Artificial Intelligence to Facilitate Clinical Trial Recruitment in Age-Related Macular Degeneration.

Objective: Recent developments in artificial intelligence (AI) have positioned it to transform several stages of the clinical trial process. In this study, we explore the role of AI in clinical trial recruitment of individuals with geographic atrophy (GA), an advanced stage of age-related macular degeneration, amidst numerous ongoing clinical trials for this condition. Design: Cross-sectional study. Subjects: Retrospective dataset from the INSIGHT Health Data Research Hub at Moorfields Eye Hospital in London, United Kingdom, including 306 651 patients (602 826 eyes) with suspected retinal disease who underwent OCT imaging between January 1, 2008 and April 10, 2023. Methods: A deep learning model was trained on OCT scans to identify patients potentially eligible for GA trials, using AI-generated segmentations of retinal tissue. This method's efficacy was compared against a traditional keyword-based electronic health record (EHR) search. A clinical validation with fundus autofluorescence (FAF) images was performed to calculate the positive predictive value of this approach, by comparing AI predictions with expert assessments. Main Outcome Measures: The primary outcomes included the positive predictive value of AI in identifying trial-eligible patients, and the secondary outcome was the intraclass correlation between GA areas segmented on FAF by experts and AI-segmented OCT scans. Results: The AI system shortlisted a larger number of eligible patients with greater precision (1139, positive predictive value: 63%; 95% confidence interval [CI]: 54%-71%) compared with the EHR search (693, positive predictive value: 40%; 95% CI: 39%-42%). A combined AI-EHR approach identified 604 eligible patients with a positive predictive value of 86% (95% CI: 79%-92%). Intraclass correlation of GA area segmented on FAF versus AI-segmented area on OCT was 0.77 (95% CI: 0.68-0.84) for cases meeting trial criteria. The AI also adjusts to the distinct imaging criteria from several clinical trials, generating tailored shortlists ranging from 438 to 1817 patients. Conclusions: This study demonstrates the potential for AI in facilitating automated prescreening for clinical trials in GA, enabling site feasibility assessments, data-driven protocol design, and cost reduction. Once treatments are available, similar AI systems could also be used to identify individuals who may benefit from treatment. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Elevated tumor necrosis factor alpha and vascular endothelial growth factor in intermediate age-related macular degeneration and geographic atrophy.

Introduction: Tumor necrosis factor alpha (TNF-α) is an inflammatory cytokine implicated in pathological changes to the retinal pigment epithelium that are similar to changes in geographic atrophy (GA), an advanced form of age related macular degeneration (AMD). TNF-α also modulates expression of other cytokines including vascular endothelial growth factor (VEGF), leading to choroidal atrophy in models of AMD. The purpose of this study was to investigate systemic TNF-α and VEGF in patients with GA and intermediate AMD (iAMD) compared to controls without AMD. Methods: We examined plasma levels of TNF-α and VEGF in patients with GA, iAMD, and controls without AMD from the University of Colorado AMD registry (2014 to 2021). Cases and controls were characterized by multimodal imaging. TNF-α and VEGF were measured via multiplex immunoassay and data were analyzed using a non-parametric rank based linear regression model fit to plasma biomarkers. Results: There were 97 GA, 199 iAMD patients and 139 controls. TNF-α was significantly increased in GA (Median:9.9pg/ml, IQR:7.3-11.8) compared to iAMD (Median:7.4, IQR:5.3-9.1) and in both GA and iAMD compared to controls (Median:6.4, IQR:5.3-7.8), p<0.01 for all comparisons. VEGF was significantly increased in iAMD (Median:8.9, IQR:4.8-14.3) compared to controls (Median:7.7, IQR:4.6-11.1), p<0.01. There was a significant positive correlation between TNF-α and VEGF in GA (0.46, p<0.01), and iAMD (0.20, p=0.01) with no significant interaction between TNF-α and VEGF in any group. Discussion: These findings suggest TNF-α and VEGF may contribute to systemic inflammatory processes associated with iAMD and GA. TNF-α and VEGF may function as systemic biomarkers for disease development.

Natural History of Visual Acuity and Microperimetry-Based Functional Outcome Measures of the Macula in Patients with Geographic Atrophy: A Retrospective Chart Review Study in Germany.

