Neovascular Age-related Macular Degeneration Research Articles

Comparative study between swept-source and spectral-domain OCTA for imaging of choroidal neovascularization in age-related macular degeneration

AIM: To compare the differences of choroidal neovascularization (CNV) measurements between swept-source and spectral-domain optical coherence tomography angiography (SS-OCTA and SD-OCTA) in neovascular age-related macular degeneration (nAMD) and the imaging reliability of the two devices. METHODS: Prospective comparative study. SS-OCTA and SD-OCTA were used to scan the same eye with the modes of 3×3 and 6×6 mm2 centered on the neovascularization. Only qualified images were chosen and the border of CNV was manually delineated by two graders independently. The area of CNV (ACNV), vascular perfusion density (PD), and vessel length density (VLD) within the delineation were calculated using Image J. The differences of CNV measurements between the two OCTA devices were compared using Bland-Altman analysis. The agreement between the two graders on the measurements of each device was compared using the intraclass correlation coefficient (ICC). RESULTS: A total of 18 patients (22 eyes) with nAMD were included. The measurements of ACNV, PD, and VLD were 7.247±4.586 and 4.901±3.741 mm2, 43.202±9.636 and 34.904±10.489, 6.339±1.228 and 5.908±1.741 mm-1 for SS-OCTA and SD-OCTA, respectively. The differences between the two devices were 2.346±3.030 mm2 (Z= -3.782, P<0.0001), 8.298±14.160 (Z=-2.419, P=0.016), and 0.431±2.114 mm-1 (Z=-0.828, P=0.408) for ACNV, PD and VLD, respectively. The ICC between two graders were 0.893 (P<0.001), 0.902 (P<0.001), 0.885 (P<0.001) for ACNV, PD, VLD in SS-OCTA, and 0.971 (P<0.001), 0.976 (P<0.001), 0.973 (P<0.001) in SD-OCTA, respectively. CONCLUSION: Both OCTA devices have high imaging reliability. Compared with SD-OCTA, SS-OCTA has a larger ACNV measurements, but doesn't show better resolution of internal vessels of CNV and well signal strength.

Anti-VEGF treatment outcome prediction based on optical coherence tomography images in neovascular age-related macular degeneration using a deep neural network.

Age-related macular degeneration (AMD) is a major cause of blindness in developed countries, and the number of affected patients is increasing worldwide. Intravitreal injections of anti-vascular endothelial growth factor (VEGF) are the standard therapy for neovascular AMD (nAMD), and optical coherence tomography (OCT) is a crucial tool for evaluating the anatomical condition of the macula. However, OCT has limitations in accurately predicting the degree of functional and morphological improvement following intravitreal injections. Artificial intelligence (AI) has been proposed as a tool for predicting the treatment response of nAMD based on OCT biomarkers. Our study focuses on the development and assessment of an AI model utilizing the DenseNet201 algorithm. The model aims to predict anatomical improvement based on OCT images before, and during anti-VEGF therapy. The training process involves two scenarios: (1) using only preinjection OCT images and (2) utilizing both OCT images before and during anti-VEGF therapy for model training. The outcomes of our investigation, involving 2068 images from a cohort of 517 Korean patients diagnosed with nAMD, indicate that the AI model we introduced surpassed the predictive performance of ophthalmologists. The model exhibited a sensitivity of 0.915, specificity of 0.426, and accuracy of 0.820. Notably, its predictive capabilities were further enhanced with the inclusion of additional OCT images taken after the first and second injections during the loading phase. The treatment prediction performance of the model was the highest when using all input modalities (before injection, and after the first and second injections) and concatenation-based fusion layers. This study highlights the potential of AI in assisting individualized and tailored nAMD treatment.

Outlier ophthalmologists in the treatment of neovascular age-related macular degeneration with intravitreal therapy

BackgroundTo compare individual ophthalmologists grouped as outliers or non-outliers based on the mean 12-month visual acuity (VA) outcomes for their patients with neovascular age-related macular degeneration (nAMD).MethodsThis prospectively designed database...

