Chemokine Receptor Profile of T Cells and Progression Rate of Geographic Atrophy Secondary to Age-related Macular Degeneration.

Purpose: Geographic atrophy (GA) secondary to age-related macular degeneration is a progressive retinal degenerative disease. Systemic chemokine receptors and known risk-associated single-nucleotide polymorphisms have been associated with GA pathogenesis. Because halting progression is pivotal for patients, we investigated the association of candidate chemokine receptors and progression rate (PR) of atrophic lesions in patients with GA. Methods: This prospective observational study conducted at a single center included 85 patients with GA and 45 healthy controls. Patients were followed up after 13 months on average. Serial fundus autofluorescence images were used to determine the PR of atrophic lesions. The proportion of chemokine receptors on peripheral lymphocytes were determined by flow cytometric analysis. Results: Patients with GA had a lower proportion of CCR6 on CD8+T cells compared to healthy controls. Importantly, the proportion of CCR6 on CD4+T cells was lower in patients with fast GA progression compared to patients with slow progression of disease, suggesting that dysregulation of CCR6 could be involved in progression of GA. We also found that GA patients had a markedly higher percentage of CCR5 on CD4+ and CD8+T cells compared to healthy controls. After stratification according to ARMS2 polymorphism, we found a significantly lower level of CCR5 on CD8+T cells among patients with high-risk genotypes compared with patients with the low-risk genotype. Conclusions: Our study finds that chemokine receptors are dysregulated in patients with GA and that CCR6 might be involved in GA progression, making it a potential target for intervention.

Treatment of geographic atrophy: an update on data related to pegcetacoplan.

PURPOSE OF REVIEW: Geographic atrophy is an advanced and currently untreatable form of age-related macular degeneration (AMD), which leads to significant compromise of visual function and quality of life. Dysregulation of the complement cascade has been directly implicated in AMD pathogenesis. Pegcetacoplan is a pegylated highly selective bicyclic peptide that inhibits the cleavage of complement component 3 (C3), which represents a key step in propagation of the complement cascade. The phase 2 FILLY trial as well as the phase 3 OAKS and DERBY trials have evaluated the safety and efficacy of pegcetacoplan for the treatment of GA. RECENT FINDINGS: The FILLY, OAKS and DERBY trials have demonstrated that local inhibition of C3 cleavage with pegcetacoplan can reduce geographic atrophy lesion growth compared with sham with an effect size of approximately 11-35% depending on the specific trial and specific geographic atrophy phenotype considered. Overall pegcetacoplan has appeared to be well tolerated with the notable side effect of a dose-dependent increase in the rate of exudative AMD development in treated eyes. SUMMARY: The FILLY, OAKS and DERBY trials have demonstrated that pegcetacoplan is a potentially viable treatment for geographic atrophy. Additional data from the 2-year outcomes of DERBY and OAKS as well as data from the ongoing 3-year GALE extension study will provide additional insights into the potential therapeutic benefit of pegcetacoplan. Future studies assessing complement inhibition at earlier stages of AMD, with the goal of preventing geographic atrophy formation, are warranted.

Diagnosis and Management of Patients With Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Delphi Consensus Exercise.

Geographic atrophy (GA) is a progressive and irreversible retinal disease with no comprehensive recommendations for diagnosis or monitoring. We used a Delphi approach to determine consensus in key areas around diagnosis and management of GA. A steering committee of eight retina specialists developed two sequential online surveys administered to eye care professionals (ECPs). Consensus was defined as agreement by ≥ 75% of respondents. Up to 177 ECPs from eight countries completed one or both surveys. Consensus was achieved in several topics related to diagnostic imaging, including the use of optical coherence tomography, and the urgent need for treatments and beneficial interventions to reduce the associated burden. Currently, low-vision aids and smoking cessation are considered the most beneficial interventions. We demonstrate consensus for diagnosis and management of patients with GA including best practices in patient identification and monitoring, and unmet needs. [Ophthalmic Surg Lasers Imaging Retina 2023;54:589-598.].

Pegcetacoplan for the treatment of geographic atrophy secondary to age-related macular degeneration (OAKS and DERBY): two multicentre, randomised, double-masked, sham-controlled, phase 3 trials.

