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.

Efficacy and safety of avacincaptad pegol in patients with geographic atrophy (GATHER2): 12-month results from a randomised, double-masked, phase 3 trial.

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

Kinetics of Heterogeneous Background in Stargardt's Disease over Time.

Stargardt's disease (STGD1) is caused by mutations in the ABCA4 gene. Different lesions characterised by decreased autofluorescence levels are found in fundus autofluorescence (FAF) from STGD1 patients and could be used as outcome indicators for disease progression. We investigated the fate of foci with reduced autofluorescence (FRA) within the heterogeneous background of STGD1 patients using FAF imaging. Genetically confirmed STGD1 patients presenting heterogeneous background autofluorescence on high-quality FAF images at a minimum of two visits at least 12 months apart were chosen. A grid centred on the fovea was used to define five different zones. Within each zone, five FRA were randomly selected for each eye. The eccentricity of foci was determined at different time points for each patient. Analysis of 175 randomly chosen FRA showed consistent centrifugal displacement over time, most notably in eyes showing areas with definitely decreased autofluorescence. Interestingly, FRA did not leave an area of hypo-autofluorescence on FAF in locations where they were previously located. These findings may help to better understand STGD1 progression, improve FAF interpretation, and shed light on the nature of heterogeneous background.

Efficacy and safety of brolucizumab versus aflibercept in eyes with polypoidal choroidal vasculopathy in Japanese participants of HAWK.

PURPOSE: To compare the efficacy and safety of brolucizumab versus aflibercept in eyes with polypoidal choroidal vasculopathy (PCV) over 96 weeks in the HAWK study. DESIGN: HAWK was a global, 2-year, randomised, double-masked, multicentre phase III trial in participants with neovascular age-related macular degeneration. METHODS: Of the Japanese participants with PCV, 39 received brolucizumab 6 mg and 30 received aflibercept 2 mg. After 3 monthly loading doses, brolucizumab-treated eyes received an injection every 12 weeks (q12w) but were adjusted to q8w if disease activity was detected. Aflibercept-treated eyes received fixed q8w dosing. Mean change in best-corrected visual acuity (BCVA), the proportion of participants on q12w, retinal thickness, retinal fluid changes and safety were assessed to Week 96. RESULTS: Mean change in BCVA (early treatment diabetic retinopathy study (ETDRS) letters) from baseline to week 48/week 96 was+10.4/+11.4 for brolucizumab and +11.6/+11.1 for aflibercept. For brolucizumab-treated eyes, the probability of only q12w dosing after loading through week 48 was 76%, and 68% through week 96. Fluid resolution was greater with brolucizumab than aflibercept: respective proportions of eyes with intraretinal fluid and/or subretinal fluid were 7.7% and 30% at week 48% and 12.8% and 16.7% at week 96. Brolucizumab exhibited an overall well-tolerated safety profile despite a higher rate of intraocular inflammation compared with aflibercept. CONCLUSION: In Japanese eyes with PCV, brolucizumab q12w/q8w monotherapy resulted in robust and consistent BCVA gains that were comparable to q8w aflibercept dosing. Anatomical outcomes favoured brolucizumab over aflibercept, with 76% of brolucizumab participants maintained on q12w dosing after loading to week 48.

Transplantation of Human Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium in a Swine Model of Geographic Atrophy.