Correlation of retinal fluid and photoreceptor and RPE loss in neovascular AMD by automated quantification, a real-world FRB! analysis.

To quantify ellipsoid zone (EZ) loss during anti-VEGF therapy for neovascular age-related macular degeneration (nAMD) and correlate these findings with nAMD disease activity using artificial intelligence-based algorithms. Spectral domain optical coherence tomography (Spectralis, Heidelberg Engineering) images from nAMD treatment-naïve patients from the Fight Retinal Blindness! (FRB!) Registry from Zürich, Switzerland were processed at baseline and over 3 years of follow-up. An approved deep learning algorithm (Fluid Monitor, RetInSight) was used to automatically quantify intraretinal fluid (IRF), subretinal fluid (SRF) and pigment epithelial detachment (PED). An ensemble U-net deep learning algorithm was used to automated quantify EZ integrity based on EZ layer thickness. The impact of fluid volumes on EZ thickness and late-stages outcomes were calculated using Wilcoxon rank-sum tests, a linear mixed model and a longitudinal panel regression model. Two hundred and eleven eyes from 158 patients were included. The mean ± SD EZ loss area in the central 6 mm was 1.81 ± 2.68 mm2 at baseline and reached 6.21 ± 6.15 mm2 at month 36. Higher fluid volumes (top 25%) of IRF and PED in the central 1 and 6 mm of the macula were significantly associated with more advanced EZ thinning and loss compared to the low fluid volume subgroup. The high SRF subgroup in the linear regression model showed no statistically significant association with EZ integrity in the central macula; however, the longitudinal analysis revealed an increased EZ thickness with no additional loss. Intraretinal fluid and PED volumes and their resolution pattern have an impact on alteration of the underlying EZ layer. AI-supported quantifications are helpful in quantifying early signs of macular atrophy and providing individual risk profiles as a basis for tailored therapies for optimized visual outcomes.

Ocular Pharmacokinetics of Faricimab Following Intravitreal Administration in Patients With Retinal Disease.

To characterize faricimab ocular and systemic pharmacokinetics (PK) in patients with neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME) and to assess the effect of faricimab ocular exposure on clinical endpoints. A population PK (popPK) model was developed using pooled data from phase 1 to 3 studies in patients with nAMD/DME. The dataset included 1095 faricimab aqueous humor (AH) concentrations from 284 patients and 8372 faricimab plasma concentrations from 2246 patients. Following intravitreal administration, faricimab PK was accurately described by a linear three-compartment model with sequential vitreous humor (VH), AH, and plasma compartments. Faricimab VH elimination to AH is the slowest process, with an estimated half-life (t1/2) of 7.5 days. Due to flip-flop kinetics, plasma, AH, and VH concentrations declined in parallel. Disease had no effect on faricimab PK. Plasma exposure was ∼6000-fold lower than VH exposure. Age, anti-drug antibodies, body weight, and sex statistically significantly influenced PK parameters but had no clinically meaningful effect on ocular and systemic exposure. VH t1/2 alone could not explain faricimab dosing frequency. Exposure-response analyses showed similar gains in best-corrected visual acuity across faricimab exposure ranges and dosing regimens. Faricimab ocular and systemic pharmacokinetics were quantified and accurately described by the popPK model, developed using a large dataset from patients with nAMD/DME. Exposure-response analyses suggest that faricimab phase 3 dosing algorithms are appropriate to select the most suitable dosing regimen. The popPK analysis suggested that faricimab dosing frequency was influenced by several factors and not by VH t1/2 alone.

Ocular Pharmacodynamics of Intravitreal Faricimab in Patients With Neovascular Age-Related Macular Degeneration or Diabetic Macular Edema.