BACKGROUND: Geographic atrophy is a leading cause of progressive, irreversible vision loss. The objectives of OAKS and DERBY were to assess the efficacy and safety of pegcetacoplan compared with sham treatment in patients with geographic atrophy. METHODS: OAKS and DERBY were two 24-month, multicentre, randomised, double-masked, sham-controlled, phase 3 studies, in which patients aged 60 years and older with geographic atrophy secondary to age-related macular degeneration were enrolled at 110 clinical sites and 122 clinical sites worldwide, respectively. Patients were randomly assigned (2:2:1:1) by central web-based randomisation system to intravitreal 15 mg per 0·1 mL pegcetacoplan monthly or every other month, or sham monthly or every other month using stratified permuted block randomisation (stratified by geographic atrophy lesion area at screening, history or presence of active choroidal neovascularisation in the eye not under assessment, and block size of six). Study site staff, patients, reading centre personnel, evaluating physicians, and the funder were masked to group assignment. Sham groups were pooled for the analyses. The primary endpoint was the change from baseline to month 12 in the total area of geographic atrophy lesions in the study eye based on fundus autofluorescence imaging, in the modified intention-to-treat population (ie, all patients who received one or more injections of pegcetacoplan or sham and had a baseline and at least one post-baseline value of lesion area). Key secondary endpoints (measured at 24 months) were change in monocular maximum reading speed of the study eye, change from baseline in mean functional reading independence index score, change from baseline in normal luminance best-corrected visual acuity score, and change from baseline in the mean threshold sensitivity of all points in the study eye by mesopic microperimetry (OAKS only). Safety analyses included patients who were randomly assigned and received at least one injection of pegcetacoplan or sham. The now completed studies are registered with ClinicalTrials.gov, NCT03525613 (OAKS) and NCT03525600 (DERBY). FINDINGS: Between Aug 30, 2018, and July 3, 2020, 1258 patients were enrolled in OAKS and DERBY. The modified intention-to-treat populations comprised 614 (96%) of 637 patients in OAKS (202 receiving pegcetacoplan monthly, 205 pegcetacoplan every other month, and 207 sham) and 597 (96%) of 621 patients in DERBY (201 receiving pegcetacoplan monthly, 201 pegcetacoplan every other month, and 195 sham). In OAKS, pegcetacoplan monthly and pegcetacoplan every other month significantly slowed geographic atrophy lesion growth by 21% (absolute difference in least-squares mean -0·41 mm2, 95% CI -0·64 to -0·18; p=0·0004) and 16% (-0·32 mm2, -0·54 to -0·09; p=0·0055), respectively, compared with sham at 12 months. In DERBY, pegcetacoplan monthly and pegcetacoplan every other month slowed geographic atrophy lesion growth, although it did not reach significance, by 12% (-0·23 mm2, -0·47 to 0·01; p=0·062) and 11% (-0·21 mm2, -0·44 to 0·03; p=0·085), respectively, compared with sham at 12 months. At 24 months, pegcetacoplan monthly and pegcetacoplan every other month slowed geographic atrophy lesion growth by 22% (-0·90 mm2, -1·30 to -0·50; p<0·0001) and 18% (-0·74 mm2, -1·13 to -0·36; p=0·0002) in OAKS, and by 19% (-0·75 mm2, -1·15 to -0·34; p=0·0004) and 16% (-0·63 mm2, -1·05 to -0·22; p=0·0030) in DERBY, respectively, compared with sham. There were no differences in key secondary visual function endpoints at 24 months. Serious ocular treatment-emergent adverse events were reported in five (2%) of 213, four (2%) of 212, and one (<1%) of 211 patients in OAKS, and in four (2%) of 206, two (1%) of 208, and two (1%) of 206 patients in DERBY receiving pegcetacoplan monthly, pegcetacoplan every other month, and sham, respectively, at 24 months. New-onset exudative age-related macular degeneration was reported in 24 (11%), 16 (8%), and four (2%) patients in OAKS, and in 27 (13%), 12 (6%), and nine (4%) patients in DERBY receiving pegcetacoplan monthly, pegcetacoplan every other month, and sham, respectively, at 24 months. INTERPRETATION: Pegcetacoplan, the first treatment approved by the US Food and Drug Administration for geographic atrophy, slowed geographic atrophy lesion growth with an acceptable safety profile. FUNDING: Apellis Pharmaceuticals.