BACKGROUND: The aim of this study was to test the feasibility and safety of subretinal transplantation of human induced pluripotent stem cell (hiPSC)-derived retinal pigment epithelium (RPE) cells into the healthy margins and within areas of degenerative retina in a swine model of geographic atrophy (GA). METHODS: Well-delimited selective outer retinal damage was induced by subretinal injection of NaIO3 into one eye in minipigs (n = 10). Thirty days later, a suspension of hiPSC-derived RPE cells expressing green fluorescent protein was injected into the subretinal space, into the healthy margins, and within areas of degenerative retina. In vivo follow-up was performed by multimodal imaging. Post-mortem retinas were analyzed by immunohistochemistry and histology. RESULTS: In vitro differentiated hiPSC-RPE cells showed a typical epithelial morphology, expressed RPE-related genes, and had phagocytic ability. Engrafted hiPSC-RPE cells were detected in 60% of the eyes, forming mature epithelium in healthy retina extending towards the border of the atrophy. Histological analysis revealed RPE interaction with host photoreceptors in the healthy retina. Engrafted cells in the atrophic zone were found in a patchy distribution but failed to form an epithelial-like layer. CONCLUSIONS: These results might support the use of hiPSC-RPE cells to treat atrophic GA by providing a housekeeping function to aid the overwhelmed remnant RPE, which might improve its survival and therefore slow down the progression of GA.

Enlargement of Geographic Atrophy From First Diagnosis to End of Life.

IMPORTANCE: Treatments for geographic atrophy (GA), a late stage of age-related macular degeneration (AMD), are currently under development. Understanding the natural course is needed for optimal trial design. Although enlargement rates of GA and visual acuity (VA) in the short term are known from clinical studies, knowledge of enlargement in the long term, life expectancy, and visual course is lacking. OBJECTIVE: To determine long-term enlargement of GA. DESIGN, SETTING, AND PARTICIPANTS: In this study, participant data were collected from 4 population-based cohort studies, with up to 25 years of follow-up and eye examinations at 5-year intervals: the Rotterdam Study cohorts 1, 2, and 3 and the Blue Mountains Eye Study. Data were collected from 1990 to 2015, and data were analyzed from January 2019 to November 2020. MAIN OUTCOMES AND MEASURES: Area of GA was measured pixel by pixel using all available imaging. Area enlargement and enlargement of the square root-transformed area, time until GA reached the central fovea, and time until death were assessed, and best-corrected VA, smoking status, macular lesions according to the Three Continent AMD Consortium classification, a modified version of the Wisconsin age-related maculopathy grading system, and AMD genetic variants were covariates in Spearman, Pearson, or Mann-Whitney analyses. RESULTS: Of 171 included patients, 106 (62.0%) were female, and the mean (SD) age at inclusion was 82.6 (7.1) years. A total of 147 of 242 eyes with GA (60.7%) were newly diagnosed in our study. The mean area of GA at first presentation was 3.74 mm2 (95% CI, 3.11-4.67). Enlargement rate varied widely between persons (0.02 to 4.05 mm2 per year), with a mean of 1.09 mm2 per year (95% CI, 0.89-1.30). Stage of AMD in the other eye was correlated with GA enlargement (Spearman ρ = 0.34; P = .01). Foveal involvement was already present in incident GA in 55 of 147 eyes (37.4%); 23 of 42 eyes (55%) developed this after a mean (range) period of 5.6 (3-12) years, and foveal involvement did not develop before death in 11 of 42 eyes (26%). After first diagnosis, 121 of 171 patients with GA (70.8%) died after a mean (SD) period of 6.4 (5.4) years. Visual function was visually impaired (less than 20/63) in 47 of 107 patients (43.9%) at last visit before death. CONCLUSIONS AND RELEVANCE: In this study, enlargement of GA appeared to be highly variable in the general population. More than one-third of incident GA was foveal at first presentation; those with extrafoveal GA developed foveal GA after a mean of 5.6 years. Future intervention trials should focus on recruiting those patients who have a high chance of severe visual decline within their life expectancy.

Impact of Baseline Characteristics on Geographic Atrophy Progression in the FILLY Trial Evaluating the Complement C3 Inhibitor Pegcetacoplan.