Background/Objectives: Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD) leading to the progressive and irreversible loss of visual function. Characteristics of GA include atrophic lesions resulting from the loss of photoreceptors, retinal pigment epithelium, and choriocapillaris. During GA progression, atrophic lesions typically advance from the macular periphery to the center, affecting foveal light sensitivity and visual acuity. This study analyzed changes in light sensitivity and visual acuity during the natural course of GA progression using the topographic analysis of structural and functional changes based on Early Treatment Diabetic Retinopathy Study (ETDRS) charts, multimodal imaging, and microperimetry assessment. Methods: Medical chart data of GA patients between 2014 and 2022 from the Internationale Innovative Ophthalmochirurgie GbR (I.I.O.) research center (Düsseldorf, Germany) were retrospectively analyzed. All patient eyes fulfilling the phase 3 OAKS study inclusion criteria were included and followed up for 60 months. The imputation of missing measurements and dropouts was performed by linear mixed models. Results: A total of 20 GA eyes from 13 GA patients were included in the study. At the index, 53.8% of patients had bilateral GA, with 70.0% of the eyes showing multifocal GA and 30.0% subfoveal encroachment (SFE). A total of 35.0% of the eyes had 2-5, and 15.0% over 20, areas of atrophy. Over time, the GA lesion size increased from 6.4 mm2 to 11.8 mm2 (1.08 mm2/year). After an average observation time of 2.9 years, 78.6% of the initially unaffected study eyes developed SFE. The percentage of study eyes without visual impairment decreased from 55.0% to 30.0%, with mean normal-luminance best-corrected visual acuity (NL-BCVA) reducing from 63.7 to 55.7 ETDRS letters. The share of absolute scotoma points in microperimetry assessment increased from 15.7% to 43.5% while overall average macular sensitivity declined from 15.7 dB to 7.4 dB. Conclusions: The substantial deterioration of macular outcomes and visual function was comprehensively detected. The results were a documentation of structural and functional aspects of the natural progression of GA for a 60-month follow-up, providing a typical outline for AMD patients with GA.

Genetic Insights into Age-Related Macular Degeneration.

One of the major causes of vision impairment among elderly people in developed nations is age-related macular degeneration (AMD). The distinctive features of AMD are the accumulation of extracellular deposits called drusen and the gradual deterioration of photoreceptors and nearby tissues in the macula. AMD is a complex and multifaceted disease influenced by several factors such as aging, environmental risk factors, and a person's genetic susceptibility to the condition. The interaction among these factors leads to the initiation and advancement of AMD, where genetic predisposition plays a crucial role. With the advent of high-throughput genotyping technologies, many novel genetic loci associated with AMD have been identified, enhancing our knowledge of its genetic architecture. The common genetic variants linked to AMD are found on chromosome 1q32 (in the complement factor H gene) and 10q26 (age-related maculopathy susceptibility 2 and high-temperature requirement A serine peptidase 1 genes) loci, along with several other risk variants. This review summarizes the common genetic variants of complement pathways, lipid metabolism, and extracellular matrix proteins associated with AMD risk, highlighting the intricate pathways contributing to AMD pathogenesis. Knowledge of the genetic underpinnings of AMD will allow for the future development of personalized diagnostics and targeted therapeutic interventions, paving the way for more effective management of AMD and improved outcomes for affected individuals.

Combination of optical coherence tomography-derived shape and texture features are associated with development of sub-foveal geographic atrophy in dry AMD.

Geographic atrophy (GA) is an advanced form of dry age-related macular degeneration (AMD) that leads to progressive and irreversible vision loss. Identifying patients with greatest risk of GA progression is important for targeted utilization of emerging therapies. This study aimed to comprehensively evaluate the role of shape-based fractal dimension features ( F fd ) of sub-retinal pigment epithelium (sub-RPE) compartment and texture-based radiomics features ( F t ) of Ellipsoid Zone (EZ)-RPE and sub-RPE compartments for risk stratification for subfoveal GA (sfGA) progression. This was a retrospective study of 137 dry AMD subjects with a 5-year follow-up. Based on sfGA status at year 5, eyes were categorized as Progressors and Non-progressors. A total of 15 shape-based F fd of sub-RPE surface and 494 F t from each of sub-RPE and EZ-RPE compartments were extracted from baseline spectral domain-optical coherence tomography scans. The top nine features were identified from F fd and F t feature pool separately using minimum Redundancy maximum Relevance feature selection and used to train a Random Forest (RF) classifier independently using three-fold cross validation on the training set ( S t , N = 90) to distinguish between sfGA Progressors and Non-progressors. Combined F fd and F t was also evaluated in predicting risk of sfGA progression. The RF classifier yielded AUC of 0.85, 0.79 and 0.89 on independent test set ( S v , N = 47) using F fd , F t , and their combination, respectively. Using combined F fd and F t , the improvement in AUC was statistically significant on S v with p-values of 0.032 and 0.04 compared to using only F fd and only F t , respectively. Combined F fd and F t appears to identify high-risk patients. Our results show that FD and texture features could be potentially used for predicting risk of sfGA progression and future therapeutic response.