Evaluate the ocular pharmacodynamics (PD) of intravitreal faricimab, a bispecific inhibitor of angiopoietin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A), in patients with neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME). Aqueous humor (AH) samples (1025 free Ang-2 concentrations and 1345 free VEGF-A concentrations) were collected from approximately 300 faricimab-treated patients with nAMD or DME in phase2/3 trials. A population pharmacokinetic pharmacodynamic (popPKPD) model was developed to describe the dynamic effect of faricimab on free AH Ang-2 and VEGF-A. Mean baseline Ang-2 concentrations were 8.1 and 13.4pg/mL in patients with nAMD and DME, respectively. The corresponding mean baseline VEGF-A concentrations were 58 and 135pg/mL, respectively. Overall, approximately 79% of Ang-2 (84% within 8 weeks postdose and 55% beyond 12 weeks postdose) and 7% of VEGF-A postdose observations were below the lower limit of quantification. Model-derived Ang-2 and VEGF-A concentration-time profiles for patients on every 4-week/every 8-week dosing were predicted to maintain greater than 50% suppression of Ang-2 concentrations for the entire dosing period. Patients on every 12-week/16-week dosing were predicted to have greater than 50% Ang-2 suppression for 12 or more weeks, whereas 50% VEGF-A suppression was maintained for 9 to 10 weeks. At 8 weeks postdose, the median Ang-2 concentrations remained suppressed by approximately 80%. At 16 weeks postdose, the median VEGF-A concentrations returned to baseline, but median Ang-2 levels remained below baseline. A popPKPD analysis demonstrated faricimab's rapid and sustained suppression of AH Ang-2 and VEGF-A. A popPKPD analysis suggested that sustained suppression of ocular Ang-2 contributes to faricimab's extended durability, observed in clinical trials.

The impact of vitreomacular traction on vitreous vascular endothelial growth factor and placental growth factor levels in neovascular age-related macular degeneration patients.

To investigate the effect of vitreomacular traction (VMT) on vitreous vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) levels in patients with active neovascular age-related macular degeneration (nAMD). A prospective, interventional, case-control study. The study included a total of 70 patients from whom vitreous samples were obtained. The patients were categorized into four group: 10 patients with active nAMD accompanying VMT, 17 patients with VMT, 24 patients with active nAMD and 19 healthy patients without any diagnosis other than cataract. VEGF and PlGF levels were measured. The mean vitreous VEGF level was 34.7 ± 4.98 pg/ml in the nAMD and VMT group, 32.36 ± 4.55 pg/ml in the VMT group, 34.02 ± 3.79 pg/ml in the nAMD group, and 32.33 ± 2.4 pg/ml in the healthy control group. The mean vitreous PlGF level was 58.92 ± 20.83 pg/ml in the nAMD and VMT group, 46.29 ± 3.45 pg/ml in the VMT group, 54.64 ± 16.88 pg/ml in the nAMD group, and 53.66 ± 19.35 pg/ml in the healthy control group. No significant differences were observed in terms of vitreous VEGF and PlGF concentrations among the groups (p > 0.05 and p > 0.05, respectively). Aqueous humour VEGF and PlGF levels were significantly higher than vitreous levels in nAMD patients (p = 0.005 and p = 0.005, respectively). The present study found no increases in vitreous VEGF and PlGF levels in both VMT + nAMD and VMT cases. Furthermore, patients with nAMD had significantly higher levels of PlGF and VEGF in aqueous humour compared to vitreous levels.

Real-World Long-Term Outcomes of Intravitreal Faricimab in Previously Treated Chronic Neovascular Age-Related Macular Degeneration.

