of explant cultured or not in the presence of IL-1ß. Glutamate receptor antagonists were evaluated for their ability to reduce photoreceptor cell death in the presence of IL1-ß or monocytes. RESULTS: We here show that IL-1ß does not induce death in isolated photoreceptors, suggesting an indirect effect. We demonstrate that IL-1ß leads to glutamate-induced rod photoreceptor cell death as it increases the extracellular glutamate concentrations in the retina through the inhibition of its conversion to glutamine in Müller cells, increased release from Müller cells, and diminished reuptake. The inhibition of non-NMDA receptors completely and efficiently prevented rod apoptosis in retinal explants cultured in the presence of IL-1ß or, more importantly, in vivo, in a model of subretinal inflammation. CONCLUSIONS: Our study emphasizes the importance of inflammation in the deregulation of glutamate homeostasis and provides a comprehensive mechanism of action for IL-1ß-induced rod degeneration.


Asunto(s)
Ácido Glutámico/metabolismo , Homeostasis/fisiología , Interleucina-1beta/toxicidad , Degeneración Retiniana/inducido químicamente , Degeneración Retiniana/metabolismo , Células Fotorreceptoras Retinianas Bastones/metabolismo , Animales , Técnicas de Cocultivo , Homeostasis/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Células Fotorreceptoras Retinianas Bastones/efectos de los fármacos
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