Phase 2 Trial Evaluating Minocycline for Geographic Atrophy in Age-Related Macular Degeneration: A Nonrandomized Controlled Trial.

Importance: Existing therapies to slow geographic atrophy (GA) enlargement in age-related macular degeneration (AMD) have relatively modest anatomic efficacy, require intravitreal administration, and increase the risk of neovascular AMD. Additional therapeutic approaches are desirable. Objective: To evaluate the safety and possible anatomic efficacy of oral minocycline, a microglial inhibitor, for the treatment of GA in AMD. Design, Setting, and Participants: This was a phase 2, prospective, single-arm, 45-month, nonrandomized controlled trial conducted from December 2016 to April 2023. Patients with GA from AMD in 1 or both eyes were recruited from the National Institutes of Health (Bethesda, Maryland) and Bristol Eye Hospital (Bristol, UK). Study data were analyzed from September 2022 to May 2023. Intervention: After a 9-month run-in phase, participants began oral minocycline, 100 mg, twice daily for 3 years. Main Outcomes and Measures: The primary outcome measure was the difference in rate of change of square root GA area on fundus autofluorescence between the 24-month treatment phase and 9-month run-in phase. Results: Of the 37 participants enrolled (mean [SD] age, 74.3 [7.6] years; 21 female [57%]), 36 initiated the treatment phase. Of these participants, 21 (58%) completed at least 33 months, whereas 15 discontinued treatment (8 by request, 6 for adverse events/illness, and 1 death). Mean (SE) square root GA enlargement rate in study eyes was 0.31 (0.03) mm per year during the run-in phase and 0.28 (0.02) mm per year during the treatment phase. The primary outcome measure of mean (SE) difference in enlargement rates between the 2 phases was -0.03 (0.03) mm per year (P = .39). Similarly, secondary outcome measures of GA enlargement rate showed no differences between the 2 phases. The secondary outcome measures of mean difference in rate of change between 2 phases were 0.2 letter score per month (95% CI, -0.4 to 0.9; P = .44) for visual acuity and 0.7 µm per month (-0.4 to 1.8; P = .20) for subfoveal retinal thickness. Of the 129 treatment-emergent adverse events among 32 participants, 49 (38%) were related to minocycline (with no severe or ocular events), including elevated thyrotropin level (15 participants) and skin hyperpigmentation/discoloration (8 participants). Conclusions and Relevance: In this phase 2 nonrandomized controlled trial, oral minocycline was not associated with a decrease in GA enlargement over 24 months, compared with the run-in phase. This observation was consistent across primary and secondary outcome measures. Oral minocycline at this dose is likely not associated with slower rate of enlargement of GA in AMD.

Patient acceptability of intravitreal complement inhibitors in geographic atrophy (GA): protocol for a UK-based cross-sectional study.

INTRODUCTION: Geographic atrophy (GA) is the advanced form of the non-neovascular ('dry') type of age-related macular degeneration (AMD). Previously untreatable, complement inhibitors delivered by regular intravitreal injections have recently been demonstrated to slow down the progression of GA lesions in phase 3 trials. One such treatment, Syfovre (pegcetacoplan), was approved by the US Food and Drug Administration in February 2023. These therapies slow down, but do not stop or reverse, the progression of GA; they may also increase the risk of developing the neovascular ('wet') type of AMD. In light of these developments, this study aims to quantify the acceptability of these new intravitreal injection treatments to patients with GA in the UK and explore factors that may influence the acceptability of these treatments. METHODS AND ANALYSIS: In this cross-sectional, non-interventional study, the primary objective is to determine the proportion of patients with GA that find regular intravitreal therapy acceptable for slowing the progression of GA. We will use a validated acceptability questionnaire in order to quantify the acceptability of new treatments among patients with GA. The correlation between acceptability and functional and structural biomarkers of GA will be established. We will also explore demographic, general health and ocular factors that may influence acceptability. 180 individuals with a diagnosis of GA will be recruited from 7 to 8 participating National Health Service trusts across the UK. Multiple regression analysis will be conducted to determine the simultaneous effects of multiple factors on patient acceptability. ETHICS AND DISSEMINATION: The study received ethical approval from the Health Research Authority on 14 March 2023 (IRAS Project ID: 324854). Findings will be disseminated through peer-reviewed publications and conference presentations to the medical retina community, as well as through dialogue with patients and macular disease charities.