The complement system: a novel therapeutic target for age-related macular degeneration.

INTRODUCTION: With the recent FDA approvals of pegcetacoplan (SYFOVRE, Apellis Pharmaceuticals) and avacincaptad pegol (IZERVAY, Astellas Pharmaceuticals), modulation of the complement system has emerged as a promising therapeutic approach for slowing progression of geographic atrophy (GA) in AMD. AREAS COVERED: This article reviews the current understanding of the complement system, its role in AMD, and the various complement-targeting therapies in development for the treatment of GA, including monoclonal antibodies, aptamers, protein analogs, and gene therapies. Approved and investigational agents have largely focused on interfering with the activity of complement components 3 and 5, owing to their central roles in the classical, lectin, and alternative complement pathways. Other investigational therapies have targeted formation of membrane attack complex (a terminal step in the complement cascade which leads to cell lysis), complement factors H and I (which serve regulatory functions in the alternative pathway), complement factors B and D (within the alternative pathway), and complement component 1 (within the classical pathway). Clinical trials investigating these agents are summarized, and the potential benefits and limitations of these therapies are discussed. EXPERT OPINION: Targeting the complement system is a promising therapeutic approach for slowing the progression of GA in AMD, potentially improving visual outcomes. However, increased risk of exudative conversion must be considered, and further research is required to identify clinical criteria and best practices for initiating complement inhibitor therapy for GA.

Therapeutic targeting of the complement system in ocular disease.

The complement system is involved in the pathogenesis of several ocular diseases, providing a rationale for the investigation of complement-targeting therapeutics for these conditions. Dry age-related macular degeneration, as characterised by geographic atrophy (GA), is currently the most active area of research for complement-targeting therapeutics, with a complement C3 inhibitor approved in the United States earlier this year marking the first approved therapy for GA. This review discusses the role of complement in ocular disease, provides an overview of the complement-targeting agents currently under development for ocular conditions, and reflects on the lessons that can be learned from the preclinical investigations and clinical trials conducted in this field to date.

Geographic atrophy: Mechanism of disease, pathophysiology, and role of the complement system.

Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD), characterized by atrophic lesions that first start in the outer retina and progressively expand to cover the macula and the fovea, the center of the macula, leading to irreversible loss of vision over time. GA is distinct from wet or neovascular AMD (nAMD), the other form of advanced AMD. Neovascular AMD is characterized by new invading leaky blood vessels in the macula that can lead to acute vision loss. GA and nAMD may coexist in the same eye. The underlying pathophysiology of GA is complex and thought to involve chronic inflammation due to overactivation of the complement system that leads to the loss of photoreceptors, retinal pigment epithelium (RPE), and the underlying choriocapillaris. The disappearance of these structures appears as sharply demarcated atrophic lesions that are typical of GA. Researchers have reported about 1 million reported cases of GA in the United States, and about 160,000 cases occur per year. The most important risk factors for GA are increasing age and family history. Diagnosis of GA is usually made by using multimodal imaging techniques. Lesions associated with GA are highly heterogeneous, and the growth rate may differ from patient to patient. Despite the progressive nature of GA, the fovea may be spared until much later in the disease, thereby retaining central vision in patients. With time, atrophic lesions may progressively grow to involve the fovea, thereby severely impairing central vision. Vision loss can happen rapidly once the lesions reach the fovea. However, even without the involvement of the fovea, ongoing vision impairment impacting daily life may be present. Median time from GA not involving the center of the fovea (without subfoveal involvement) to GA with lesion boundary affecting the foveal center (subfoveal involvement) ranges from 1.4 to 2.5 years. GA can greatly impact patients' functioning and quality of life and limit their independence by interfering with activities of daily living, including difficulties with reading, driving, watching television, recognizing faces, and being unable to do household chores. No treatments have been available until intravitreal pegcetacoplan was recently approved by the US Food and Drug Administration for GA secondary to AMD. DISCLOSURES: Dr Bakri serves as a consultant to Apellis Pharmaceuticals, as well as AbbVie, Adverum, Eyepoint, iLumen, Iveric Bio, Genentech, Novartis, Outlook Therapeutics, Pixium, Regeneron, Roche, and Regenxbio. Drs Sharp, Luo, and Sarda are employees of Apellis Pharmaceuticals. Dr Bektas and Ms Khan are employees of RTI Health Solutions. Apellis developed and led the concept design of this publication, review and interpretation, approval, and decision to publish. This research was developed under a research contract between RTI Health Solutions and Apellis Pharmaceuticals and was funded by Apellis Pharmaceuticals. This supplement is to describe the disease of geographic atrophy and was funded by Apellis. Apellis Pharmaceuticals has developed Syfovre (pegcetacoplan), the first and only treatment for geographic atrophy.