PURPOSE: To evaluate the effect of select baseline characteristics on geographic atrophy (GA) progression in eyes receiving intravitreal pegcetacoplan or sham. DESIGN: Phase 2 multicenter, randomized, single-masked, sham-controlled trial. METHODS: Patients with GA received 15 mg pegcetacoplan monthly or every other month (EOM), or sham injection monthly or EOM for 12 months. Primary efficacy endpoint was change in GA lesion size (square root) from baseline. Post hoc analysis evaluated the effects of age; gender; lesion size, focality, and location (extrafoveal vs foveal); pseudodrusen status; best-corrected visual acuity (BCVA); and low-luminance deficit (LLD) on GA progression at Month 12. RESULTS: Of 246 randomized patients, 192 with 12-month data were included in this analysis. Overall mean (standard deviation) change in lesion size (mm) was 0.26 (0.17) (P < .01), 0.27 (0.27) (P < .05), and 0.36 (0.21) in the monthly pegcetacoplan (n = 67), EOM pegcetacoplan (n = 58), and sham (n = 67) groups, respectively. In univariate analysis, patients with extrafoveal lesions (P < .001), BCVA ≥20/60 (P = .001), and larger LLD (P = .002) had greater mean changes in lesion size. Multivariate analysis confirmed significant association of extrafoveal lesions (P = .001) and larger LLD (P = .023) with GA progression. Monthly and EOM pegcetacoplan significantly reduced progression (P < .05) when controlling for these risk factors. CONCLUSIONS: Extrafoveal lesions and larger LLD are potential risk factors for GA progression. Pegcetacoplan treatment significantly controlled GA progression even after accounting for these risk factors.

Characterizing New-Onset Exudation in the Randomized Phase 2 FILLY Trial of Complement Inhibitor Pegcetacoplan for Geographic Atrophy.

OBJECTIVES: To evaluate clinical characteristics of eyes in which investigator-determined new-onset exudative age-related macular degeneration (eAMD) developed during the FILLY trial. DESIGN: Post hoc analysis of the phase 2 study of intravitreal pegcetacoplan in geographic atrophy (GA). SUBJECTS: Patients with GA secondary to age-related macular degeneration (AMD), n = 246. INTERVENTION: Either 15 mg intravitreal pegcetacoplan or sham given monthly or every other month for 12 months followed by a 6-month off-treatment period. MAIN OUTCOME MEASURES: Time of new eAMD onset in the study eye, history of eAMD in the fellow eye, presence of double-layer sign (DLS) on structural OCT in the study eye, changes in retinal anatomic features by structural OCT and fluorescein angiography (FA), and changes in visual acuity. RESULTS: Exudation was reported in 26 study eyes across treatment groups over 18 months. Mean time to eAMD diagnosis was 256 days (range, 31-555 days). Overall, a higher proportion of patients with a baseline history of eAMD in the fellow eye (P = 0.016) and a DLS in the study eye (P = 0.0001) demonstrated eAMD. Among study eyes in which eAMD developed, 18 of 26 (69%) had history of fellow-eye eAMD and 19 of 26 (73.1%) had DLS at baseline, compared with 76 of 217 study eyes (35%; P = 0.0007) and 70 of 215 study eyes (32.5%; P < 0.0001), respectively, in which eAMD did not develop. All 21 patients with structural OCT imaging at the time of eAMD diagnosis demonstrated subretinal fluid, intraretinal cysts, or both consistent with exudation. Among 17 patients who underwent FA at eAMD diagnosis, 10 showed detectable macular neovascularization (MNV), all occult lesions. Development of eAMD did not have an appreciable impact on visual acuity, and all patients responded to anti-vascular endothelial growth factor (VEGF) therapy. CONCLUSIONS: Intravitreal pegcetacoplan slowed the rate of GA growth and was associated with an unexpected dose-dependent increased incidence of eAMD with no temporal clustering of onset. Exudative AMD seemed to be associated with baseline eAMD in the contralateral eye and a DLS, suggestive of nonexudative MNV, in the study eye. The safety profile of pegcetacoplan was acceptable to proceed to phase 3 studies without adjustments to enrollment criteria.