Metformin Use and Age-Related Macular Degeneration in Patients Without Diabetes.

Importance: Metformin use may protect against the development of age-related macular degeneration (AMD) based on results from observational studies. However, its potential effectiveness among patients without diabetes remains unclear. Objective: To assess the association between metformin use and the development of AMD in patients without diabetes. Design, Setting, and Participants: This case-control study used data from 2006 to 2017 in the Merative MarketScan Research Database, a nationwide insurance claims database that includes between 27 and 57 million patients in the US with primary or Medicare supplemental health insurance. Cases with AMD and controls without AMD aged 55 years or older were matched 1:1 by year, age, anemia, hypertension, region, and Charlson Comorbidity Index score. Then, cases and matched controls without a diagnosis of diabetes were selected. In subgroup analyses, cases with dry AMD and their matched controls were identified to explore the association between metformin use and AMD staging in patients without diabetes. Data were analyzed between March and September 2023. Exposures: Exposure to metformin in the 2 years prior to the index date (ie, date of AMD diagnosis in cases and date of a randomly selected eye examination for controls) was assessed from the claims database and categorized into quartiles based on cumulative dose (1-270, 271-600, 601-1080, and >1080 g/2 y). Exposure to other antidiabetic medications was also noted. Main Outcomes and Measures: Odds of new-onset AMD development as assessed by multivariable conditional logistic regression after adjusting for known risk factors for AMD, including female sex, hyperlipidemia, smoking, and exposures to other antidiabetic medications. Asymptotic Cochran-Armitage tests for trend were also performed. Results: We identified 231 142 patients with any AMD (mean [SD] age, 75.1 [10.4] years; 140 172 females [60.6%]) and 232 879 matched controls without AMD (mean [SD] age, 74.9 [10.5] years; 133 670 females [57.4%]), none of whom had a diagnosis of diabetes. The sample included 144 147 cases with dry AMD that were matched to 144 530 controls. In all, 2268 (1.0%) cases and 3087 controls (1.3%) were exposed to metformin in the 2 years before their index visit. After data adjustment, exposure to any metformin was associated with reduced odds of any AMD development (adjusted odds ratio [AOR], 0.83; 95% CI, 0.74-0.87), specifically in the dosing quartiles of 1 to 270, 271 to 600, and 601 to 1080 g/2 y. Any metformin use was also associated with a reduced odds of developing dry AMD (AOR, 0.85; 95% CI, 0.79-0.92), specifically in the dosing quartiles of 1 to 270 and 271 to 600 g/2 y. Adjusted odds ratios for any AMD and dry AMD development did not differ across the dosing quartiles. Asymptotic Cochran-Armitage tests for trend revealed 2-sided P = .51 and P = .66 for the any and dry AMD samples, respectively. Conclusions and Relevance: In this case-control study of a population without a diagnosis of diabetes, metformin use was associated with reduced odds of developing AMD. This association does not appear to be dose dependent. These findings provide further impetus to study metformin's usefulness in protecting against AMD in prospective clinical trials.

Vision protection therapy for prevention of neovascular age-related macular degeneration.