Geographic Atrophy after Reabsorption of Pigment Epithelial Detachment (GARPED) study.

BACKGROUND: To describe the occurrence, rate of geographic atrophy (GA) expansion, and changes in visual acuity (VA) after reabsorption of subfoveal pigment epithelial detachments (PED). METHODS: Included patients had reabsorption of a PED followed by GA. Patients underwent clinical examination with SD-OCT. Images were classified by size with grading occurring post reabsorption. VA was recorded pre-reabsorption, post-reabsorption, and over time. RESULTS: The average age of the cohort, consisting of 22 eyes from 19 participants, was 86.9 years at reabsorption. Prior to reabsorption, the VA was 20/80 and then declined to 20/200 (p = 0.001) with an average follow-up time of 30.2 months. There was no significant VA change after the initial loss with reabsorption. The average initial lesion size of GA was 0.987 mm2 with an average growth rate of 0.274 mm/year. CONCLUSIONS: This study longitudinally examined GA growth rate in patients with reabsorbed PEDs. These patients started with a drusenoid or serous PED, had a dramatic reduction in vision and GA that occurred in place of the PED. These GA lesions have a slower growth rate and a smaller area of onset compared to rates previously reported in the literature. They do not show significant VA change after reabsorption. As we have entered the era of GA therapy, these patients may not benefit from current treatments.

Identifying geographic atrophy.

PURPOSE OF REVIEW: Age-related macular degeneration (AMD) is one of the leading causes of blindness and can progress to geographic atrophy (GA) in late stages of disease. This review article highlights recent literature which assists in the accurate and timely identification of GA, and monitoring of GA progression. RECENT FINDINGS: Technology for diagnosing and monitoring GA has made significant advances in recent years, particularly regarding the use of optical coherence tomography (OCT). Identification of imaging features which may herald the development of GA or its progression is critical. Deep learning applications for OCT in AMD have shown promising growth over the past several years, but more prospective studies are needed to demonstrate generalizability and clinical utility. SUMMARY: Identification of GA and of risk factors for GA development or progression is essential when counseling AMD patients and discussing prognosis. With new therapies on the horizon for the treatment of GA, identification of risk factors for the development and progression of GA will become critical in determining the patients who would be appropriate candidates for new targeted therapies.

Randomized Phase IIb Study of Brimonidine Drug Delivery System Generation 2 for Geographic Atrophy in Age-Related Macular Degeneration.

PURPOSE: To evaluate the safety and efficacy of repeat injections of Brimonidine Drug Delivery System (Brimo DDS) Generation 2 (Gen 2) containing 400-µg brimonidine in patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD). DESIGN: A phase IIb, randomized, multicenter, double-masked, sham-controlled, 30-month study (BEACON). PARTICIPANTS: Patients diagnosed with GA secondary to AMD and multifocal lesions with total area of > 1.25 mm2 and ≤ 18 mm2 in the study eye. METHODS: Enrolled patients were randomized to treatment with intravitreal injections of 400-µg Brimo DDS (n = 154) or sham procedure (n = 156) in the study eye every 3 months from day 1 to month 21. MAIN OUTCOME MEASURES: The primary efficacy endpoint was GA lesion area change from baseline in the study eye, assessed with fundus autofluorescence imaging, at month 24. RESULTS: The study was terminated early, at the time of the planned interim analysis, because of a slow GA progression rate (∼ 1.6 mm2/year) in the enrolled population. Least squares mean (standard error) GA area change from baseline at month 24 (primary endpoint) was 3.24 (0.13) mm2 with Brimo DDS (n = 84) versus 3.48 (0.13) mm2 with sham (n = 91), a reduction of 0.25 mm2 (7%) with Brimo DDS compared with sham (P = 0.150). At month 30, GA area change from baseline was 4.09 (0.15) mm2 with Brimo DDS (n = 49) versus 4.52 (0.15) mm2 with sham (n = 46), a reduction of 0.43 mm2 (10%) with Brimo DDS compared with sham (P = 0.033). Exploratory analysis showed numerically smaller loss over time in retinal sensitivity assessed with scotopic microperimetry with Brimo DDS than with sham (P = 0.053 at month 24). Treatment-related adverse events were usually related to the injection procedure. No implant accumulation was observed. CONCLUSIONS: Multiple intravitreal administrations of Brimo DDS (Gen 2) were well tolerated. The primary efficacy endpoint at 24 months was not met, but there was a numeric trend for reduction in GA progression at 24 months compared with sham treatment. The study was terminated early because of the lower-than-expected GA progression rate in the sham/control group. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosures may be found after the references.

