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.

Geographic atrophy: current and future therapeutic agents and practical considerations for retinal specialists.

PURPOSE OF REVIEW: Geographic atrophy (GA) from age-related macular degeneration (AMD) remains a leading cause of vision loss. The purpose of this review is to summarize currently available intravitreal therapeutics, and discuss pipeline therapeutics that are currently in clinical trials. RECENT FINDINGS: The FDA approval of pegcetacoplan and avacincaptad pegol, both approved in 2023, represent the first therapeutics to treat GA. These are delivered via intravitreal injections, and have been shown to slow progression of GA. Both drugs have a risk of new onset neovascular age-related macular degeneration (nAMD). Initial indications seem to be that pegcetacoplan therapy has higher risks of inflammation, vasculitis, and nonarteritic ischemic optic neuropathy (NAION) as compared to avacincaptad pegol, but more real-world data will help to clarify this further. Pipeline therapeutics that we discuss include intravitreal gene therapy, oral anticomplement therapy, and intravitreal injections of a novel glycoprotein. SUMMARY: Both pegcetacoplan and avacincaptad pegol are FDA approved to treat GA. The decision to treat patients is still complex and nuanced, but the approval of two treatments for GA is a tremendous advance in our field. Future therapeutics may further refine our ability to treat patients more effectively and safely.

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.

Two studies to learn if avacincaptad pegol works and is safe in people with geographic atrophy: a plain language summary of the GATHER1 and GATHER 2 studies.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of two publications. One publication is about the GATHER1 study, which was published in the journal Ophthalmology in 2021. The other publication is about the GATHER2 study, which was published in the journal The Lancet in 2023. Both studies included adult participants with geographic atrophy (GA). GA is an advanced form of dry age-related macular degeneration (dry AMD). The participants in both studies each received treatment in one of their eyes. In both studies, the researchers wanted to learn if avacincaptad pegol (ACP) could help to slow the worsening of the participants' GA over time. WHAT WERE THE RESULTS?: In these studies, the researchers found that ACP helped to slow the growth of the GA area in the participants' eyes compared with a sham injection. Participants who received ACP had a similar ability to read differently sized letters on a chart 1 year after treatment compared with participants who received no ACP through a sham injection. In the GATHER1 study, none of the participants had serious medical problems in the eye that received the injection. In the GATHER2 study, 2 out of 225 participants (less than 1%) who received ACP had serious medical problems in the eye that received the injection. In the group who received the sham injection, 2 out of the 222 participants (less than 1%) had serious medical problems in the eye that received the sham injection. WHAT DO THE RESULTS MEAN?: ACP could be a treatment option for people with GA. The results from several studies are needed to decide which treatments work best and are safest. Other studies may provide new information or different results. Always talk to a doctor before making any treatment changes.

Deep-learning automated quantification of longitudinal OCT scans demonstrates reduced RPE loss rate, preservation of intact macular area and predictive value of isolated photoreceptor degeneration in geographic atrophy patients receiving C3 inhibition treatment.