To access the effect of vision protection therapy on neovascular conversion in age-related macular degeneration (AMD). Patient unidentified data aggregated by Vestrum Health, LLC (VH) from over 320 US retina specialists was analyzed to compare the conversion rate from dry to neovascular (wet) AMD in a practice employing VPT (VPT group) compared to those employing standard care alone (SCA group) between January 2017 through July 2023. 500,00 eyes were filtered then matched for neovascular conversion risk factors by propensity scoring and compared in a 10/1 ratio of 7370 SCA and 737 VPT treated eyes. SCA eyes had significantly fewer clinical encounters and shorter follow up than the VPT group. Despite this, the risk of neovascular conversion by PS was significantly lower in the VPT group compared to SCA (HR 5.73, p < 0.0001). Analysis matching the encounter frequency of both groups as a post-randomization variable produced a similar HR (HR 5.98, p < 0.0001). Because 9% of eyes in the VPT group were not treated with VPT due to bilateral early (low-risk) AMD, analysis comparing the SCA group to VPT-treated eyes was done that also showed significantly lower conversion rates in the VPT-treated eyes, with or without encounter frequency matching (HR 5.84, 5.65, p < 0.0001). Visual acuity was consistently better in VPT eyes compared to SCA eyes throughout the study time window. The advantage of VPT over SCA increased with increased SCA encounter frequency and higher conversion risk factors, including age and ICD10 coded dry AMD severity. Neovascular (wet) AMD is the main cause of irreversible visual loss worldwide. Consistent with two prior studies, the current study finds Vision Protection Therapy markedly more effective at both recognizing and preventing neovascular AMD than the current standard of care, benefiting the highest risk dry AMD eyes the most.

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 in AMD: Prognostic Factors Based on Long-Term Follow-Up.

INTRODUCTION: The aim of this large-scale long-term retrospective study was to show the enlargement rate (ER) of geographic atrophy (GA) in age-related macular degeneration (AMD), defined as complete retinal pigment epithelium and outer retinal atrophy (cRORA), to find predictors of progression in a clinical routine setting and to compare GA evaluation methods. METHODS: All patients available in our database with follow-up of at least 24 months and cRORA in at least one eye, regardless of neovascular AMD being present, were included. SD-OCT and fundus autofluorescence (FAF) evaluations were performed according to a standardized protocol. The cRORA area ER, the cRORA square root area ER, the FAF GA area, and the condition of the outer retina (inner-/outer-segment [IS/OS] line and external limiting membrane [ELM] disruption scores) were determined. RESULTS: 204 eyes of 129 patients were included. Mean follow-up time was 4.2 ± 2.2 (range 2-10) years. 109 of 204 (53.4%) eyes were classified as MNV-associated GA in AMD (initially or during follow-up); 95 of 204 (46.6%) eyes were classified as pure GA in AMD. The primary lesion was unifocal in 146 (72%) eyes and multifocal in 58 (28%) eyes. A strong correlation was observed between the area of cRORA (SD-OCT) and the FAF GA area (r = 0.924; p < 0.001). Mean ER was 1.44 ± 1.2 mm2/year, mean square root ER 0.29 ± 0.19 mm/year. There was no significant difference in mean ER between eyes without (pure GA) and with intravitreal anti-VEGF injections (MNV-associated GA) (0.30 ± 0.19 mm/year vs. 0.28 ± 0.20 mm/year; p = 0.466). Eyes with multifocal atrophy pattern at baseline had a significantly higher mean ER compared to eyes with unifocal pattern (0.34 ± 0.19 mm/year vs. 0.27 ± 1.19 mm/year; p = 0.008). There were moderate significant correlations between ELM and IS/OS disruption scores and visual acuity at baseline, 5 and 7 years (all r values ca. -0.5; p < 0.001). In multivariate regression analysis, a multifocal cRORA pattern at baseline (p = 0.022) and a smaller baseline lesion size (p = 0.036) were associated with a higher mean ER. CONCLUSION: SD-OCT-evaluated cRORA area might serve as a GA parameter comparable to traditional FAF measurement in clinical routine. The dispersion pattern and baseline lesion size might be predictors of ER, whereas anti-VEGF treatment seems not to be associated with ER.

Exploring patient acceptability of emerging intravitreal therapies for geographic atrophy: A mixed-methods study.