ASYMETRIC GROWTH OF MACULAR ATROPHY ASSOCIATED WITH UNDERLYING MATURE, NONEXUDATIVE CHOROIDAL NEOVASCULARIZATION.

BACKGROUND/PURPOSE: To describe a case study that shows a possible association between the slow growth rate of macular atrophy and the presence of underlying mature, nonexudative choroidal neovascularization. METHODS: Case report. PATIENT: An 82-year-old woman with mixed age-related macular degeneration in both eyes was followed up for 6 years, with the last ranibizumab treatment given in the left eye more than 2 years previously. Evaluations included fluorescein angiography, spectral-domain optical coherence tomography, and optical coherence tomography angiography. RESULTS: During follow-up, there was a peculiar growth of macular atrophy, involving mainly the superior nasal sector. No signs of exudation on fluorescein angiography or spectral-domain optical coherence tomography were apparent throughout this period. However, optical coherence tomography angiography showed a mature, nonexudative choroidal neovascularization under the foveal sparing area and surrounding all the boundaries of atrophy except in the superonasal sector. Macular atrophy growth was observed mainly in the region devoid of blood vessels. CONCLUSION: Growth of macular atrophy was more prominent in the region where mature, nonexudative choroidal neovascularization was absent. Nutrients provided by vessels from choroidal neovascularization may provide support to adjacent retinal pigment epithelium cells, slowing down the progression of atrophy.

Development of a Genotype Assay for Age-Related Macular Degeneration: The EYE-RISK Consortium.

PURPOSE: To develop a genotype assay to assess associations with common and rare age-related macular degeneration (AMD) risk variants, to calculate an overall genetic risk score (GRS), and to identify potential misdiagnoses with inherited macular dystrophies that mimic AMD. DESIGN: Case-control study. PARTICIPANTS: Individuals (n = 4740) from 5 European cohorts. METHODS: We designed single-molecule molecular inversion probes for target selection and used next generation sequencing to sequence 87 single nucleotide polymorphisms (SNPs), coding and splice-site regions of 10 AMD-(related) genes (ARMS2, C3, C9, CD46, CFB, CFH, CFI, HTRA1, TIMP3, and SLC16A8), and 3 genes that cause inherited macular dystrophies (ABCA4, CTNNA1, and PRPH2). Genetic risk scores for common AMD risk variants were calculated based on effect size and genotype of 52 AMD-associated variants. Frequency of rare variants was compared between late AMD patients and control individuals with logistic regression analysis. MAIN OUTCOME MEASURES: Genetic risk score, association of genetic variants with AMD, and genotype-phenotype correlations. RESULTS: We observed high concordance rates between our platform and other genotyping platforms for the 69 successfully genotyped SNPs (>96%) and for the rare variants (>99%). We observed a higher GRS for patients with late AMD compared with patients with early/intermediate AMD (P < 0.001) and individuals without AMD (P < 0.001). A higher proportion of pathogenic variants in the CFH (odds ratio [OR] = 2.88; P = 0.006), CFI (OR = 4.45; P = 0.005), and C3 (OR = 6.56; P = 0.0003) genes was observed in late AMD patients compared with control individuals. In 9 patients, we identified pathogenic variants in the PRPH2, ABCA4, and CTNNA1 genes, which allowed reclassification of these patients as having inherited macular dystrophy. CONCLUSIONS: This study reports a genotype assay for common and rare AMD genetic variants, which can identify individuals at intermediate to high genetic risk of late AMD and enables differential diagnosis of AMD-mimicking dystrophies. Our study supports sequencing of CFH, CFI, and C3 genes because they harbor rare high-risk variants. Carriers of these variants could be amendable for new treatments for AMD that currently are under development.

Non-neovascular age-related macular degeneration with subretinal fluid.