To study the real-world outcomes of intravitreal faricimab (IVF) in longstanding neovascular age-related macular degeneration (nAMD) over a one-year study period. Retrospective single-center cohort study of patients with previously treated nAMD receiving IVF with at least 12 months of follow up. Main outcome measures include injection intervals, visual acuity (VA), and optical coherence tomography features. 263 eyes from 217 patients received 6.4±2.3 IVF injections over one year. Injection interval increased after switching to IVF (5.9±1.8 vs 7.6±2.4 weeks) (p<0.01). There was no improvement in VA after switching to IVF at any time period (p>0.15). Average CST decreased after the first IVF injection and was sustained for one year (313.7±96.0 vs. 288.2±80.6 μm) (p<0.01). There was a statistically significant resolution of subretinal fluid but not IRF at all time points (40.8-50.4%) (p<0.01). Persistent fluid after the first IVF injection was resolved in 34.4% (n=45) by one year. IVF was discontinued in 31 eyes (11.8%), four (1.6%) that experienced intraocular inflammation. Longstanding nAMD eyes switched to IVF experienced a significant extension in injection interval, stable visual acuity, improvement in CST, and resolution of fluid on OCT in many patients over one year.

A pilot study : retinal sensitivity change in neovascular age-related macular degeneration patients with better baseline visual acuity

This study evaluated changes in retinal sensitivity (RS) during aflibercept treatment in neovascular age-related macular degeneration (nAMD) patients with good vision. Treatment-naive nAMD patients with visual acuity better than 20/40 were treated with an aflibercept loading regiment, and RS was measured using the MAIA microperimetry device. The study examined RS differences based on visit, region, adjacent local pathology, outer retinal changes and optical coherence tomography angiography (OCTA) data were investigated. Twelve patients completed the protocol. Mean RS improved from 17.9 (3.9) µm at baseline to 20.4 (4.7) µm at final visit, while best-corrected visual acuity (BCVA) did not change. (P = 0.041) RS at baseline is worst in the presence of intraretinal fluid (IRF) and improved after treatment for all retinal pathologies except IRF. RS improvement occurred even with initial outer retinal damage. A Linear mixed model showed subretinal hyperreflective material, baseline IRF height, outer retinal integrity, fibrovascular pigment epithelial detachment height, and local choroidal vascular index as factors associated with RS. In conclusion, RS improved with aflibercept treatment in nAMD eyes with good initial visual acuity, despite no change in BCVA, except when IRF was present.

Aflibercept 8 mg/0.07 mL (Eylea HD)

Reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class. The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada’s federal, provincial, and territorial governments, with the exception of Quebec. This review assesses aflibercept (Eylea HD) 8 mg (0.07 mL), solution for intravitreal injection. Indication: For the treatment of neovascular (wet) age-related macular degeneration (nAMD).

Levodopa is associated with reduced development of new-onset geographic atrophy in patients with age-related macular degeneration.

Geographic atrophy (GA) is a significant cause of vision loss in patients with age-related macular degeneration (AMD). Current treatments are limited to anti-complement drugs, which have limited efficacy to delay progression with significant risk of complications. Levodopa (L-DOPA) is a byproduct of melanin synthesis that is associated with reduced development of neovascular AMD. In this study, we determined if L-DOPA was associated with a reduced likelihood of new-onset GA. We performed a retrospective analysis in the Vestrum Health Retina Database. We included eyes with non-neovascular AMD without GA and 1-5years of follow-up. Eyes were divided into two groups. Exposed to L-DOPA before or on the date of non-neovascular AMD without GA diagnosis, and eyes not exposed to L-DOPA. We extracted age, sex, AREDS2 status, dry AMD stage, smoking history, and conversion rate to GA at years 1 through 5. Propensity score matching was used to match L-DOPA and control groups. Cox proportional hazard regression, adjusting for age, sex, AMD severity, AREDS2 use, smoking status, and L-DOPA use was employed to calculate hazard ratios for new-onset GA detection. We identified 112,089 control and 844 L-DOPA exposed eyes with non-neovascular AMD without GA. After propensity score matching, 2532 control and 844 L-DOPA exposed eyes remained that were well-matched for age, sex, AMD severity, AREDS2 use, and smoking status. We found that L-DOPA exposure was associated with a significantly reduced likelihood (HR = 0.68, 95% CI: 0.48-0.95, P = 0.025) of new-onset GA detection. L-DOPA use was associated with reduced detection of new-onset GA.