C5 inhibitor avacincaptad pegol treatment for geographic atrophy: A comprehensive review.

Geographic atrophy (GA) remains a leading cause of central vision loss with no known cure. Until recently, there were no approved treatments for GA, often resulting in poor quality of life for affected patients. GA is characterized by atrophic lesions on the retina that may eventually threaten the fovea. Emerging treatments have demonstrated the ability to reduce the rate of lesion growth, potentially preserving visual function. Avacincaptad pegol (ACP; Astellas Pharma Inc), a complement component 5 inhibitor, is an FDA-approved treatment for GA that has been evaluated in numerous clinical trials. Here we review the current clinical trial landscape of ACP, including critical post hoc analyses that suggest ACP may reduce the risk of severe loss among patients with GA.

Geographic atrophy (GA) is an advanced form of eye disease age-related macular degeneration. In people with GA, light-sensitive cells at the back of the eye (the retina) start to die, forming lesions. GA lesions usually get bigger over time and can lead to blindness. New medicines are being studied that work by slowing the growth of GA lesions. Avacincaptad pegol (ACP) is one medicine that acts on the immune system and is designed to block the C5 protein, helping stop the immune system from attacking cells in the retina. Based on clinical studies, ACP was shown to slow the growth of GA over time and has been approved by the FDA. This review article summarizes research on ACP.

Prosthetic Visual Acuity with the PRIMA Subretinal Microchip in Patients with Atrophic Age-Related Macular Degeneration at 4 Years Follow-up.

Objective: To assess the efficacy and safety of the PRIMA neurostimulation system with a subretinal microchip for improving visual acuity (VA) in patients with geographic atrophy (GA) due to age-related macular degeneration (AMD) at 48-months postimplantation. Design: Feasibility clinical trial of the PRIMA subretinal prosthesis in patients with atrophic AMD, measuring best-corrected ETDRS VA (Clinicaltrials.govNCT03333954). Subjects: Five patients with GA, no foveal light perception, and VA of logarithm of the minimum angle of resolution (logMAR) 1.3 to 1.7 (20/400-20/1000) in their worse-seeing "study" eye. Methods: In patients subretinally implanted with a photovoltaic neurostimulation array containing 378 pixels of 100 µm in size, the VA was measured with and without the PRIMA system using ETDRS charts at 1 m. The system's external components, augmented reality glasses, and pocket computer provide image processing capabilities, including zoom. Main Outcome Measures: Visual acuity using ETDRS charts with and without the system, as well as light sensitivity in the central visual field, measured by Octopus perimetry. Anatomical outcomes demonstrated by fundus photography and OCT up to 48 months postimplantation. Results: All 5 subjects met the primary end point of light perception elicited by the implant in the scotoma area. In 1 patient, the implant was incorrectly inserted into the choroid. One subject died 18 months postimplantation due to study-unrelated reasons. ETDRS VA results for the remaining 3 subjects are reported here. Without zoom, VA closely matched the pixel size of the implant: 1.17 ± 0.13 pixels, corresponding to a mean logMAR of 1.39, or Snellen of 20/500, ranging from 20/438 to 20/565. Using zoom at 48 months, subjects improved their VA by 32 ETDRS letters versus baseline (standard error 5.1) 95% confidence intervals (13.4, 49.9; P < 0.0001). Natural peripheral visual function in the treated eye did not decline after surgery or during the 48-month follow-up period (P = 0.08). Conclusions: Subretinal implantation of PRIMA in subjects with GA experiencing profound vision loss due to AMD is feasible and well tolerated, with no reduction of natural peripheral vision up to 48 months. Prosthetic central vision provided by photovoltaic neurostimulation enabled patients to reliably recognize letters and sequences of letters, and with zoom, it improved VA of up to 8 ETDRS lines. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Clinical Characteristics and Progression of Pachychoroid and Conventional Geographic Atrophy.