BACKGROUND/OBJECTIVES: The acceptability of emerging intravitreal therapies for patients with Geographic Atrophy (GA) is currently unknown. This study therefore aimed to investigate the extent to which regular intravitreal injections may be acceptable to GA patients. SUBJECTS/METHODS: Thirty UK-based individuals with GA secondary to age-related macular degeneration (AMD), recruited from two London-based hospitals, were interviewed in April-October 2021 regarding acceptability of new GA treatments. Participants responded to a structured questionnaire, as well as open-ended questions in a semi-structured interview. The Theoretical Framework of Acceptability (TFA) informed framework analysis of the qualitative data. RESULTS: Twenty participants (67%) were female, and median (interquartile range (IQR)) age was 83 (78, 87) years. 37% of participants had foveal centre-involving GA, and better eye median (IQR) logMAR visual acuity was 0.30 (0.17, 0.58). Data suggested that 18 participants (60% (95% CI: 41-79%)) would accept the treatment, despite awareness of potential drawbacks. Eight participants (27% (95% CI: 10-43%) were ambivalent or undecided about treatment, and four (13%) (95% CI: 0-26%) would be unlikely to accept treatment. Reducing the frequency of injections from monthly to every other month increased the proportion of participants who considered the treatments acceptable. Conversely, factors limiting acceptability clustered around: the limited magnitude of treatment efficacy; concerns about side effects or the increased risk of neovascular AMD; and the logistical burden of regular clinic visits for intravitreal injections. Misunderstandings of potential benefits indicate the need for appropriately-designed patient education tools to support decision-making. CONCLUSIONS: Our study suggests a majority of participants would be positive about intravitreal treatment for GA, in spite of potential burdens.

A Systematic Review of Clinical Practice Guidelines for Age-related Macular Degeneration.

BACKGROUND: In response to the recommendations of the World Health Organization (WHO) World report on vision, the WHO is developing a Package of Eye Care Interventions (PECI) to support the integration of eye care into health systems within countries. This study was done to systematically review clinical practice guidelines (CPGs) related to age-related macular degeneration (AMD) to provide evidence-based recommendations. METHODS: All AMD-related CPGs published between 2010 and 2020 were reviewed and evaluated using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool. RESULTS: Of 3778 CPGs identified, 48 underwent full-text screening and eight underwent quality appraisal. Five National Institute for Health and Care Excellence (NICE, UK) guidelines for AMD were finally selected for data extraction. Intravitreal anti-vascular endothelial growth factor (VEGF) treatment was strongly recommended for advanced, active neovascular AMD based on high-quality evidence. Photodynamic therapy and laser photocoagulation were not recommended as an adjunct to anti-VEGF therapy as first-line treatment for AMD. Recommendations on other interventions, including epiretinal brachytherapy, miniature lens system implantation, and limited macular translocation, were weak and evidence mostly came from low-quality case series studies. Hence these interventions were recommended to be used only with special arrangements or research. Existing evidence on treating geographic atrophy was limited, an implantable miniature telescope might be an effective intervention to improve vision but was still under investigation. DISCUSSION: Current CPGs recommend anti-VEGF therapy for patients with late active neovascular AMD, while other interventions should be used with caution and further researches are warranted.

Color Vision and Microperimetry Changes in Nonexudative Age-Related Macular Degeneration After Risuteganib Treatment: Exploratory Endpoints in a Multicenter Phase 2a Double-Masked, Randomized, Sham-Controlled, Crossover Clinical Trial.