Avacincaptad pegol for geographic atrophy secondary to age-related macular degeneration: 18-month findings from the GATHER1 trial.

BACKGROUND/OBJECTIVES: To assess the safety and efficacy of avacincaptad pegol (ACP), a C5 inhibitor, for geographic atrophy (GA) secondary to age-related macular degeneration (AMD) over an 18-month treatment course. SUBJECTS/METHODS: This study was an international, prospective, randomized, double-masked, sham-controlled, phase 2/3 clinical trial that consisted of 2 parts. In part 1, 77 participants were randomized 1:1:1 to receive monthly intravitreal injections of ACP 1 mg, ACP 2 mg, or sham. In part 2, 209 participants were randomized 1:2:2 to receive monthly ACP 2 mg, ACP 4 mg, or sham. The mean rate of change of GA over 18 months was measured by fundus autofluorescence. RESULTS: Compared with their respective sham cohorts, monthly ACP treatment reduced the mean GA growth (square root transformation) over 18 months by 28.1% (0.168 mm, 95% CI [0.066, 0.271]) for the 2 mg cohort and 30.0% (0.167 mm, 95% CI [0.062, 0.273]) for the 4 mg cohort. ACP treatment was generally well tolerated over 18 months, with most ocular adverse events (AEs) related to the injection procedure. Macular neovascularization (MNV) was more frequent in both 2 mg (11.9%) and 4 mg (15.7%) cohorts than their respective sham control groups (2.7% and 2.4%). CONCLUSIONS: Over this 18-month study, ACP 2 mg and 4 mg showed continued reductions in the progression of GA growth compared to sham and continued to be generally well tolerated. A pivotal phase 3 GATHER2 trial is currently underway to support the efficacy and safety of ACP as a potential treatment for GA.

Associations of systemic health and medication use with the enlargement rate of geographic atrophy in age-related macular degeneration.

BACKGROUND: The associations of geographic atrophy (GA) progression with systemic health status and medication use are unclear. METHODS: We manually delineated GA in 318 eyes in the Age-Related Eye Disease Study. We calculated GA perimeter-adjusted growth rate as the ratio between GA area growth rate and mean GA perimeter between the first and last visit for each eye (mean follow-up=5.3 years). Patients' history of systemic health and medications was collected through questionnaires administered at study enrolment. We evaluated the associations between GA perimeter-adjusted growth rate and 27 systemic health factors using univariable and multivariable linear mixed-effects regression models. RESULTS: In the univariable model, GA perimeter-adjusted growth rate was associated with GA in the fellow eye at any visit (p=0.002), hypertension history (p=0.03), cholesterol-lowering medication use (p<0.001), beta-blocker use (p=0.02), diuretic use (p<0.001) and thyroid hormone use (p=0.03). Among the six factors, GA in the fellow eye at any visit (p=0.008), cholesterol-lowering medication use (p=0.002), and diuretic use (p<0.001) were independently associated with higher GA perimeter-adjusted growth rate in the multivariable model. GA perimeter-adjusted growth rate was 51.1% higher in patients with versus without cholesterol-lowering medication use history and was 37.8% higher in patients with versus without diuretic use history. CONCLUSIONS: GA growth rate may be associated with the fellow eye status, cholesterol-lowering medication use, and diuretic use. These possible associations do not infer causal relationships, and future prospective studies are required to investigate the relationships further.

The intraocular implant and visual rehabilitation improve the quality of life of elderly patients with geographic atrophy secondary to age-related macular degeneration.

