UNASSIGNED: No established biomarkers currently exist for therapeutic efficacy and durability of anti-VEGF therapy in neovascular age-related macular degeneration (nAMD). This study evaluated radiomic-based quantitative OCT biomarkers that may be predictive of anti-VEGF treatment response and durability.
UNASSIGNED: Assessment of baseline biomarkers using machine learning (ML) classifiers to predict tolerance to anti-VEGF therapy.
UNASSIGNED: Eighty-one participants with treatment-naïve nAMD from the OSPREY study, including 15 super responders (patients who achieved and maintained retinal fluid resolution) and 66 non-super responders (patients who did not achieve or maintain retinal fluid resolution).
UNASSIGNED: A total of 962 texture-based radiomic features were extracted from fluid, subretinal hyperreflective material (SHRM), and different retinal tissue compartments of OCT scans. The top 8 features, chosen by the minimum redundancy maximum relevance feature selection method, were evaluated using 4 ML classifiers in a cross-validated approach to distinguish between the 2 patient groups. Longitudinal assessment of changes in different texture-based radiomic descriptors (delta-texture features) between baseline and month 3 also was performed to evaluate their association with treatment response. Additionally, 8 baseline clinical parameters and a combination of baseline OCT, delta-texture features, and the clinical parameters were evaluated in a cross-validated approach in terms of association with therapeutic response.
UNASSIGNED: The cross-validated area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity were calculated to validate the classifier performance.
UNASSIGNED: The cross-validated AUC by the quadratic discriminant analysis classifier was 0.75 ± 0.09 using texture-based baseline OCT features. The delta-texture features within different OCT compartments between baseline and month 3 yielded an AUC of 0.78 ± 0.08. The baseline clinical parameters sub-retinal pigment epithelium volume and intraretinal fluid volume yielded an AUC of 0.62 ± 0.07. When all the baseline, delta, and clinical features were combined, a statistically significant improvement in the classifier performance (AUC, 0.81 ± 0.07) was obtained.
UNASSIGNED: Radiomic-based quantitative assessment of OCT images was shown to distinguish between super responders and non-super responders to anti-VEGF therapy in nAMD. The baseline fluid and SHRM delta-texture features were found to be most discriminating across groups.

UNASSIGNED: To investigate serum cholesterol efflux capacity (the ability of the serum to accept cholesterol) and factors that regulate it using nuclear magnetic resonance-quantified measures of lipoprotein particle composition and size and apolipoproteins metrics in patients with age-related macular degeneration (AMD).
UNASSIGNED: Case-control study.
UNASSIGNED: Four hundred two serum samples from 80 patients with early AMD (eAMD), and 212 patients with neovascular AMD (nAMD), including 80 with typical nAMD (tAMD) and 132 with polypoidal choroidal vasculopathy (PCV), and 110 age- and gender matched control participants.
UNASSIGNED: Serum from participants showed cholesterol efflux capacity measured using in vitro cell assays and lipoprotein subfractions measured using nuclear magnetic resonance (Nightingale, Ltd). Associations between cholesterol efflux capacity (measured in percentage) and lipid subfractions were investigated in the patients and control participants.
UNASSIGNED: Cholesterol efflux capacity and lipid subfractions in control, eAMD, and nAMD. Associations between HDL subfractions and cholesterol efflux capacity.
UNASSIGNED: Cholesterol efflux capacity was higher in patients with eAMD (68.0 ± 11.3% [mean ± standard deviation]) and nAMD (75.9 ± 27.7%) than in the control participants (56.9 ± 16.7%) after adjusting for age, gender, and use of lipid-lowering drug (P < 0.0001). Nuclear magnetic resonance lipidomics demonstrated that the mean diameter of HDL was larger both in eAMD (9.96 ± 0.27 mm [mean ± standard deviation]) and PCV (9.97 ± 0.23 mm) compared with that of the control participants (9.84 ± 0.24 mm; P = 0.0001 for both). Among the 28 HDL subfractions, most of the small, medium, and large HDLs, but none of the 7 extra large HDLs fractions, were associated moderately with cholesterol efflux capacity in eAMD and PCV (R = 0.149-0.277).
UNASSIGNED: Serum cholesterol efflux capacity was increased in eAMD and PCV, but not tAMD, possibly reflecting differential underlying pathophysiologic features of lipid dysregulation in tAMD and PCV. Further studies should be directed toward investigating the diverse biological activities of HDL in AMD, including macular pigment transport, regulation of inflammation, and local cholesterol transport system.