Purpose: To elucidate the clinical characteristics and progression rates of pachychoroid and conventional geographic atrophy (GA). Design: Retrospective, multicenter, observational study. Participants: A total of 173 eyes from 173 patients (38 eyes with pachychoroid GA and 135 with conventional GA) from 6 university hospitals in Japan were included. All patients were Japanese, aged ≥50 years and with fundus autofluorescence images having analyzable image quality. A total of 101 eyes (22 with pachychoroid GA and 79 with conventional GA) were included in the follow-up group. Methods: The studied eyes were classified as having pachychoroid or conventional GA; the former was diagnosed if the eye had features of pachychoroid and no drusen. The GA area was semiautomatically measured on fundus autofluorescence images, and the GA progression rate was calculated for the follow-up group. Multivariable linear regression analysis was used to determine whether the rate of GA progression was associated with GA subtype. Main Outcome Measures: Clinical characteristics and progression rates of pachychoroid and conventional GA. Results: The pachychoroid GA group was significantly younger (70.3 vs. 78.7 years; P < 0.001), more male-dominant (89.5 vs. 55.6%; P < 0.001), and had better best-corrected visual acuity (0.15 vs. 0.40 in logarithm of the minimum angle of resolution; P = 0.002), thicker choroid (312.4 vs. 161.6 µm; P < 0.001), higher rate of unifocal GA type (94.7 vs. 49.6%; P < 0.001), and smaller GA area (0.59 vs. 3.76 mm2;P < 0.001) than the conventional GA group. In the follow-up group, the mean GA progression rate (square-root transformation) was significantly lower in the pachychoroid GA group than in the conventional GA group (0.11 vs. 0.27 mm/year; P < 0.001). Conclusions: Demographic and ocular characteristics differed between GA subtypes. The progression rate of pachychoroid GA, adjusted for age and baseline GA area, was significantly lower than that of conventional GA. Japanese patients with conventional GA showed characteristics and progression rates similar to those in White populations. Some characteristics of GA in Japanese population differ from those in Waucasian populations, which may be due to the inclusion of pachychoroid GA. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Strong versus Weak Data Labeling for Artificial Intelligence Algorithms in the Measurement of Geographic Atrophy.

Purpose: To gain an understanding of data labeling requirements to train deep learning models for measurement of geographic atrophy (GA) with fundus autofluorescence (FAF) images. Design: Evaluation of artificial intelligence (AI) algorithms. Subjects: The Age-Related Eye Disease Study 2 (AREDS2) images were used for training and cross-validation, and GA clinical trial images were used for testing. Methods: Training data consisted of 2 sets of FAF images; 1 with area measurements only and no indication of GA location (Weakly labeled) and the second with GA segmentation masks (Strongly labeled). Main Outcome Measures: Bland-Altman plots and scatter plots were used to compare GA area measurement between ground truth and AI measurements. The Dice coefficient was used to compare accuracy of segmentation of the Strong model. Results: In the cross-validation AREDS2 data set (n = 601), the mean (standard deviation [SD]) area of GA measured by human grader, Weakly labeled AI model, and Strongly labeled AI model was 6.65 (6.3) mm2, 6.83 (6.29) mm2, and 6.58 (6.24) mm2, respectively. The mean difference between ground truth and AI was 0.18 mm2 (95% confidence interval, [CI], -7.57 to 7.92) for the Weakly labeled model and -0.07 mm2 (95% CI, -1.61 to 1.47) for the Strongly labeled model. With GlaxoSmithKline testing data (n = 156), the mean (SD) GA area was 9.79 (5.6) mm2, 8.82 (4.61) mm2, and 9.55 (5.66) mm2 for human grader, Strongly labeled AI model, and Weakly labeled AI model, respectively. The mean difference between ground truth and AI for the 2 models was -0.97 mm2 (95% CI, -4.36 to 2.41) and -0.24 mm2 (95% CI, -4.98 to 4.49), respectively. The Dice coefficient was 0.99 for intergrader agreement, 0.89 for the cross-validation data, and 0.92 for the testing data. Conclusions: Deep learning models can achieve reasonable accuracy even with Weakly labeled data. Training methods that integrate large volumes of Weakly labeled images with small number of Strongly labeled images offer a promising solution to overcome the burden of cost and time for data labeling. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Advancements in Imaging and Therapeutic Options for Dry Age-Related Macular Degeneration and Geographic Atrophy.