OBJECTIVE: To evaluate the role of automated optical coherence tomography (OCT) segmentation, using a validated deep-learning model, for assessing the effect of C3 inhibition on the area of geographic atrophy (GA); the constituent features of GA on OCT (photoreceptor degeneration (PRD), retinal pigment epithelium (RPE) loss and hypertransmission); and the area of unaffected healthy macula.To identify OCT predictive biomarkers for GA growth. METHODS: Post hoc analysis of the FILLY trial using a deep-learning model for spectral domain OCT (SD-OCT) autosegmentation. 246 patients were randomised 1:1:1 into pegcetacoplan monthly (PM), pegcetacoplan every other month (PEOM) and sham treatment (pooled) for 12 months of treatment and 6 months of therapy-free monitoring. Only participants with Heidelberg SD-OCT were included (n=197, single eye per participant).The primary efficacy endpoint was the square root transformed change in area of GA as complete RPE and outer retinal atrophy (cRORA) in each treatment arm at 12 months, with secondary endpoints including RPE loss, hypertransmission, PRD and intact macular area. RESULTS: Eyes treated PM showed significantly slower mean change of cRORA progression at 12 and 18 months (0.151 and 0.277 mm, p=0.0039; 0.251 and 0.396 mm, p=0.039, respectively) and RPE loss (0.147 and 0.287 mm, p=0.0008; 0.242 and 0.410 mm, p=0.00809). PEOM showed significantly slower mean change of RPE loss compared with sham at 12 months (p=0.0313). Intact macular areas were preserved in PM compared with sham at 12 and 18 months (p=0.0095 and p=0.044). PRD in isolation and intact macula areas was predictive of reduced cRORA growth at 12 months (coefficient 0.0195, p=0.01 and 0.00752, p=0.02, respectively) CONCLUSION: The OCT evidence suggests that pegcetacoplan slows progression of cRORA overall and RPE loss specifically while protecting the remaining photoreceptors and slowing the progression of healthy retina to iRORA.

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.

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.

Investigational drugs inhibiting complement for the treatment of geographic atrophy.

INTRODUCTION: Geographic atrophy (GA) is a progressive form of age-related macular degeneration (AMD) that leads to severe visual impairment and central vision loss. Traditional treatment options for GA are limited, highlighting the need for new therapeutic approaches. In recent years, targeting the complement system has emerged as a promising strategy for the treatment of GA. AREAS COVERED: This expert opinion article reviews the investigational drugs inhibiting the complement cascade for the treatment of GA. Specifically, it focuses on the recent FDA approved pegcetacoplan, a C3 complement inhibitor, and avacincaptad pegol, a C5 complement inhibitor, highlighting their potential efficacy and safety profiles based on clinical trial data. EXPERT OPINION: FDA approval of intravitreal pegcetacoplan and avacincaptad pegol marks significant progress in the landscape of GA treatment. However, variable results from trials underscore the complex nature of GA and the importance of patient selection. Complement inhibition holds promise, but ongoing research is vital to refine treatment strategies and offer improved outcomes for GA patients.

INFLAMMATORY CELL ACTIVITY IN TREATED NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Histologic Case Study.

BACKGROUND: Imaging indicators of macular neovascularization risk can help determine patient eligibility for new treatments for geographic atrophy secondary to age-related macular degeneration. Because type 1 macular neovascularization includes inflammation, we assessed by histology the distribution of cells with inflammatory potential in two fellow eyes with age-related macular degeneration. METHODS: Two eyes of a White woman in her 90's with type 3 macular neovascularization treated with antivascular endothelial growth factor were prepared for high-resolution histology. Eye-tracked spectral domain optical coherence tomography applied to the preserved donor eyes linked in vivo imaging to histology. Cells were enumerated in the intraretinal, subretinal, and subretinal retinal pigment epithelium (RPE)-basal lamina compartments on 199 glass slides. Cells with numerous organelles were considered to RPE-derived; cells with sparse RPE organelles were considered non-RPE phagocytes. RESULTS: Both eyes had soft drusen and abundant subretinal drusenoid deposit. In the retina and subretinal space, RPE-derived cells, including hyperreflective foci, were common (n = 125 and 73, respectively). Non-RPE phagocytes were infrequent (n = 5 in both). Over drusen, RPE morphology transitioned smoothly from the age-normal layer toward the top, suggesting transdifferentiation. The sub-RPE-basal lamina space had RPE-derived cells (n = 87) and non-RPE phagocytes (n = 49), including macrophages and giant cells. CONCLUSION: Numerous sub-RPE-basal lamina cells of several types are consistent with the documented presence of proinflammatory lipids in drusen and aged Bruch's membrane. The relatively compartmentalized abundance of infiltrating cells suggests that drusen contents are more inflammatory than subretinal drusenoid deposit, perhaps reflecting their environments. Ectopic RPE occurs frequently. Some manifest as hyperreflective foci. More cells may be visible as optical coherence tomography technologies evolve.