VEGF inhibition increases expression of HIF-regulated angiogenic genes by the RPE limiting the response of wet AMD eyes to aflibercept

Neovascular age-related macular degeneration (nvAMD) is the leading cause of severe vision loss in the elderly in the developed world. While the introduction of therapies targeting vascular endothelial growth factor (VEGF) has provided the first opportunity to significantly improve vision in patients with nvAMD, many patients respond inadequately to current anti-VEGF therapies. It was recently demonstrated that expression of a second angiogenic mediator, angiopoietin-like 4 (ANGPTL4), synergizes with VEGF to promote choroidal neovascularization (CNV) in mice and correlates with reduced response to anti-VEGF therapy in patients with nvAMD. Here, we report that expression of ANGPTL4 in patients with nvAMD increases following treatment with anti-VEGF therapy and that this increase is dependent on accumulation of hypoxia-inducible factor (HIF)-1α in response to inhibition of VEGF/KDR signaling in the retinal pigment epithelium (RPE). We therefore explored HIF-1 inhibition with 32-134D, a recently developed pharmacologic HIF-inhibitor, for the treatment of nvAMD. 32-134D prevented the expression of both VEGF and ANGPTL4 and was at least as effective as aflibercept in treating CNV in mice. Moreover, by preventing the increase in HIF-1α accumulation in the RPE in response to anti-VEGF therapy, combining 32-134D with aflibercept was more effective than either drug alone for the treatment of CNV. Collectively, these results help explain why many patients with nvAMD respond inadequately to anti-VEGF therapy and suggest that the HIF inhibitor 32-134D will be an effective drug-alone or in combination with current anti-VEGF therapies-for the treatment of patients with this blinding disease.

First-year real-world experience of intravitreal brolucizumab injection for refractory neovascular age-related macular degeneration.

To investigate the first-year real-world anatomical and functional outcomes of intravitreal brolucizumab injection in eyes with refractory neovascular age-related macular degeneration (nAMD). Retrospective observational study. nAMD patients who showed poor response to previous anti-vascular endothelial growth factor (VEGF) agents were switched to brolucizumab. Functional and anatomical outcomes were evaluated at initial treatment of nAMD, after treatment with other anti-VEGF agents and after switching and treating with brolucizumab for 1 year. Safety profile was also evaluated after brolucizumab injection. Best-corrected visual acuity (BCVA), central foveal thickness (CFT), subfoveal choroidal thickness (SFCT), and the presence of fluid in different compartments (intraretinal fluid [IRF], subretinal fluid [SRF], pigment epithelial detachment [PED]) were assessed at each time point. A total of 40 eyes of 40 patients were included in the study. BCVA remained unchanged throughout treatment (p > 0.05). CFT did not change after treatment with other anti-VEGF agents (p = 0.588) but decreased after switching to brolucizumab (p < 0.001). SFCT decreased after treatment with other anti-VEGF agents (p = 0.025) but not after switching to brolucizumab (p = 0.236). Presence of SRF (p = 0.001) and PED (p = 0.001) decreased significantly after switching to brolucizumab, despite their persistence with prior treatments using other anti-VEGF agents. However, IRF persisted even after switching to brolucizumab (p = 0.745). Intraocular inflammation (IOI)-related adverse events were reported in 3 eyes (7.14%). Analysis of first-year real-world outcomes after switching to brolucizumab in nAMD patients refractory to other anti-VEGF agents showed improved anatomic outcomes, limited functional improvement and low incidence of IOI-related adverse events.

Early Choriocapillaris Dysfunction in Fellow Eyes of Patients with Unilateral Neovascular Age-Related Macular Degeneration.