UNASSIGNED: To establish the safety, tolerability, pharmacokinetics, and pharmacodynamics of an intravitreal injection of recombinant human complement factor H (CFH), GEM103, in individuals with genetically defined age-related macular degeneration (AMD) and geographic atrophy (GA).
UNASSIGNED: Phase I single ascending-dose, open-label clinical trial (ClinicalTrials.gov identifier, NCT04246866).
UNASSIGNED: Twelve individuals 50 years of age or older with a confirmed diagnosis of foveal GA in the study eye.
UNASSIGNED: Participants were assigned to the increasing dose cohorts and received 1 50-μl intravitreal injection of GEM103 at doses of 50 μg/eye, 100 μg/eye, 250 μg/eye, or 500 μg/eye; dose escalation was dependent on the occurrence of dose-limiting toxicities.
UNASSIGNED: Safety assessments included ocular and systemic adverse events (AEs), ocular examinations, clinical laboratory and vital signs, and serum antidrug antibody levels. Biomarkers, measured in the aqueous humor (AH), included CFH and complement activation biomarkers factor Ba and complement component 3a.
UNASSIGNED: No dose-limiting toxicities were reported, enabling escalation to the maximum study dose. No anti-GEM103 antidrug antibodies were detected during the study. Four participants experienced AEs; these were nonserious, mild or moderate in severity, and unrelated to GEM103. The AEs in 2 of these participants were related to the intravitreal injection procedure. No clinically significant ophthalmic changes and no ocular inflammation were observed. Visual acuity was maintained and stable throughout the 8-week follow-up period. No choroidal neovascularization occurred. CFH levels increased in a dose-dependent manner after GEM103 administration with supraphysiological levels observed at week 1; levels were more than baseline for 8 weeks or more in all participants receiving single doses of 100 μg or more. Complement activation biomarkers were reduced 7 days after dose administration.
UNASSIGNED: A single intravitreal administration of GEM103 (up to 500 μg/eye) was well tolerated in individuals with GA. Of the few mild or moderate AEs reported, none were determined to be related to GEM103. No intraocular inflammation or choroidal neovascularization developed. CFH levels in AH were increased and stable for 8 weeks, with pharmacodynamic data suggesting that GEM103 restored complement regulation. These results support further development in a repeat-dose trial in patients with GA with AMD.

UNASSIGNED: To evaluate the therapeutic benefit of a novel peptide, ALM201, in ocular pathologic vascularization.
UNASSIGNED: Experimental study in mouse, rat, and rabbit animal models.
UNASSIGNED: Ten-week-old Lister Hooded male rats, 8-week-old Brown Norway male rats, 9-day-old C57BL/6J mice, and 12-month-old New Zealand male rabbits.
UNASSIGNED: Corneal vascularization was scored for vessel density and vessel distance to suture in a rat corneal suture model. Ocular penetration and biodistribution were evaluated by matrix-assisted laser desorption/ionization mass spectrometry imaging after topical ALM201 application to rabbit eyes. A mouse choroidal sprouting assay, with aflibercept as positive control, was used to evaluate choroidal neovascularization (CNV) in the posterior segment tissue. Efficacy of topical ALM201 was assessed using a rat laser CNV model of neovascular age-related macular degeneration.
UNASSIGNED: Clinical scoring and histologic analysis of vascularized corneas, sprouting area, lesion size, and vessel leakiness in posterior segments.
UNASSIGNED: Assessment of ALM201 treatment in the rat corneal suture model showed a significant decrease in vessel density (P = 0.0065) and vessel distance to suture (P = 0.021) compared with vehicle control (phosphate-buffered saline [PBS]). Infiltration of inflammatory cells into the corneal stroma also was reduced significantly compared with PBS (724.5 ± 122 cells/mm2 vs. 1837 ± 195.9 cells/mm2, respectively; P = 0.0029). Biodistribution in rabbit eyes confirmed ALM201 bioavailability in anterior and posterior ocular segments 1 hour after topical instillation. ALM201 treatment significantly suppressed choroid vessel sprouting when compared with PBS treatment (44.5 ± 14.31 pixels vs. 120.9 ± 33.37 pixels, respectively; P = 0.04) and was not inferior to aflibercept (65.63 ± 11.86 pixels; P = 0.7459). Furthermore, topical ALM201 significantly improved vessel leakiness (leakage scores: 2.1 ± 0.7 vs. 2.9 ± 0.1; P = 0.0274) and lesion size (144,729 ± 33,239 μm3 vs. 187,923 ± 28,575 μm3; P = 0.03) in the rat laser CNV model when compared with topical PBS vehicle.
UNASSIGNED: ALM201 is a promising novel molecule with anti-inflammatory and antivascularization activity and is a strong candidate to meet the clinical need of a new, topically delivered therapeutic agent for treating inflammation and pathologic vascularization in the anterior and posterior segments of the eye.