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.

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.

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.

Piloting a forced-choice task to elicit treatment preferences in geographic atrophy.

OBJECTIVE: Geographic Atrophy (GA) is the advanced form of the non-neovascular ('dry') type of age-related macular degeneration (AMD) and responsible for one-quarter of legal blindness in the UK. New therapies delivered by intravitreal injection are in late-stage development, and two such therapies (pegcetacoplan (Syfovre) and avacincaptad pegol (Izervay)) have now been approved for clinical use by the US Food and Drug Administration. These therapies slow down, but do not stop or reverse, progression of GA and they may also increase the risk of developing the neovascular ('wet') type of AMD. Within a larger study exploring the acceptability of these new treatments to people living with GA, we developed a forced-choice exercise to evaluate how participants weigh up benefits and drawbacks of different treatment regimens. This research note reports quantitative and qualitative findings from this exercise. RESULTS: Twenty-eight participants took part in this exercise. The exercise demonstrated that participants were generally, although not unanimously, in favour of less frequent treatment for GA that was slightly less efficacious in terms of preserving visual function but presented a lower risk of developing wet AMD. Even among a small sample, the exercise demonstrated the highly personal and idiosyncratic decision-making processes influencing participants' choices of preferred hypothetical GA treatment.

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.

Complement inhibitors for age-related macular degeneration.