PURPOSE: To evaluate the various patterns of subretinal fluid (SRF) in eyes with age-related macular degeneration (AMD) in the absence of macular neovascularisation (MNV) and to assess the long-term outcomes in these eyes. METHODS: This retrospective study included only eyes with non-neovascular AMD and associated SRF. Eyes with evidence of MNV were excluded. Spectral-domain optical coherence tomography (SD-OCT) was obtained at baseline and at follow-up, and qualitative and quantitative SD-OCT analysis of macular drusen including drusenoid pigment epithelial detachment (PED) and associated SRF was performed to determine anatomic outcomes. RESULTS: Forty-five eyes (45 patients) were included in this analysis. Mean duration of follow-up was 49.7±36.7 months. SRF exhibited three different morphologies: crest of fluid over the apex of the drusenoid PED, pocket of fluid at the angle of a large druse or in the crypt of confluent drusen or drape of low-lying fluid over confluent drusen. Twenty-seven (60%) of the 45 eyes with fluid displayed collapse of the associated druse or drusenoid PED and 24 (53%) of the 45 eyes developed evidence of complete or incomplete retinal pigment epithelial and outer retinal atrophy. CONCLUSION: Non-neovascular AMD with SRF is an important clinical entity to recognise to avoid unnecessary anti-vascular endothelial growth factor therapy. Clinicians should be aware that SRF can be associated with drusen or drusenoid PED in the absence of MNV and may be the result of retinal pigment epithelial (RPE) decompensation and RPE pump failure.

C5 Inhibitor Avacincaptad Pegol for Geographic Atrophy Due to Age-Related Macular Degeneration: A Randomized Pivotal Phase 2/3 Trial.

PURPOSE: The complement pathway may play a key role in the pathogenesis of age-related macular degeneration (AMD). The safety and efficacy of avacincaptad pegol (Zimura, IVERIC bio Inc, New York, NY), a C5 inhibitor, were assessed in participants with geographic atrophy (GA) secondary to AMD (GATHER1 Study). DESIGN: International, prospective, randomized, double-masked, sham-controlled, pivotal phase 2/3 clinical trial. PARTICIPANTS: A total of 286 participants with GA secondary to AMD. MAIN OUTCOME MEASURES: The primary efficacy endpoint was the mean rate of change in GA over 12 months measured by fundus autofluorescence (FAF) at 3 timepoints: baseline, month 6, and month 12. RESULTS: The reduction in the mean rate of GA growth (square root transformation) over 12 months was 27.4% (P = 0.0072) for the avacincaptad pegol 2 mg cohort and 27.8% (P = 0.0051) for the avacincaptad pegol 4 mg cohort compared with their corresponding sham cohorts. The results for both dose groups were statistically significant. Avacincaptad pegol was generally well tolerated after monthly administration over 12 months. There were no avacincaptad pegol-related adverse events (AEs) or inflammation. Further, there were no ocular serious AEs (SAEs) and no cases of endophthalmitis. The most frequent ocular AEs were related to the injection procedure. CONCLUSIONS: Intravitreal administration of avacincaptad pegol 2 mg and 4 mg led to a significant reduction of GA growth in eyes with AMD over a 12-month period. Because C5 inhibition theoretically preserves C3 activity, it may offer additional safety advantages. A second confirmatory pivotal clinical trial is underway to confirm the efficacy and safety of avacincaptad pegol in slowing the GA growth (GATHER2 Study).

Imaging Features Associated with Progression to Geographic Atrophy in Age-Related Macular Degeneration: Classification of Atrophy Meeting Report 5.