INTRODUCTION: The objective of this prospective study was to evaluate the effects of intraocular macular lens implantation and visual rehabilitation on the quality of life of patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD). METHODS: Patients with bilaterally decreased near vision (not better than 0.3 logMAR with the best correction), pseudophakia, were included in the project. The Scharioth macula lens (SML) was implanted into the patients' better-seeing eye. Intensive visual rehabilitation of the ability to perform nearby activities was performed for 20 consecutive postoperative days. All subjects were examined before and after SML implantation ophthalmologically. The National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) was administered before and 6 months after surgery. RESULTS: Twenty eligible patients with mean age 81 years (63 to 92 years) were included in the project: 7 males and 13 females. Nineteen of them completed the 6-month follow-up. Near uncorrected visual acuity was 1.321 ± 0.208 logMAR before SML implantation and improved to 0.547 ± 0.210 logMAR after 6 months (dz = - 2.846, p < 0.001, BF10 = 3.29E + 07). In the composite score of the NEI VFQ-25, there was an improvement in the general score and the specific domains related to the implantation. Participants reported fewer difficulties in performing near activities (dz = 0.91, p = 0.001, BF10 = 39.718) and upturns in mental health symptoms related to vision (dz = 0.62, p = .014, BF10 = 3.937). CONCLUSION: SML implantation, followed by appropriate rehabilitation, improved near vision and increased the quality of life of visually handicapped patients with AMD in our project.

Longitudinal change of reticular pseudodrusen area in ultrawide-field imaging.

This study aimed to investigate the longitudinal change in the reticular pseudodrusen (RPD) area in the fundus and its association with late age-related macular degeneration (AMD). 91 RPD eyes (55 patients; age 67.9 ± 7.3 years) with > 5 years' follow-up (6.8 ± 0.9 years) from a single medical center were enrolled. Ultrawide-field photography images were analyzed using the concentric rings method, and the RPD area was semi-quantitatively classified according to the affected segment number into central, intermediate, and extensive types. Correlations of longitudinal changes in the RPD area and late AMD risk were investigated. RPD area increased significantly during the follow-up (p < 0.001). The increase rate correlated with age (r = 0.207; p = 0.048), RPD area at first visit (r = - 0.222; p = 0.035), and the decrease rate of subfoveal choroidal thickness (SFCT) (r = 0.217; p = 0.039). Many central (18/49, 36.7%) and intermediate (15/23, 65.2%) types switched to the more advanced type during the follow-up. Macular neovascularization and geographic atrophy developed in 12.3% and 18.7% of patients by 7 years. Late AMD incidence was significantly higher in eyes with large than in those with small RPD areas (p = 0.002). Larger RPD area at baseline, faster increase in RPD area, thinner SFCT, rapid decrease in SFCT, and the presence of late AMD on fellow eye were associated with late AMD. All RPD areas progressively increase over time. The regular assessment of RPD area may help to predict late AMD risk in RPD eyes.

The Fovea-Protective Impact of Double-Layer Sign in Eyes With Foveal-Sparing Geographic Atrophy and Age-Related Macular Degeneration.

Purpose: The purpose of this study was to investigate the impact of double-layer sign (DLS) on geographic atrophy (GA) progression in eyes with foveal-sparing GA and age-related macular degeneration (AMD). Methods: This is a retrospective, consecutive case series of eyes with foveal-sparing GA secondary to AMD with more than 6 months of follow-up. The size of the foveal-sparing area was measured on the fundus autofluorescence images at the first and last visits. Each eye was evaluated for the presence or absence of DLS inside the foveal-sparing area. We graded eyes based on the presence of DLS within the foveal-sparing area and compared the progression of GA between two groups (DLS (+) versus DLS (-)). Results: We identified 25 eyes with foveal-sparing GA with at least 2 follow-up visits (average interval = 22.7 ± 11.8 months between visits). The mean foveal sparing area was 1.74 ± 0.87 mm2 (range = 0.42-4.14 mm2) at baseline and 1.26 ± 0.75 mm2 (range = 0.25-2.92 mm2) at the last visit. Seventeen eyes (65.3%) were graded as DLS (+) within the foveal-sparing area. Square root progression of GA toward the fovea was significantly faster in the DLS (-) eyes (0.149 ± 0.078 mm/year) compared to the DLS (+) group (0.088 ± 0.052 mm/year; P = 0.04). Conclusions: The DLS (-) group showed significantly faster centripetal GA progression than the DLS (+) group. Our data suggest that the presence of DLS in the spared foveal area could be a protective factor against foveal progression of GA in eyes with AMD.