Age-related macular degeneration (AMD) is a leading cause of vision loss in the elderly, with dry AMD (d-AMD) leading to geographic atrophy (GA) and significant visual impairment. Multimodal imaging plays a crucial role in d-AMD diagnosis and management, allowing for detailed classification of patient phenotypes and aiding in treatment planning and prognosis determination. Treatment approaches for d-AMD have recently witnessed profound change with the development of specific drugs targeting the complement cascade, with the first anticomplement agents recently approved for GA treatment. Additionally, emerging strategies such as gene therapy and laser treatments may offer potential benefits, though further research is needed to fully establish their efficacy. However, the lack of effective therapies capable of restoring damaged retinal cells remains a major challenge. In the future, genetic treatments aimed at preventing the progression of d-AMD may emerge as a powerful approach. Currently, however, their development is still in the early stages.

Pre-Clinical Studies of a Novel Bispecific Fusion Protein Targeting C3b and VEGF in Neovascular and Nonexudative AMD Models.

INTRODUCTION: KNP-301 is a bi-specific fragment crystallizable region (Fc) fusion protein, which inhibits both C3b and vascular endothelial growth factor (VEGF) simultaneously for patients with late-stage age-related macular degeneration (AMD). The present study evaluated in vitro potency, in vivo efficacy, intravitreal pharmacokinetics (IVT PK), and injectability of KNP-301. METHODS: C3b and VEGF binding of KNP-301 were assessed by surface plasmon resonance (SPR) and enzyme-linked immunosorbent assay (ELISA), and cellular bioassays. A laser-induced choroidal neovascularization (CNV) model and a sodium iodate-induced nonexudative AMD model were used to test the in vivo efficacy of mouse surrogate of KNP-301. Utilizing fluorescein angiography (FA) and spectral-domain optical coherence tomography (SD-OCT) scans, the reduction in disease lesions were analyzed in a CNV mouse model. In the nonexudative AMD mouse model, outer nuclear layer (ONL) was assessed by immunofluorescence staining. Lastly, intravitreal pharmacokinetic study was conducted with New Zealand white rabbits via IVT administration of KNP-301 and injectability of KNP-301 was examined by a viscosity test at high concentrations. RESULTS: KNP-301 bound C3b selectively, which resulted in a blockade of the alternative pathway, not the classical pathway. KNP-301 also acted as a VEGF trap, impeding VEGF-mediate signaling. Our dual-blockade strategy was effective in both neovascular and nonexudative AMD models. Moreover, KNP-301 had an advantage of potentially less frequent dosing due to the long half-life in the intravitreal chamber. Our viscosity assessment confirmed that KNP-301 meets the criteria of the IVT injection. CONCLUSIONS: Unlike current therapies, KNP-301 is expected to cover patients with late-stage AMD of both neovascular and nonexudative AMD, and its long-term PK profile at the intravitreal chamber would allow convenience in the dosing interval of patients.

Phase 1 Study of JNJ-81201887 Gene Therapy in Geographic Atrophy Secondary to Age-Related Macular Degeneration.

PURPOSE: To evaluate the safety and tolerability of a single intravitreal injection of JNJ-81201887 (JNJ-1887) in patients with geographic atrophy (GA) secondary to advanced dry age-related macular degeneration (AMD). DESIGN: Phase 1, open-label, single-center, first-in-human clinical study. PARTICIPANTS: Adult patients (≥50 years of age) with GA secondary to AMD in the study-treated eye (treated eye) with Snellen best-corrected visual acuity of 20/200 or worse in the treated eye (20/80 or worse after the first 3 patients), a total GA lesion size between 5 and 20 mm2 (2-8 disc area), and best-corrected visual acuity of 20/800 or better in fellow, nontreated eye were included. METHODS: Patients (n = 17) were enrolled sequentially into low-dose (3.56 × 1010 viral genome/eye; n = 3), intermediate-dose (1.07 × 1011 viral genome/eye; n = 3), and high-dose (3.56 × 1011 viral genome/eye; n = 11) cohorts without steroid prophylaxis and assessed for safety and tolerability over 24 months. MAIN OUTCOME MEASURES: Safety and tolerability outcomes included assessment of ocular and nonocular treatment-emergent adverse events (AEs) over 24 months. Secondary outcomes included GA lesion size and growth rate. RESULTS: Baseline patient characteristics were consistent with the disease under study, and all enrolled patients demonstrated foveal center-involved GA. JNJ-81201887 was well-tolerated across all cohorts, with no dose-limiting AEs. No serious or systemic AEs related to study intervention occurred. Overall, 5 of 17 patients (29%) experienced 5 events of mild ocular inflammation related to study treatment; examination findings in all resolved, and AEs resolved in 4 of 5 patients after topical steroids or observation. One unresolved vitritis event, managed with observation, occurred in a patient with an unrelated fatal AE. No endophthalmitis or new-onset choroidal neovascularization was reported. Geographic atrophy lesion growth rate was similar among all cohorts over 24 months. For treated eyes in the high-dose cohort, GA lesion growth rate showed continued decline through 24 months, with a reduction in mean square root lesion growth from 0.211 mm at months 0 through 6 to 0.056 mm at months 18 through 24. CONCLUSIONS: All 3 studied doses of JNJ-1887 showed a manageable safety profile through 24 months of follow-up. Further investigation of JNJ-1887 for the treatment of GA is warranted. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