To investigate early changes in AMD by evaluating and comparing choriocapillaris (CC) flow in fellow eyes of patients with unilateral neovascular age-related macular degeneration (nAMD) and in healthy controls using swept-source optical coherence tomography angiography (SS-OCTA). Patients with unilateral nAMD and no/early/intermediate AMD (no/e/iAMD) in their fellow eye and normal controls who underwent SS-OCT and OCTA where included. CC perfusion was assessed on MATLAB as percentage of flow deficits (FD%) in the central 4.5 × 4.5 mm macular region, after removing artifacts. 81 eyes/patients (22 eyes with noAMD, 30 with eAMD, 29 with iAMD) with unilateral nAMD and 24 controls were analyzed. Median FD% was 8.97 (IQR 8.58-9.53) in AMD group, 8.92 (IQR 8.64-9.27) in noAMD group, 8.96 (IQR 8.46-9.38) in eAMD group, 9.05 (IQR 8.58-9.8) in iAMD group, and 8.22 (IQR 7.78-8.55) in controls. A statistically significant difference in FD% was observed between controls and AMD group (p < 0.001), as well as between each AMD subgroup and controls (noAMD vs controls p = 0.0037; eAMD vs control p = 0.0012; iAMD vs controls p = 0.0002). This study suggests that CC dysfunction may occur in fellow eyes of patients with unilateral nAMD before visible AMD signs, potentially preceding RPE changes. Further longitudinal studies are needed to confirm these findings and explore the correlation with AMD development/progression.

Real world efficacy and durability of faricimab in patients with neovascular AMD (nAMD) who had sub-optimal response to prior anti-VEGF therapy.

Age-related macular degeneration (AMD) remains a primary cause of blindness, with neovascular AMD (nAMD) presenting particular treatment challenges. Despite anti-vascular endothelial growth factor (anti-VEGF) therapies, many patients exhibit a suboptimal response to the previously available anti-vascular endothelial growth factor (anti-VEGF) therapies. This study evaluates the efficacy and treatment interval extension of faricimab in this patient cohort. In a retrospective single-centre study at University Hospitals of Bristol and Weston, UK, nAMD patients suboptimally responsive to previous anti-VEGF therapies were switched to faricimab. Treatment started with an initiation phase of 4 monthly injections followed by a 'Treat and Extend' protocol. Outcomes included best-recorded visual acuity (BRVA), central subfield thickness (CST), the presence of retinal fluid, and treatment intervals. Among 98 eyes of 79 patients, following faricimab treatment, significant reductions in CST and retinal fluid were noted, indicating decreased disease activity. While BRVA changes were not statistically significant, the anatomical improvements suggest a potential therapeutic benefit. Notably, 40% of patients achieved extended treatment intervals, reducing the treatment burden. Faricimab offers a promising alternative for nAMD patients with suboptimal responses to prior anti-VEGF treatments, demonstrating significant anatomical improvements and the possibility of extended dosing intervals. These findings highlight the need for prospective real-world studies to further assess faricimab's role in nAMD management and its long-term impact on patient outcomes.

ONS-5010 (bevacizumab-vikg) Safety and Efficacy in Subfoveal Choroidal Neovascularization Secondary to Age-related Macular Degeneration.