Long-term observations of macular thickness after subretinal implantation of a photovoltaic prosthesis in patients with atrophic age-related macular degeneration.

Objective. Subretinal prostheses electrically stimulate the residual inner retinal neurons to partially restore vision. We investigated the changes in neurosensory macular structures and it is thickness associated with subretinal implantation in geographic atrophy (GA) secondary to age-related macular degeneration (AMD).Approach. Using optical coherence tomography, changes in distance between electrodes and retinal inner nuclear layer (INL) as well as alterations in thickness of retinal layers were measured over time above and near the subretinal chip implanted within the atrophic area. Retinal thickness (RT) was quantified across the implant surface and edges as well as outside the implant zone to compare with the natural macular changes following subretinal surgery, and the natural course of dry AMD.Main results. GA was defined based on complete retinal pigment epithelium and outer retinal atrophy (cRORA). Based on the analysis of three patients with subretinal implantation, we found that the distance between the implant and the target cells was stable over the long-term follow-up. Total RT above the implant decreased on average, by 39 ± 12µm during 3 months post-implantation, but no significant changes were observed after that, up to 36 months of the follow-up. RT also changed near the temporal entry point areas outside the implantation zone following the surgical trauma of retinal detachment. There was no change in the macula cRORA nasal to the implanted zone, where there was no surgical trauma or manipulation.Significance. The surgical delivery of the photovoltaic subretinal implant causes minor RT changes that settle after 3 months, and then remain stable over long-term with no adverse structural or functional effects. Distance between the implant and the INL remains stable up to 36 months of the follow-up.

Emerging opportunities for C3 inhibition in the eye.

The eye presents a unique opportunity for complement component 3 (C3) therapeutics. Drugs can be delivered directly to specific parts of the eye, and growing evidence has established a pivotal role for C3 in age-related macular degeneration (AMD). Emerging data show that C3 may be important to the pathophysiology of other eye diseases as well. This article will discuss the location of C3 expression in the eye as well as the preclinical and clinical data regarding C3's functions in AMD. We will provide a comprehensive review of developing C3 inhibitors for the eye, including the Phase 2 and 3 data for the C3 inhibitor pegcetacoplan as a treatment for the geographic atrophy of AMD. Developing evidence also points toward C3 as a therapeutic target for stages of AMD preceding geographic atrophy. We will also discuss data illuminating C3's relationship to other eye diseases, such as Stargardt disease, diabetic retinopathy, and glaucoma. In addition to being a converging point and centerpiece of the complement cascade, C3 has broad effects as a multifaceted controller of opsonophagocytosis, microglia/macrophage recruitment, and downstream terminal pathway activity. C3 is a crucial player in the pathophysiology of AMD but also seems to have importance in other diseases that are major causes of blindness. Directions for further investigation will be highlighted, as culminating evidence suggests that we may be approaching an era of C3 therapeutics for the eye.

Differences in Long-Term Progression of Atrophy between Neovascular and Nonneovascular Age-Related Macular Degeneration.

PURPOSE: To compare the enlargement rates of geographic atrophy (GA) over 5 years of follow-up with those of macular atrophy (MA) associated with macular neovascularization (MNV). DESIGN: Retrospective, longitudinal, comparative case series. PARTICIPANTS: Consecutive series of patients with age-related macular degeneration and GA (dry) or with MA and MNV. METHODS: Atrophic regions detected on serial registered fundus autofluorescence images were semiautomatically delineated, and the measurements of these areas were recorded every 6 ± 3 months for the first 2 years of follow-up and at yearly intervals for up to 5 years. MAIN OUTCOME MEASURES: Annual raw and square root-transformed rates of atrophy growth. RESULTS: The study included 117 eyes of 95 patients (61 in the GA cohort and 56 in the MA cohort); 100% and 38.5% of the eyes completed 2 and 5 years of follow-up, respectively. The mean size of lesions at baseline was similar between the 2 groups (raw: 1.74 vs. 1.53 mm2, P = 0.56; square root-transformed: 1.17 vs. 1.02 mm, P = 0.26). The overall enlargement rates were greater for the GA cohort (raw: 1.72 vs. 1.32 mm2/year, P = 0.002; square root-transformed: 0.41 vs. 0.33 mm/year, P = 0.03), and so was the area of atrophy growth at 5 years (raw: +8.06 vs. +4.55 mm2, P = 0.001; square root-transformed: +1.93 vs. +1.38 mm, P = 0.02). The estimated square root-transformed area was also significantly greater for the GA cohort at 2 years (1.84 vs. 1.67 mm, P = 0.01). CONCLUSIONS: The presence of MNV was associated with a slower rate of expansion, resulting in overall smaller areas of atrophy over time. These findings support the hypothesis that MNV may protect against the progression of atrophy.