BACKGROUND: Age-related macular degeneration (AMD) is a common eye disease and leading cause of sight loss worldwide. Despite its high prevalence and increasing incidence as populations age, AMD remains incurable and there are no treatments for most patients. Mounting genetic and molecular evidence implicates complement system overactivity as a key driver of AMD development and progression. The last decade has seen the development of several novel therapeutics targeting complement in the eye for the treatment of AMD. This review update encompasses the results of the first randomised controlled trials in this field. OBJECTIVES: To assess the effects and safety of complement inhibitors in the prevention or treatment of AMD. SEARCH METHODS: We searched CENTRAL on the Cochrane Library, MEDLINE, Embase, LILACS, Web of Science, ISRCTN registry, ClinicalTrials.gov, and the WHO ICTRP to 29 June 2022 with no language restrictions. We also contacted companies running clinical trials for unpublished data. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with parallel groups and comparator arms that studied complement inhibition for advanced AMD prevention/treatment. DATA COLLECTION AND ANALYSIS: Two authors independently assessed search results and resolved discrepancies through discussion. Outcome measures evaluated at one year included change in best-corrected visual acuity (BCVA), untransformed and square root-transformed geographic atrophy (GA) lesion size progression, development of macular neovascularisation (MNV) or exudative AMD, development of endophthalmitis, loss of ≥ 15 letters of BCVA, change in low luminance visual acuity, and change in quality of life. We assessed risk of bias and evidence certainty using Cochrane risk of bias and GRADE tools. MAIN RESULTS: Ten RCTs with 4052 participants and eyes with GA were included. Nine evaluated intravitreal (IVT) administrations against sham, and one investigated an intravenous agent against placebo. Seven studies excluded patients with prior MNV in the non-study eye, whereas the three pegcetacoplan studies did not. The risk of bias in the included studies was low overall. We also synthesised results of two intravitreal agents (lampalizumab, pegcetacoplan) at monthly and every-other-month (EOM) dosing intervals. Efficacy and safety of IVT lampalizumab versus sham for GA For 1932 participants in three studies, lampalizumab did not meaningfully change BCVA given monthly (+1.03 letters, 95% confidence interval (CI) -0.19 to 2.25) or EOM (+0.22 letters, 95% CI -1.00 to 1.44) (high-certainty evidence). For 1920 participants, lampalizumab did not meaningfully change GA lesion growth given monthly (+0.07 mm², 95% CI -0.09 to 0.23; moderate-certainty due to imprecision) or EOM (+0.07 mm², 95% CI -0.05 to 0.19; high-certainty). For 2000 participants, lampalizumab may have also increased MNV risk given monthly (RR 1.77, 95% CI 0.73 to 4.30) and EOM (RR 1.70, 95% CI 0.67 to 4.28), based on low-certainty evidence. The incidence of endophthalmitis in patients treated with monthly and EOM lampalizumab was 4 per 1000 (0 to 87) and 3 per 1000 (0 to 62), respectively, based on moderate-certainty evidence. Efficacy and safety of IVT pegcetacoplan versus sham for GA For 242 participants in one study, pegcetacoplan probably did not meaningfully change BCVA given monthly (+1.05 letters, 95% CI -2.71 to 4.81) or EOM (-1.42 letters, 95% CI -5.25 to 2.41), as supported by moderate-certainty evidence. In contrast, for 1208 participants across three studies, pegcetacoplan meaningfully reduced GA lesion growth when given monthly (-0.38 mm², 95% CI -0.57 to -0.19) and EOM (-0.29 mm², 95% CI -0.44 to -0.13), with high certainty. These reductions correspond to 19.2% and 14.8% versus sham, respectively. A post hoc analysis showed possibly greater benefits in 446 participants with extrafoveal GA given monthly (-0.67 mm², 95% CI -0.98 to -0.36) and EOM (-0.60 mm², 95% CI -0.91 to -0.30), representing 26.1% and 23.3% reductions, respectively. However, we did not have data on subfoveal GA growth to undertake a formal subgroup analysis. In 1502 participants, there is low-certainty evidence that pegcetacoplan may have increased MNV risk when given monthly (RR 4.47, 95% CI 0.41 to 48.98) or EOM (RR 2.29, 95% CI 0.46 to 11.35). The incidence of endophthalmitis in patients treated with monthly and EOM pegcetacoplan was 6 per 1000 (1 to 53) and 8 per 1000 (1 to 70) respectively, based on moderate-certainty evidence. Efficacy and safety of IVT avacincaptad pegol versus sham for GA In a study of 260 participants with extrafoveal or juxtafoveal GA, monthly avacincaptad pegol probably did not result in a clinically meaningful change in BCVA at 2 mg (+1.39 letters, 95% CI -5.89 to 8.67) or 4 mg (-0.28 letters, 95% CI -8.74 to 8.18), based on moderate-certainty evidence. Despite this, the drug was still found to have probably reduced GA lesion growth, with estimates of 30.5% reduction at 2 mg (-0.70 mm², 95% CI -1.99 to 0.59) and 25.6% reduction at 4 mg (-0.71 mm², 95% CI -1.92 to 0.51), based on moderate-certainty evidence. Avacincaptad pegol may have also increased the risk of developing MNV (RR 3.13, 95% CI 0.93 to 10.55), although this evidence is of low certainty. There were no cases of endophthalmitis reported in this study. AUTHORS' CONCLUSIONS: Despite confirmation of the negative findings of intravitreal lampalizumab across all endpoints, local complement inhibition with intravitreal pegcetacoplan meaningfully reduces GA lesion growth relative to sham at one year. Inhibition of complement C5 with intravitreal avacincaptad pegol is also an emerging therapy with probable benefits on anatomical endpoints in the extrafoveal or juxtafoveal GA population. However, there is currently no evidence that complement inhibition with any agent improves functional endpoints in advanced AMD; further results from the phase 3 studies of pegcetacoplan and avacincaptad pegol are eagerly awaited. Progression to MNV or exudative AMD is a possible emergent adverse event of complement inhibition, requiring careful consideration should these agents be used clinically. Intravitreal administration of complement inhibitors is probably associated with a small risk of endophthalmitis, which may be higher than that of other intravitreal therapies. Further research is likely to have an important impact on our confidence in the estimates of adverse effects and may change these. The optimal dosing regimens, treatment duration, and cost-effectiveness of such therapies are yet to be established.

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.