BACKGROUND AND OBJECTIVE: To explore the association between best-corrected visual acuity (BCVA) improvement and changes in microperimetry (MP) and color vision in patients with nonexudative age-related macular degeneration following administration of two 1.0-mg intravitreal doses of risuteganib. PATIENTS AND METHODS: In a phase 2a, prospective, double-masked, sham-controlled study, eyes with nonexudative age-related macular degeneration and Early Treatment Diabetic Retinopathy Study BCVA between 20/40 and 20/200 were randomized to intravitreal risuteganib (1.0 mg) or sham injection. The risuteganib group received a second 1.0-mg dose, and patients in the sham group crossed over to receive 1.0 mg of risuteganib at week 16. Exploratory endpoints included changes in color vision and mesopic MP. RESULTS: Thirty-nine patients (risuteganib, n = 25; sham, n = 14) completed the study. There was a significant (P < .05) correlation between BCVA and the total error score (TES) for both Lanthony and Hue Style. Confusion index was close to the criterion for significance (P = .056) in the risuteganib group. All color vision metrics demonstrated a trend toward improvement in risuteganib responders (BCVA letter gain ≥8 letters) and no change in the nonresponders, with significant differences seen in confusion index between the risuteganib and control group (P = .0493) and between responders and nonresponders (P = .0478). MP showed that risuteganib responders improved in mean sensitivity and change in number of loci ≤11 dB and ≤0 dB, whereas nonresponders worsened. CONCLUSION: All color vision and MP parameters tested trended toward improvement in risuteganib-treated patients and risuteganib responders. Statistically significant improvement was evident in two metrics: confusion index (in risuteganib-treated patients and responders) and number of loci with decreased sensitivity (in responders). A significant correlation between BCVA and both TES Lanthony and TES Hue Style in risuteganib patients provides concurrent evidence of objective and subjective improvement of retinal function. [Ophthalmic Surg Lasers Imaging Retina 2022;53:430-438.].

Investigational drugs in clinical trials for macular degeneration.

INTRODUCTION: Intravitreal anti-vascular endothelial growth factor (VEGF) injections for exudative age-related macular degeneration (eAMD) are effective and safe but require frequent injections and have nonresponding patients. Geographic atrophy/dry AMD (gaAMD) remains an unmet medical need. New therapies are needed to address this leading cause of blindness in the increasing aged population. AREAS COVERED: This paper reviews the pathogenesis of macular degeneration, current and failed therapeutics, therapies undergoing clinical trials and a rationale for why certain AMD therapies may succeed or fail. EXPERT OPINION: VEGF-inhibitors reduce both vascular leakage and neovascularization. Experimental therapies that only address neovascularization or leakage will unlikely supplant anti-VEGF therapies. The most promising future therapies for eAMD, are those that target, more potently inhibit and have a more sustained effect on the VEGF pathway such as KSI-301, RGX-314, CLS-AX, EYEP-1901, OTX-TKI. GaAMD is a phenotype of phagocytic retinal cell loss. Inhibiting phagocytic activity of retinal microglial/macrophages at the border of geographic atrophy and reducing complement derived activators of microglial/macrophage is the most promising strategy. Complement inhibitors (Pegcetacoplan and Avacincaptad pegol) will likely obtain FDA approval but will serve to pave the way for combined complement and direct phagocytic inhibitors such as AVD-104.

Reticular Pseudodrusen: The Third Macular Risk Feature for Progression to Late Age-Related Macular Degeneration: Age-Related Eye Disease Study 2 Report 30.

PURPOSE: To analyze reticular pseudodrusen (RPD) as an independent risk factor for progression to late age-related macular degeneration (AMD), alongside traditional macular risk factors (soft drusen and pigmentary abnormalities) considered simultaneously. DESIGN: Post hoc analysis of 2 clinical trial cohorts: Age-Related Eye Disease Study (AREDS) and AREDS2. PARTICIPANTS: Eyes with no late AMD at baseline in AREDS (6959 eyes, 3780 participants) and AREDS2 (3355 eyes, 2056 participants). METHODS: Color fundus photographs (CFPs) from annual visits were graded for soft drusen, pigmentary abnormalities, and late AMD. Presence of RPD was from grading of fundus autofluorescence images (AREDS2) and deep learning grading of CFPs (AREDS). Proportional hazards regression analyses were performed, considering AREDS AMD severity scales (modified simplified severity scale [person] and 9-step scale [eye]) and RPD presence simultaneously. MAIN OUTCOME MEASURES: Progression to late AMD, geographic atrophy (GA), and neovascular AMD. RESULTS: In AREDS, for late AMD analyses by person, in a model considering the simplified severity scale simultaneously, RPD presence was associated with a higher risk of progression: hazard ratio (HR), 2.15 (95% confidence interval [CI], 1.75-2.64). However, the risk associated with RPD presence differed at different severity scale levels: HR, 3.23 (95% CI, 1.60-6.51), HR, 3.81 (95% CI, 2.38-6.10), HR, 2.28 (95% CI, 1.59-3.27), and HR, 1.64 (95% CI, 1.20-2.24), at levels 0-1, 2, 3, and 4, respectively. Considering the 9-step scale (by eye), RPD presence was associated with higher risk: HR, 2.54 (95% CI, 2.07-3.13). The HRs were 5.11 (95% CI, 3.93-6.66) at levels 1-6 and 1.78 (95% CI, 1.43-2.22) at levels 7 and 8. In AREDS2, by person, RPD presence was not associated with higher risk: HR, 1.18 (95% CI, 0.90-1.56); by eye, it was HR, 1.57 (95% CI, 1.31-1.89). In both cohorts, RPD presence carried a higher risk for GA than neovascular AMD. CONCLUSIONS: Reticular pseudodrusen represent an important risk factor for progression to late AMD, particularly GA. However, the added risk varies markedly by severity level, with highly increased risk at lower/moderate levels and less increased risk at higher levels. Reticular pseudodrusen status should be included in updated AMD classification systems, risk calculators, and clinical trials.