"Izervay (avacincaptad pegol): paving the way for vision preservation in geographic atrophy".

Age-related macular degeneration (AMD) is a progressive retinal disease that primarily affects the macula, leading to central vision loss and impaired color vision. Among its most severe forms is geographic atrophy (GA), which results in irreversible central blindness. While numerous risk factors, including age, smoking, and genetics, contribute to the development of AMD, effective treatment options for GA have been limited. This article centers on Izervay [avacincaptad pegol (ACP)], an FDA-approved drug designed to address the unmet medical needs of patients with GA secondary to AMD. The pathophysiology of GA involves oxidative damage, chronic inflammation, and cell death, primarily due to complement system dysregulation. Previous treatments for GA have shown limited efficacy, leaving patients searching for more effective solutions. Izervay, with its unique mechanism of action, inhibits complement protein C5, disrupting the formation of the membrane attack complex and slowing retinal cell degeneration. Clinical trials have demonstrated Izervay's ability to significantly reduce the growth of GA lesions, offering hope for improved outcomes. Additionally, the drug has exhibited a tolerable safety profile, with common side effects including conjunctival hemorrhage and increased intraocular pressure. Izervay represents a breakthrough in AMD treatment, offering the potential to preserve vision in those at risk of irreversible vision loss due to GA. While further research is necessary to evaluate long-term efficacy and accessibility, its approval opens new possibilities in AMD management, transforming the lives of individuals affected by this condition.

Circulating Anti-Endothelial Cell Antibodies in Patients with Geographic Atrophy Related to Dry Age-Related Macular Degeneration.

Background and Objectives: Age-related macular degeneration (AMD) is one of the leading causes of central vision loss among elderly patients, and its dry form accounts for the majority of cases. Although several causes and mechanisms for the development and progression of AMD have previously been identified, the pathogenesis of this complex disease is still not entirely understood. As inflammation and immune system involvement are strongly suggested to play a central role in promoting the degenerative process and stimulating the onset of complications, we aimed to analyze the frequency of serum anti-retinal (ARAs) and anti-endothelial cell antibodies (AECAs) in patients with dry AMD and to determine their relationship with the clinical features of the disease, notably the area of geographic atrophy (GA). Materials and Methods: This study included 41 patients with advanced-stage dry AMD and 50 healthy controls without AMD, matched for gender and age. ARAs were detected by indirect immunofluorescence using monkey retina as an antigen substrate, and the presence of AECAs was determined using cultivated human umbilical vein endothelial cells and primate skeletal muscle. Results: ARAs were detected in 36 (87.8%) AMD patients (titers ranged from 1:20 to 1:320) and in 16 (39.0%) (titers ranged from 1:10 to 1:40) controls (p = 0.0000). Twenty of the forty-one patients (48.8%) were positive for AECAs, while in the control group, AECAs were present only in five sera (10.0%). The titers of AECAs in AMD patients ranged from 1:100 to 1:1000, and in the control group, the AECA titers were 1:100 (p = 0.0001). There were no significant correlations between the presence of AECAs and disease activity. Conclusions: This study demonstrates a higher prevalence of circulating AECAs in patients with dry AMD; however, no correlation was found between the serum levels of these autoantibodies and the area of GA.

Prevalence of Age-Related Macular Degeneration in Patients with Chronic Exposure to P2X7R Inhibitors.