This was a prospective multicenter, randomized, double-masked, active-controlled study, the aim of which was to demonstrate the efficacy and safety of intravitreal ONS-5010 (bevacizumab-vikg) in eyes with neovascular age-related macular degeneration (nAMD). This was a phase III trial on ONS-5010 (NORSE TWO). Treatment-naïve nAMD patients aged 50 years and older with a best-corrected distance visual acuity (BCVA) of 25 to 67 Early Treatment Diabetic Retinopathy Study (ETDRS) letters and evidence of disease activity were included. Subjects randomized to ONS-5010 received monthly intravitreal doses of 1.25 mg of ONS-5010, bevacizumab-vikg (Outlook Therapeutics) for 12 months. Subjects randomized to ranibizumab received 0.50 mg of ranibizumab on days 0, 30, 60, 150, and 240 based on the PIER study dosing regimen. The primary end point was the proportion of subjects who gained ≥ 15 letters from baseline in BCVA at 11 months, and evaluating the safety and tolerability of intravitreal injections of ONS-5010 administered monthly from baseline to 12 months. One hundred thirteen subjects were included in the ONS-5010 group and 115 subjects were included in the ranibizumab group. Respectively, 41.7% and 23.1% of patients gained ≥ 15 letters (3 lines) of visual acuity, with a risk difference of 0.1859 [95% CI = 0.0442, 0.3086]; P = 0.0052. The change in BCVA from baseline to 11 months was found to be 11.2 ± 12.19 and 5.8 ± 14.80 ETDRS letters, respectively. The number of subjects gaining ≥ 5 and ≥ 10 letters and subjects losing < 15 letters was significantly higher in the ONS-5010 group. Similarly, subjects with a Snellen visual acuity equivalent of 20/200 (35 ETDRS letters) or worse at 11 months were significantly fewer in the ONS-5010 group. Only one subject in the ONS-5010 group had a study-related serious ocular adverse event (SAE), namely, elevated intraocular pressure. The most common adverse event in the ONS-5010 group was conjunctival hemorrhage (8.8%), and reduced visual acuity in the ranibizumab group (12.2%). In the prescribed treatment plan, ONS-5010 exhibited strong effectiveness in improving or stabilizing visual acuity and was also well tolerated. Bevacizumab and ranibizumab displayed a comparable safety profile. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Brolucizumab in patients with neovascular age-related macular degeneration: Real-life outcomes from a tertiary care eye hospital.

To report real-world clinical evidence of brolucizumab in treating neovascular age-related macular degeneration (nAMD). This study included 37 eyes with nAMD treated with intravitreal injections of brolucizumab. The main outcomes were best corrected visual acuity (BCVA) changes, central retinal thickness (CRT), and serious ocular adverse events. Intraretinal fluid (IRF) and subretinal fluid (SRF), subretinal hyperreflective material (SHRM), pigment epithelial detachments (PEDs), hyperreflective foci, macular atrophy, and retinal pigment epithelial tears were evaluated. The mean BCVA of all patients showed a post-treatment value of 0.47 ± 0.33 log of minimum angle of resolution (LogMAR), compared to a baseline measure of 0.50 ± 0.28 LogMAR ( P = 0.372). For treatment-naïve patients, a non-statistically significant improvement in BCVA was observed ( P = 0.116). Both treatment-naive patients and the entire patient cohort exhibited a statistically significant improvement in the mean CRT after injections. Majority of patients exhibited improvements in optical coherence tomography findings, specifically in the resolution of IRF, SRF, SHRM, and PEDs. Four eyes experienced ocular adverse events in the form of intraocular inflammation. Brolucizumab did not yield a substantial improvement in BCVA, but it exhibited efficacy in reducing CRT in the entire study population and treatment-naive patients with nAMD. Our study identified intraocular inflammation as a significant adverse event with brolucizumab. Thus, precise patient selection, education, and vigilant inflammation monitoring are crucial for patients undergoing this treatment.

Complement proteins and complement regulatory proteins are associated with age-related macular degeneration stage and treatment response