Persistent Hypertransmission Defects Detected on En Face Swept Source Optical Computed Tomography Images Predict the Formation of Geographic Atrophy in Age-Related Macular Degeneration.

PURPOSE: To determine whether persistent hypertransmission defects (hyperTDs), previously shown to have a greatest linear dimension (GLD) ≥250 µm on en face swept source OCT (SS-OCT) images, serve as a stand-alone early biomarker for the future formation geographic atrophy (GA). DESIGN: Post hoc cohort study using a subgroup of a prospective study. METHODS: Patients with intermediate age-related macular degeneration (iAMD) underwent 6- × 6-mm SS-OCT raster scans at baseline and during their follow-up period. En face images were generated using a slab with segmentation boundaries positioned 64 µm to 400 µm beneath the Bruch's membrane. Two graders independently evaluated all en face structural images for the presence of hyperTDs with a GLD ≥250 µm and GA. RESULTS: A total of 190 eyes were included with a mean ± SD follow-up of 31 ± 13.2 months. At baseline, 31 eyes (16%) had at least 1 hyperTD ≥250 µm, and 13 eyes (42%) progressed to GA. In those eyes without a hyperTD ≥250 µm at baseline, 42 (26%) developed hyperTDs ≥250 µm during their follow-up, and 11 eyes (7%) progressed to GA. At the last available follow-up visit, 25 eyes (13%) progressed to GA and of these 25 eyes, a prior hyperTD ≥250 µm was detected in 24 eyes before GA formed. A time-dependent Cox-survival regression analysis estimated an 80-fold (95% CI, 10.7-614, P < .001) increased risk of developing GA once a hyperTD ≥250 µm appeared. CONCLUSIONS: Persistent hyperTDs detected on en face OCT images were shown to serve as an early stand-alone OCT biomarker for the future formation of GA.

Fundus autofluorescence and optical coherence tomography biomarkers associated with the progression of geographic atrophy secondary to age-related macular degeneration.

OBJECTIVES: To investigate the impact of qualitatively graded and deep learning quantified imaging biomarkers on growth of geographic atrophy (GA) secondary to age-related macular degeneration. METHODS: This prospective study included 1062 visits of 181 eyes of 100 patients with GA. Spectral-domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) images were acquired at each visit. Hyperreflective foci (HRF) were quantitatively assessed in SD-OCT volumes using a validated deep learning algorithm. FAF images were graded for FAF patterns, subretinal drusenoid deposits (SDD), GA lesion configuration and atrophy enlargement. Linear mixed models were calculated to investigate associations between all parameters and GA progression. RESULTS: FAF patterns were significantly associated with GA progression (p < 0.001). SDD was associated with faster GA growth (p = 0.005). Eyes with higher HRF concentrations showed a trend towards faster GA progression (p = 0.072) and revealed a significant impact on GA enlargement in interaction with FAF patterns (p = 0.01). The fellow eye status had no significant effect on lesion enlargement (p > 0.05). The diffuse-trickling FAF pattern exhibited significantly higher HRF concentrations than any other pattern (p < 0.001). CONCLUSION: Among a wide range of investigated biomarkers, SDD and FAF patterns, particularly in interaction with HRF, significantly impact GA progression. Fully automated quantification of retinal imaging biomarkers such as HRF is both reliable and merited as HRF are indicators of retinal pigment epithelium dysmorphia, a central pathogenetic mechanism in GA. Identifying disease markers using the combination of FAF and SD-OCT is of high prognostic value and facilitates individualized patient management in a clinical setting.