UNASSIGNED: To investigate the association of risk alleles in complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) with complement activation products in the aqueous humor in eyes with neovascular age-related macular degeneration (nAMD) including polypoidal choroidal vasculopathy (PCV), retinal angiomatous proliferation (RAP), and pachychoroid neovasculopathy (PNV).
UNASSIGNED: Prospective, comparative, observational study.
UNASSIGNED: Treatment-naïve patients with nAMD and cataract patients as controls.
UNASSIGNED: The study included 236 eyes of 236 patients with nAMD and 49 control eyes of 49 patients. Aqueous humor samples were collected from 67 eyes with drusen-associated nAMD, 72 eyes with PCV, 26 eyes with RAP, and 71 eyes with PNV before intravitreal anti-VEGF injection and cataract surgery in the 49 control eyes. Clinical samples were measured for complement component 3a (C3a), C4a, and C5a using a bead-based immunoassay. Genotyping of the ARMS2 A69S (rs10490924), CFH I62V (rs800292), and CFH Y402H (rs1061170) was performed using TaqMan genotyping.
UNASSIGNED: The levels of complement activation products (C3a, C4a, and C5a) in the aqueous humor in each genotype of ARMS2 and CFH.
UNASSIGNED: The C3a level in the aqueous humor was significantly elevated (P = 0.006) in patients with nAMD and the ARMS2 A69S risk allele, whereas the levels of the complement activation products were not associated with CFH I62V and Y402H genotypes. Among the control eyes, no significant differences were seen in any complement activation products for all genetic polymorphisms. The levels of the complement activation products in the aqueous humor of eyes with the nAMD subtypes for each genetic polymorphism did not show significant differences.
UNASSIGNED: The C3a concentration in the aqueous humor was significantly higher in Japanese nAMD patients with the ARMS2 A69S risk allele, whereas it was not elevated in the patients with CFH I62V. Age-related maculopathy susceptibility 2 A69S polymorphism is strongly associated with local complement activation in nAMD patients.

UNASSIGNED: To evaluate longitudinally the performance of the Notal Vision Home OCT (NVHO), comprising a spectral-domain OCT device for patient self-imaging at home, telemedicine infrastructure for automated data upload, and deep learning algorithm for automated OCT evaluation. The aims were to study the system\'s performance in daily image acquisition and automated analysis and to characterize the dynamics of retinal fluid exudation in neovascular age-related macular degeneration (nAMD).
UNASSIGNED: Pilot prospective, observational longitudinal study.
UNASSIGNED: Four individuals (mean age, 73.8 years) with nAMD (one or both eyes) undergoing anti-vascular endothelial growth factor therapy in routine clinical practice.
UNASSIGNED: The participants performed daily self-imaging at home with the NVHO for 1 month. The macular cube scans were uploaded automatically to the Notal Health Cloud. They underwent evaluation separately by the Notal OCT Analyzer (NOA) and human expert graders for fluid presence, segmentation, and volume.
UNASSIGNED: Daily self-imaging completion, image quality, acquisition time, agreement between automated and human grading of retinal fluid, and temporal dynamics of fluid volume.
UNASSIGNED: Of 240 self-imaging attempts initiated, the number successfully completed was 211 (87.9%). Of these, 97.6% had satisfactory quality. For fluid presence, the NOA agreed with human grading in 94.7% of cases. From a subset of 24 scans with fluid, for agreement between NOA and human fluid volume measurements, the correlation coefficient was 0.996 and mean absolute difference was 1.5 nl (vs. 0.995 and 1.2 nl, respectively, for interhuman agreement). Graphic plots of fluid volume revealed wide variation in the dynamics of fluid exudation and treatment response.
UNASSIGNED: The participants could perform daily self-imaging at home and generate macular cube scans of satisfactory quality. Automated quantitative OCT analysis achieved high agreement with human grading. Daily self-imaging with automated OCT analysis permitted detailed characterization of the dynamics of fluid exudation and revealed wide variation between eyes. Metrics describing these dynamics may become important disease biomarkers. Home OCT telemedicine systems represent an alternative paradigm of disease monitoring; they may allow highly personalized retreatment decisions, with fewer unnecessary injections and clinic visits.