Impact of Baseline Quantitative OCT Features on Response to Risuteganib for the Treatment of Dry Age-Related Macular Degeneration: The Importance of Outer Retinal Integrity.

OBJECTIVE: The purpose of the study was to perform a post hoc analysis to explore the effect of baseline anatomic characteristics identified on OCT on best-corrected visual acuity (BCVA) responses to risuteganib from the completed phase II study in subjects with dry age-related macular degeneration (AMD). DESIGN: Post hoc analysis of a randomized, double-masked, placebo-controlled, phase II study. SUBJECTS: Eyes with intermediate dry AMD with BCVA between 20/40 and 20/200. Patients with concurrent vision-influencing or macula-obscuring ocular pathologies were excluded. METHODS: Patients were randomized to receive a 1-mg intravitreal risuteganib injection or a sham injection at baseline. A second 1-mg intravitreal injection of risuteganib was given at week 16 to those in the treatment arm. Two independent, masked reading centers evaluated the baseline anatomic characteristics on OCT to explore features associated with positive responses to risuteganib. MAIN OUTCOME MEASURES: Treatment response was defined as a gain of ≥ 8 letters in BCVA from baseline to week 28 in the treatment arm, compared with baseline to week 12 in the sham group. Anatomic parameters, measured by retinal segmentation platforms, including measures of retinal thickness were compared between the responders and nonresponders to risuteganib. RESULTS: Thirty-nine patients completed the study and underwent analysis. In the treatment arm, 48% of eyes demonstrated treatment responses, compared with 7% in the sham group. In the quantitative anatomic assessment, enhanced ellipsoid integrity, greater outer retinal thickness, and decreased geographic atrophy were associated with increased BCVA gains to risuteganib. CONCLUSIONS: This post hoc analysis demonstrated that baseline OCT features may help determine the likelihood of a functional response to risuteganib. The characterization of higher-order OCT features may provide important information regarding biomarkers for treatment response and could facilitate optimized clinical trial enrollment and enrichment.

Exudative versus Nonexudative Age-Related Macular Degeneration: Physiopathology and Treatment Options.

Age-related macular degeneration (AMD) is an eye disease typically associated with the aging and can be classified into two types-namely, the exudative and the nonexudative AMD. Currently available treatments for exudative AMD use intravitreal injections, which are associated with high risk of infection that can lead to endophthalmitis, while no successful treatments yet exist for the nonexudative form of AMD. In addition to the pharmacologic therapies administered by intravitreal injection already approved by the Food and Drug Administration (FDA) in exudative AMD, there are some laser treatments approved that can be used in combination with the pharmacological therapies. In this review, we discuss the latest developments of treatment options for AMD. Relevant literature available from 1993 was used, which included original articles and reviews available in PubMed database and also information collected from Clinical Trials Gov website using "age-related macular degeneration" and "antiangiogenic therapies" as keywords. The clinical trials search was limited to ongoing trials from 2015 to date.