PURPOSE: P2X7 receptor (P2X7R) is a purinergic cation channel whose activation has been linked with age-related macular degeneration (ARMD). Several nucleoside reverse transcriptase inhibitors, zidovudine (AZT), lamivudine (3TC) and abacavir (ABC), have been shown to inhibit P2X7R and improve outcomes in animal models of ARMD. Our aim is to investigate the association between chronic AZT, 3TC, and ABC therapy and ARMD in a clinical setting. METHODS: This is a retrospective cohort study comparing 445 patients with HIV and confirmed usage of AZT, 3TC, and ABC against 200 patients with HIV without usage of AZT, 3TC, and ABC and 445 non-HIV infected patients. Fundus examination and spectral domain optical coherence tomography (SD-ODT) were used to measure prevalence of early-intermediate stage ARMD, geographic atrophy, and exudative ARMD. RESULTS: There was no statistically significant difference in the prevalence of early-intermediate stage ARMD between the HIV infected patients with a history of AZT, 3TC, and ABC use and the HIV infected patients without AZT, 3TC, and ABC use (p = 0.887). There was also no statistically significant difference in the prevalence of geographical atrophy (p = 0.062) and exudative AMD (p > 0.999) between the HIV infected patients with a history of AZT, 3TC, and ABC use and non-HIV infected patients. CONCLUSION: We did not find an effect of P2X7R inhibiting antiretrovirals usage on early-intermediate stage ARMD, geographical atrophy, or exudative ARMD. Studies with larger cohort and more rigorous medication history are needed to assess the effects on geographical atrophy or exudative ARMD.

Ophthalmologists' awareness of geographic atrophy: An Italian survey including 365 participants.

PURPOSE: Geographic atrophy (GA) is a severe complication of age-related macular degeneration (AMD) and leads to irreversible visual decline. To date, no effective treatment is available for GA patients. However, a number of new therapies have recently been approved and several others are in the pipeline. This rapid evolution of prospects for GA patients requires constant updating of ophthalmologists' understanding of GA and its management so as to provide the appropriate treatment. For this reason, Società Italiana di Scienze Oftalmologiche (S.I.S.O.) has designed a specific survey to gauge the position of Italian ophthalmologists in this regard. METHODS: The three hundred and sixty-five Italian ophthalmologists who agreed to take part received a seventeen-part questionnaire guaranteeing privacy and anonymity. The survey was compiled through an online portal and the results were sent directly to S.I.S.O. ETS. Two graders analyzed the data and recorded the results. RESULTS: The results showed a high level of self-assessed awareness and understanding of GA, as well as considerable willingness to further improve knowledge of the disease. Most of the participants claimed to have effective rules of conduct in place for managing GA patients, including prompt response, involving a high prevalence of nutraceutical prescriptions and lifestyle recommendations. CONCLUSIONS: This survey provided an overview of how GA patients are managed in Italy. The Italian ophthalmology community appears to be ready to adopt the upcoming treatments for GA.

Vision Loss Reduction with Avacincaptad Pegol for Geographic Atrophy: A 12-Month Post Hoc Analysis of the GATHER1 and GATHER2 Trials.

PURPOSE: To evaluate the impact of reduction in geographic atrophy (GA) lesion growth on visual acuity in the GATHER trials using categorical outcome measures. DESIGN: Randomized, double-masked, sham-controlled phase 3 trials. PARTICIPANTS: Aged ≥50 years with noncenter point-involving GA and best-corrected visual acuity (BCVA) of 25 to 80 ETDRS letters in the study eye. METHODS: GATHER1 consisted of 2 parts. In part 1, 77 patients were randomized 1:1:1 to avacincaptad pegol (ACP) 1 mg, ACP 2 mg, and sham. In part 2, 209 patients were randomized 1:2:2 to ACP 2 mg, ACP 4 mg, and sham. In GATHER2, patients were randomized 1:1 to ACP 2 mg (n = 225) and sham (n = 223). A post hoc analysis of 12-month data for pooled ACP 2 mg and sham groups is reported. MAIN OUTCOME MEASURES: Proportion of study eyes that experienced ≥10-, ≥15-, or ≥20-BCVA ETDRS letter loss from baseline to month 12; time-to-event analysis of persistent vision loss of ≥10, ≥15, or≥ 20 BCVA letters from baseline at ≥2 consecutive visits over 12 months; proportion of study eyes with BCVA loss to a level below driving eligibility threshold at month 12 among those eligible to drive at baseline. RESULTS: Lower proportions of study eyes experienced ≥10-, ≥15-, or ≥20-BCVA letter loss from baseline over 12 months with ACP 2 mg (11.6%, 4.0%, and 1.6%, respectively) versus sham (14.1%, 7.6%, and 4.5%, respectively). There was a reduction in the risk of persistent loss of ≥15 BCVA ETDRS letters with ACP 2 mg (3.4%) versus sham (7.8%) through 12 months. A lower proportion of study eyes treated with ACP 2 mg reached the threshold for driving ineligibility versus sham by 12 months. CONCLUSIONS: Treatment with ACP 2 mg delayed the risk of progression to persistent vision loss (i.e., ≥10-, ≥15-, and ≥20-BCVA letter loss or BCVA loss to a level below driving eligibility threshold) versus sham over 12 months. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

A Cost Effectiveness Analysis of Avacincaptad Pegol for the Treatment of Geographic Atrophy with Comparison to Pegcetacoplan.