UNASSIGNED: To describe the design and rationale of the phase 3 TENAYA (ClinicalTrials.gov identifier, NCT03823287) and LUCERNE (ClinicalTrials.gov identifier, NCT03823300) trials that aimed to assess efficacy, safety, and durability of faricimab, the first bispecific antibody for intraocular use, which independently binds and neutralizes both angiopoietin-2 and vascular endothelial growth factor-A (VEGF-A) versus aflibercept in patients with neovascular age-related macular degeneration (nAMD).
UNASSIGNED: Identical, global, double-masked, randomized, controlled, phase 3 clinical trials.
UNASSIGNED: Adults with treatment-naïve nAMD.
UNASSIGNED: These trials were designed to evaluate patients randomized to receive faricimab 6.0 mg up to every 16 weeks after 4 initial every-4-week doses or aflibercept 2.0 mg every 8 weeks after 3 initial every-4-week doses. The initial doses in the faricimab arm were followed by individualized fixed treatment intervals up to week 60, based on disease activity assessment at weeks 20 and 24, guided by central subfield thickness, best-corrected visual acuity (BCVA), and investigator assessment. The primary efficacy end point was BCVA change from baseline averaged over weeks 40, 44, and 48. Secondary end points included the proportion of patients receiving every-8-week, every-12-week, and every-16-week faricimab and anatomic outcomes. Safety outcomes included incidence and severity of ocular and nonocular adverse events. From week 60, faricimab-treated patients followed a personalized treatment interval (PTI), a novel protocol-driven treat-and-extend regimen with interval adjustment from every 8 weeks to every 16 weeks based on individualized treatment response measured by anatomic criteria, functional criteria, and investigator assessment of patients\' disease activity.
UNASSIGNED: Rationale for trial design and PTI approach.
UNASSIGNED: The TENAYA and LUCERNE trials were the first registrational trials in nAMD to test fixed dosing regimens up to every 16 weeks based on patients\' disease activity in year 1 and incorporate a PTI paradigm during year 2. The PTI approach was designed to tailor treatment intervals to individual patient needs, to reflect clinical practice treatment practice, and to reduce treatment burden.
UNASSIGNED: The innovative trial design rationale for the TENAYA and LUCERNE trials included maximizing the benefits of angiopoietin-2 blockade through dosing up to every 16 weeks and PTI regimens based on patients\' disease activity while fulfilling health authority requirements for potential registrational efforts.

UNASSIGNED: This study aimed to estimate the incidence and prevalence of neovascular age-related macular degeneration (nAMD) in the French population between 2008 and 2018.
UNASSIGNED: This was a retrospective, longitudinal population study using health care consumption data from the Système National des Données de Santé (SNDS; the French National Health Information Database), which covers approximately 99% of the French population.
UNASSIGNED: We identified individuals treated for nAMD from the French population 50 years of age and older. Identification criteria were nAMD diagnosis or reimbursement of nAMD treatments (anti-vascular endothelial growth factor intravitreal injection or dynamic phototherapy with verteporfin). Exclusion criteria were high myopia, diagnosis of other retinal diseases, and other treatments for macular diseases (dexamethasone implant, laser therapy, etc.).
UNASSIGNED: We calculated incidence and prevalence based on the age-matched general population in France. Adjustment for age and sex was also performed for incidence.
UNASSIGNED: Incidence and prevalence of nAMD in the French population between 2008 and 2018.
UNASSIGNED: Between 2008 and 2018, we identified 342 961 patients with nAMD (67.5% women). Mean ± standard deviation age at nAMD diagnosis or first treatment increased from 78.8 ± 8.1 years in 2008 to 81.2 ± 7.9 years in 2018. In 2018, annual incidence was 0.149% and prevalence was 1.062% for the French population 50 years of age or older. Incidence was stable over the 10-year period. Annual incidence increased with age (0.223%, 0.380%, and 0.603% in those 60 years of age or older, 70 years of age or older, and 80 years of age or older, respectively), with similar trends for prevalence. No major differences were observed among the 14 regions of France for incidence or prevalence. Neovascular age-related macular degeneration incidence in 2018 was not impacted by the availability of primary or ophthalmology care in patients\' localities.
UNASSIGNED: The LANDSCAPE study provides exhaustive nationwide data on incidence and prevalence of nAMD in France over a 10-year period.