Characterisation of macular neovascularisation in geographic atrophy.

AIM: To characterise macular neovascularisation (MNV) developing in eyes affected by geographic atrophy (GA). METHODS: In this multicentric longitudinal study involving three retina referral centres, patients previously affected by GA who developed an active MNV were included. Patients were investigated using structural optical coherence tomography (OCT), fundus autofluorescence, OCT-angiography and dye angiographies. Patients were treated with ProReNata antivascular endothelial growth factor (VEGF) injections and were revaluated after treatment. RESULTS: Among 512 patients previously diagnosed with GA, 40 eyes of 40 patients (mean age 80.8±7.9 years, mean GA area 8.73±7.39 mm2) presented with treatment-naïve exudative MNV (accounting for an estimated prevalence of 7.81%; 5.49 to 10.13, 95% CIs) and thus were included in the analysis. 67.5% of MNVs were classified as type 2 MNV, 25% as type 1, 2.5% as type 3 and 5% as mixed phenotype. In 92.5% of cases, active MNV in GA showed subretinal hyperreflective material with or without evidence of subretinal/intraretinal hyporeflective exudation. During a mean follow-up of 28±25 months, patients were treated with 6.6±6.3 anti-VEGF injections, with 2.9±1.4 injections in the first year of treatment. No patient developed GA enlargement in the area of MNV. CONCLUSIONS: MNVs in GA showed different features and therapeutic response in comparison to previously reported features of MNV in age-related macular degeneration (AMD) without GA. For these reasons, the combined phenotype (ie, GA with neovascular AMD) should be considered as a distinct entity in the research and clinical setting.

Topical Ketotifen Fumarate Inhibits Choroidal Mast Cell Degranulation and Loss of Retinal Pigment Epithelial Cells in Rat Model for Geographic Atrophy.

Purpose: This study evaluates whether topical ketotifen fumarate (KTF) can prevent geographic atrophy (GA)-like phenotypes in a rat model. Methods: Pharmacokinetics (PKs) of KTF after topical administration twice daily for 5 days was analyzed in rat retina, retinal pigment epithelium (RPE)/choroid/sclera, and in plasma by an liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Rats were then given hydrogel implants +/- 48/80 in the superior subconjunctival space and topically treated with 1% and 0.25% of KTF or phosphate buffer saline (PBS) twice daily. Rats were euthanized at 1, 2, 4, and 8 weeks postinjection. Choroidal mast cells (MCs) were stained with nonspecific esterase and the RPE monolayer was labeled with RPE65 and ZO-1 in whole mount choroids. Retinal and choroidal areas were determined in cryosections stained with picrosirius red. Dark-adapted electroretinogram (ERG) was also performed to evaluate retinal function. Results: PK results showed the highest level of KTF (average 5.6 nM/mg) in the RPE/choroid/sclera in rats given topical 1% KTF. Topical 1% KTF significantly reduced choroidal MC degranulation at 1 week and 2 weeks (both P < 0.001) and RPE loss at 4 weeks (P < 0.001) as well as retinal and choroidal thinning (both P < 0.001) and reduction in ERG amplitude at 8 weeks (P < 0.05) compared to PBS. Similar results were obtained with 0.25% KTF. Conclusions: Both 1% and 0.25% KTF eye drops effectively reduced MC degranulation, RPE loss, and retinal and choroidal thinning while preventing the decline of ERG amplitude in a GA-like rat model. These data suggest that topical KTF might be a new therapeutic drug for treating GA. Translational Relevance: The results of this study demonstrate that topical KTF successfully reduced GA-like phenotypes in a rat model and may provide a novel therapy for GA.

Ocular Therapeutics and Molecular Delivery Strategies for Neovascular Age-Related Macular Degeneration (nAMD).