PURPOSE: To provide an image-based description of retinal features associated with risk for development of geographic atrophy (GA) in eyes with age-related macular degeneration (AMD), as visualized with multimodal imaging anchored by structural OCT. DESIGN: Consensus meeting. PARTICIPANTS: International group that included those with expertise in imaging and AMD basic science and histology, and those with Reading Center experience in AMD clinical trials. METHODS: As part of the Classification of Atrophy Meeting program, an international group of experts analyzed and discussed retinal multimodal imaging features in eyes with AMD associated with GA, risk of progression to GA, or both. Attendees undertook premeeting grading exercises that were reviewed during the meeting sessions. Meeting presentations illustrated established and investigational multimodal imaging features and associated histologic features. Each of these different features were then discussed openly by the entire group to arrive at consensus definitions. These definitions were applied to 40 additional images that were graded independently by attendees to refine the consensus definitions and descriptions further. RESULTS: Consensus was reached on images with descriptors for 12 features. These features included components of outer retinal atrophy (e.g., ellipsoid zone disruption), components of complete retinal pigment epithelium (RPE) and outer retinal atrophy (e.g., RPE perturbation with associated hypotransmission or hypertransmission), features frequently seen in eyes with atrophy (e.g., refractile drusen), and features conferring risk for atrophy development (e.g., hyperreflective foci, drusen, and subretinal drusenoid deposits). CONCLUSIONS: An international consensus on terms and descriptions was reached on multimodal imaging features associated GA and with risk for GA progression in eyes with AMD. We believe this information will be useful to clinicians who manage patients with AMD, researchers who study AMD disease interventions and pathogenesis, and those who design clinical trials for therapies targeting earlier AMD stages than GA expansion.

Risk of Inflammation, Retinal Vasculitis, and Retinal Occlusion-Related Events with Brolucizumab: Post Hoc Review of HAWK and HARRIER.

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

Early Detection of Incipient Retinal Pigment Epithelium Atrophy Overlying Drusen with Fundus Autofluorescence vs. Spectral Domain Optical Coherence Tomography.

PURPOSE: This study aims to find out which tool, fundus autofluorescence (FAF) or spectral domain optical coherence tomography (SD-OCT), is more sensitive in detecting retinal pigment epithelium (RPE) demise overlying drusen and can, therefore, help predict geographic atrophy (GA) appearance in Age-Related Macular Degeneration (AMD). METHODS: A single-site, retrospective, observational, longitudinal study was conducted. Patients with intermediate AMD (iAMD) (large (>125 µm) or intermediate (63-125 µm) drusen with hyper/hypopigmentation) with a minimum follow-up of 18 months were included. Drusen with overlying incipient RPE atrophy were identified on SD-OCT defined as choroidal hypertransmission or nascent geographic atrophy (nGA). These selected drusen were, then, traced backwards in time to determine if incipient RPE atrophy overlying drusen was observed on FAF (well-demarcated region of absence of autofluorescence) before, simultaneously, or after having detected the first signs of incipient RPE atrophy on SD-OCT. The number of drusen in which signs of incipient RPE atrophy was detected earlier using FAF or SD-OCT was compared. The time elapsed from the identification with the more sensitive method to the other was recorded and analyzed. RESULTS: One hundred and thirty-three drusen in 22 eyes of 22 patients were included. Of these, 112 (84.2%) drusen showed choroidal hypertransmission and 21(15.8%) nGA. Early signs of atrophy overlying drusen were found simultaneously on SD-OCT and FAF in 52 cases (39.1%, 95% CI 30.8-47.9%), earliest on FAF in 51 (38.3%, 95% CI 30.0-47.2%) and first on SD-OCT in 30 (22.6%, 95% CI 15.8-30.6%; p < 0.05). Statistically significant differences were found between both techniques (p=0.005), with FAF detecting it earlier than SD-OCT. When RPE atrophy was found first on FAF, the median time to diagnosis with SD-OCT was 6.6 months (95% CI 5.5 to 8.6), while if detection occurred earlier on SD-OCT, the median time until identification with FAF was 12.6 months (95% CI 6.0 to 23.4; p=0.0003). CONCLUSIONS: In iAMD cases in which early atrophy overlying drusen is not detected simultaneously in FAF and SD-OCT, FAF was significantly more sensitive. Nevertheless, a multimodal approach is recommended and required to evaluate these patients.