OBJECTIVE: To describe a case of marked vision loss in a patient with neovascular age-related macular degeneration after choroidal neovascular membrane (CNV) improvement and stabilization.
METHODS: An 82-year-old male presented with 20/800 vision having dropped from 20/50 three months prior. He had been undergoing active treatment for exudative macular degeneration over the past seven years, the CNV had stabilized. An extensive ophthalmic workup was performed revealing no CNV progression and no ophthalmic cause was identified for visual loss. An MRI of the brain was obtained, which showed a metastatic brain lesion in the occipital lobe, and subsequent workup determined it originated from an adenosquamous carcinoma of the lung.
CONCLUSIONS: When there is unexplained visual loss in an otherwise stable patient with macular degeneration, suspicion for non-retinal related causes of visual loss could alter the morbidity and mortality for patients with systemic diseases.

OBJECTIVE: To describe serum vascular endothelial growth factor (sVEGF) in patients with neovascular age-related macular degeneration (nAMD) receiving anti-VEGF agents and associations between sVEGF and systemic serious adverse events (SSAEs).
METHODS: Exploratory analyses of a randomized controlled trial that enrolled 610 participants with nAMD and compared 2 anti-VEGF antibodies, ranibizumab and bevacizumab, and 2 treatment regimens, monthly vs. discontinuous, with 2 years\' follow-up.
METHODS: Adults aged 50+ years with treatment-naïve nAMD and a visual acuity of ≥25 letters (Snellen equivalent 20/320) in the affected eye.
METHODS: Intravitreal injection of anti-VEGF antibodies.
METHODS: sVEGF and occurrence of SSAE, with particular interest in arteriothromboembolic events (ATE) and immunologically mediated events (IME).
RESULTS: On average, sVEGF (measured at months 0, 1, 11, 12, 23, and 24) decreased from a geometric mean of 168 pg/mL at baseline to 64 pg/mL at month 24. The decrease was greater with bevacizumab than with ranibizumab and was dependent on time since last treatment; at month 24 sVEGF was 11% lower with bevacizumab if treated ≥3 months previously, 51% lower if treated 2 months previously, and 76% lower if treated the previous month, compared with ranibizumab. The hazard of experiencing an ATE increased with age (hazard ratio [HR] = 2.01; 95% confidence interval [CI] = 1.32-3.05; P = 0.001) and higher sVEGF (HR = 1.16; 95% CI = 1.03-1.30, per 100 unit rise in sVEGF; P = 0.013). There was no association between sVEGF and the hazard of an IME (HR = 1.01; 95% CI = 0.76-1.33; P = 0.942); however, the hazard of an IME was significantly increased by treatment with bevacizumab compared with ranibizumab (HR = 3.53; 95% CI = 1.35-9.22; P = 0.010). The hazard of an \"other SSAE\" (not categorized as ATE or IME) increased with age (HR 1.51, 95% CI 1.14-2.01, P = 0.005) and decreased if an injection had been administered within the previous month (HR = 0.68; 95% CI = 0.45-1.03; P = 0.069).
CONCLUSIONS: The decrease in sVEGF is greater with bevacizumab than with ranibizumab, but this difference is eliminated when treatment is withheld for 3 months. Higher sVEGF increased the hazard of an ATE and bevacizumab increases the hazard of an IME compared with ranibizumab.