Age-related macular degeneration (AMD) is the leading cause of vision loss in geriatric population. Intravitreal (IVT) injections are popular clinical option. Biologics and small molecules offer efficacy but relatively shorter half-life after intravitreal injections. To address these challenges, numerous technologies and therapies are under development. Most of these strategies aim to reduce the frequency of injections, thereby increasing patient compliance and reducing patient-associated burden. Unlike IVT frequent injections, molecular therapies such as cell therapy and gene therapy offer restoration ability hence gained a lot of traction. The recent approval of ocular gene therapy for inherited disease offers new hope in this direction. However, until such breakthrough therapies are available to the majority of patients, antibody therapeutics will be on the shelf, continuing to provide therapeutic benefits. The present review aims to highlight the status of pre-clinical and clinical studies of neovascular AMD treatment modalities including Anti-VEGF therapy, upcoming bispecific antibodies, small molecules, port delivery systems, photodynamic therapy, radiation therapy, gene therapy, cell therapy, and combination therapies.

Pegcetacoplan: First Approval.

Pegcetacoplan (Empaveli™) is a PEGylated pentadecapeptide developed by Apellis Pharmaceuticals for the treatment of complement-mediated diseases. It binds to complement component 3 (C3) and its activation fragment C3b, controlling the cleavage of C3 and the generation of the downstream effectors of complement activation and thus both C3b-mediated extravascular haemolysis and terminal complement-mediated intravascular haemolysis. Pegcetacoplan is the first C3-targeted paroxysmal nocturnal haemoglobinuria (PNH) therapy to be approved (in May 2021) in the USA, where it is indicated for the treatment of adults with PNH, including those switching from C5 inhibitor therapy with eculizumab and ravulizumab. A regulatory assessment of pegcetacoplan for the treatment of PNH is currently underway in the EU and Australia. Pegcetacoplan is also being investigated as a therapeutic option in other complement-mediated diseases, including age-related macular degeneration, C3 glomerulopathy and autoimmune haemolytic anaemia. The recommended dosage regimen of pegcetacoplan is 1080 mg twice weekly, administered as a subcutaneous infusion via an infusion pump with a ≥ 20 mL reservoir. This article summarizes the milestones in the development of pegcetacoplan leading to this first approval for the treatment of adults with PNH.

Biomarkers for Nonexudative Age-Related Macular Degeneration and Relevance for Clinical Trials: A Systematic Review.

TOPIC: The purpose of the review was to identify structural, functional, blood-based, and other types of biomarkers for early, intermediate, and late nonexudative stages of age-related macular degeneration (AMD) and summarize the relevant data for proof-of-concept clinical trials. CLINICAL RELEVANCE: AMD is a leading cause of blindness in the aging population, yet no treatments exist for its most common nonexudative form. There are limited data on the diagnosis and progression of nonexudative AMD compared to neovascular AMD. Our objective was to provide a comprehensive, systematic review of recently published biomarkers (molecular, structural, and functional) for early AMD, intermediate AMD, and geographic atrophy and to evaluate the relevance of these biomarkers for use in future clinical trials. METHODS: A literature search of PubMed, ScienceDirect, EMBASE, and Web of Science from January 1, 1996 to November 30, 2020 and a patent search were conducted. Search terms included "early AMD," "dry AMD," "intermediate AMD," "biomarkers for nonexudative AMD," "fundus autofluorescence patterns," "color fundus photography," "dark adaptation," and "microperimetry." Articles were assessed for bias and quality with the Mixed-Methods Appraisal Tool. A total of 94 articles were included (61,842 individuals). RESULTS: Spectral-domain optical coherence tomography was superior at highlighting detailed structural changes in earlier stages of AMD. Fundus autofluorescence patterns were found to be most important in estimating progression of geographic atrophy. Delayed rod intercept time on dark adaptation was the most widely recommended surrogate functional endpoint for early AMD, while retinal sensitivity on microperimetry was most relevant for intermediate AMD. Combinational studies accounting for various patient characteristics and machine/deep-learning approaches were best suited for assessing individualized risk of AMD onset and progression. CONCLUSION: This systematic review supports the use of structural and functional biomarkers in early AMD and intermediate AMD, which are more reproducible and less invasive than the other classes of biomarkers described. The use of deep learning and combinational algorithms will gain increasing importance in future clinical trials of nonexudative AMD.