BackgroundDysregulation of the complement system is involved in development of age-related macular degeneration (AMD). The complement cascade is regulated by membrane bound complement regulatory proteins (Cregs) on mononuclear leukocytes among others. This study aims to investigate systemic complement proteins and Cregs in AMD stages and their association with treatment response in neovascular AMD (nAMD).MethodsIn this clinical prospective study, treatment-naïve patients with nAMD, intermediate AMD (iAMD) and healthy controls were recruited and systemic complement proteins C3, C3a and C5a were investigated with electrochemiluminescence immunoassays, and Creg expression (CD35, CD46 and CD59) on T cells (CD4 + and CD8+) and monocytes (classical, intermediate and non-classical) investigated with flow cytometry. Treatment response in nAMD patients was evaluated after loading dose and after one year, and categorized as good, partial or poor. Complement proteins and Creg expression levels were compared between healthy controls, iAMD and nAMD, as well as between good, partial and poor nAMD treatment response groups. Polymorphisms in the CFH and ARMS2 genes were analyzed and compared to complement proteins and Creg expression levels in nAMD patients.ResultsOne hundred patients with nAMD, 34 patients with iAMD and 61 healthy controls were included. 94 nAMD patients completed the 1-year follow-up. Distribution of treatment response in nAMD was 61 (65%) good, 26 (28%) partial, and 7 (7%) poor responders. The distribution of 1-year treatment response was 50 (53%) good, 33 (36%) partial, and 11 (11%) poor responders. The concentrations of systemic C3, C3a, and the C3a/C3-ratio were significantly increased in patients with nAMD compared to healthy controls (P < 0.001, P = 0.002, and P = 0.035, respectively). Systemic C3 was also increased in iAMD compared to healthy controls (P = 0.031). The proportion of CD46 + CD4 + T cells and CD59 + intermediate monocytes were significantly decreased in patients with nAMD compared to healthy controls (P = 0.018 and P = 0.042, respectively). The post-loading dose partial treatment response group had significantly lower concentrations of C3a and C5a compared to the good response group (P = 0.005 and P = 0.042, respectively). The proportion of CD35 + monocytes was significantly lower in the 1-year partial response group compared to the 1-year good response group (P = 0.039). High-risk CFH genotypes in nAMD patients was associated with increased C3a, C3a/C3-ratio, and expression levels of CD35 + CD8 + T cells and CD46 + classical monocytes, while expression level of CD46 + non-classical monocytes was decreased.ConclusionElevated concentrations of systemic complement proteins were found in patients with iAMD and nAMD. Decreased Creg expression levels were found in patients with nAMD. Partially responding nAMD patients had a dysregulated complement system and Cregs compared to good responders.

Inflammasome activation aggravates choroidal neovascularization.

Inflammasome activation is implicated in diseases of aberrant angiogenesis such as age-related macular degeneration (AMD), though its precise role in choroidal neovascularization (CNV), a characteristic pathology of advanced AMD, is ill-defined. Reports on inhibition of inflammasome constituents on CNV are variable and the precise role of inflammasome in mediating pathological angiogenesis is unclear. Historically, subretinal injection of inflammasome agonists alone has been used to investigate retinal pigmented epithelium (RPE) degeneration, while the laser photocoagulation model has been used to study pathological angiogenesis in a model of CNV. Here, we report that the simultaneous introduction of any of several disease-relevant inflammasome agonists (Alu or B2 RNA, Alu cDNA, or oligomerized amyloid β (1-40)) exacerbates laser-induced CNV. These activities were diminished or abrogated by genetic or pharmacological targeting of inflammasome signaling constituents including P2rx7, Nlrp3, caspase-1, caspase-11, and Myd88, as well as in myeloid-specific caspase-1 knockout mice. Alu RNA treatment induced inflammasome activation in macrophages within the CNV lesion, and increased accumulation of macrophages in an inflammasome-dependent manner. Finally, IL-1β neutralization prevented inflammasome agonist-induced chemotaxis, macrophage trafficking, and angiogenesis. Collectively, these observations support a model wherein inflammasome stimulation promotes and exacerbates CNV and may be a therapeutic target for diseases of angiogenesis such as neovascular AMD.

Stakeholder insights on cost, quality, and incorporating patient voice in managed care decisions on neovascular (wet) age-related macular degeneration: Findings from the AMCP Market Insights program.

Wet age-related macular degeneration (AMD) is an acquired degeneration of the retina that can lead to central vision impairment. It is primarily treated with intravitreal injections of vascular endothelial growth factor inhibitors. Although vascular endothelial growth factor inhibitors can effectively prevent progression of vision loss in many patients, they require ongoing regular administration and are therefore associated with considerable treatment burden. To gain insights into the impact of wet AMD and its treatment, AMCP convened an expert panel of managed care stakeholders in April 2024 through its Market Insights program. Key issues related to wet AMD identified by participants included cost and affordability, provider-related considerations, biosimilar adoption, measuring and improving quality, and incorporating the patient voice. Suggested payer best practices related to these issues in wet AMD also emerged from the discussion.