PURPOSE: The purpose of this study was to evaluate the cost effectiveness of the treatment of geographic atrophy (GA) with intravitreal avacincaptad pegol (ACP) and to compare it with pegcetacoplan (PEG). DESIGN: Cost analysis based on data from published studies. SUBJECTS: None; based on data from published sham control compared with 2 treatment groups in each of the index studies. METHODS: Costs were based on 2022 Medicare reimbursement data for both facility (hospital-based) and nonfacility settings in Miami. Specific usage and outcomes were derived from the GATHER2 study as well as DERBY and OAKS trials. For ACP, all patients were treated every month (EM) in year 1 then randomized to every other month (EOM) or EM in year 2. Two-year models were created for patients in the facility setting for extrafoveal (ACP and PEG) and all patients (PEG). MAIN OUTCOME MEASURES: Cost, cost utility, and cost per area of GA (in United States dollars). RESULTS: The cost to treat GA with ACP in EM and EOM treatment groups over the 2 years as reported was $67 400 and $40 600, respectively. With ACP treatment over 2 years, the daily cost of delaying GA 3.4 months (EM) and 4.5 months (EOM) was $649 (EM) and $356 (EOM). The (facility-based) costs per unit area of retinal pigment epithelium saved for patients with extrafoveal GA over the 2-year period were $119 000/mm2 (EM ACP) versus $54 000/mm2 (EM PEG) (P < 0.001), $57 100/mm2 (EOM ACP) versus $31 400/mm2 (EOM PEG) (P < 0.001), and $45 300/mm2 (hypothetical EOM from outset ACP). CONCLUSION: Treatment of GA with intravitreal ACP EOM was more cost effective than EM. When assessing extrafoveal lesions, ACP was less cost effective than PEG for both EM and EOM treatment. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Non-Neovascular Age-Related Macular Degeneration Assessment: Focus on Optical Coherence Tomography Biomarkers.

The imagistic evaluation of non-neovascular age-related macular degeneration (AMD) is crucial for diagnosis, monitoring progression, and guiding management of the disease. Dry AMD, characterized primarily by the presence of drusen and retinal pigment epithelium atrophy, requires detailed visualization of the retinal structure to assess its severity and progression. Several imaging modalities are pivotal in the evaluation of non-neovascular AMD, including optical coherence tomography, fundus autofluorescence, or color fundus photography. In the context of emerging therapies for geographic atrophy, like pegcetacoplan, it is critical to establish the baseline status of the disease, monitor the development and expansion of geographic atrophy, and to evaluate the retina's response to potential treatments in clinical trials. The present review, while initially providing a comprehensive description of the pathophysiology involved in AMD, aims to offer an overview of the imaging modalities employed in the evaluation of non-neovascular AMD. Special emphasis is placed on the assessment of progression biomarkers as discerned through optical coherence tomography. As the landscape of AMD treatment continues to evolve, advanced imaging techniques will remain at the forefront, enabling clinicians to offer the most effective and tailored treatments to their patients.

AI-based support for optical coherence tomography in age-related macular degeneration.

Artificial intelligence (AI) has emerged as a transformative technology across various fields, and its applications in the medical domain, particularly in ophthalmology, has gained significant attention. The vast amount of high-resolution image data, such as optical coherence tomography (OCT) images, has been a driving force behind AI growth in this field. Age-related macular degeneration (AMD) is one of the leading causes for blindness in the world, affecting approximately 196 million people worldwide in 2020. Multimodal imaging has been for a long time the gold standard for diagnosing patients with AMD, however, currently treatment and follow-up in routine disease management are mainly driven by OCT imaging. AI-based algorithms have by their precision, reproducibility and speed, the potential to reliably quantify biomarkers, predict disease progression and assist treatment decisions in clinical routine as well as academic studies. This review paper aims to provide a summary of the current state of AI in AMD, focusing on its applications, challenges, and prospects.