Narrative review of outcome measures for geographic atrophy treatment trials—lessons learned from previous trials

Introduction

Background

Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD), marked by atrophic lesions that initially develop in the outer retina and progressively spread to the fovea, ultimately resulting in permanent vision loss (1). The global prevalence of GA exceeds 5 million people and is projected to rise to 10 million by 2040 due to increased life expectancy and an aging population (2,3). In 2023, the Food and Drug Administration (FDA) approved Pegcetacoplan (Syfovre) and Avacincaptad Pegol (Izervay) based on their efficacy in slowing the enlargement of GA lesions (4). Both drugs inhibit the complement system but at different targets: Pegcetacoplan targets complement component 3 (C3), blocking C3 and C3b activation, while Avacincaptad Pegol targets complement component 5 (C5), preventing its cleavage and the formation of the membrane attack complex (MAC) (5,6). While FDA approvals of pegcetacoplan and avacincaptad pegol represent significant milestones in the treatment of GA, their limited impact on visual function, despite slowing lesion enlargement, highlights ongoing challenges in evaluating therapeutic efficacy. Advancements in the management of GA and the approval of FDA-approved GA drugs underscore the need for outcome measures that go beyond anatomical changes to capture meaningful improvements in vision and daily functioning.

Rationale and knowledge gap

Previous comprehensive reviews, such as those by Fleckenstein et al. and Sadda et al., have systematically evaluated GA clinical trial endpoints, highlighting the diversity and limitations of commonly used outcome measures, including lesion size and visual acuity (VA) (7,8). These reviews underscored challenges related to outcome standardization and the predominance of structural endpoints in GA trials. While informative, these analyses predate recent pivotal phase 3 trials and the FDA approvals of complement inhibitors pegcetacoplan and avacincaptad pegol, which have introduced new clinical data and underscored the disconnect between anatomical improvements and functional outcomes. Furthermore, emerging outcome measures that incorporate advanced imaging biomarkers, functional tests beyond VA, and patient-reported outcomes have not been fully integrated into earlier systematic reviews and syntheses. This review, therefore, updates and extends previous work by incorporating the latest clinical trial evidence, critically examining multimodal and patient-centric outcome assessments, and proposing revised frameworks to better evaluate treatment efficacy in GA.

Objective

This paper aims to provide a narrative review of the current state of outcome measures in GA clinical research, drawing on recent GA trials and scientific literature to identify existing limitations and propose future directions. We present this article in accordance with the Narrative Review reporting checklist (available at https://aes.amegroups.com/article/view/10.21037/aes-25-39/rc).

Methods

A literature search was conducted to identify relevant studies addressing outcome measures used in GA clinical trials. The search strategy was summarized in Table 1. The databases PubMed, Embase, and ClinicalTrials.gov were searched for articles published in English up to July 15, 2025. Key search terms included “outcome measure”, “geographic atrophy”, and “clinical trials”. Articles were included if they reported original research, clinical trials, or reviews relevant to outcome assessment methods for GA treatment efficacy. No restrictions were placed on study design or trial phase to ensure a comprehensive overview.

Current state of primary outcomes in GA trials

GA trials have relied on primary outcome measures that demonstrate clear, measurable effects suitable for regulatory approval. Early studies predominantly used anatomical metrics. A systematic review by Krezel et al. in 2015 showed that VA was the most frequently used outcome in 18 (78.3%) of 23 randomized controlled trials (RCTs) in GA, followed by measures of lesion area (34.8%) (9). In 2018, a systematic review by Cheng et al. of 53 GA trials registered in ClinicalTrials.gov found that GA growth was the most common primary outcome measure in 58% of phase 2 trials and 71% of phase 3 trials, while VA was the most common primary outcome measure in 17% of phase 2 trials and 14% of phase 3 trials (10).

The FDA and National Eye Institute (NEI) currently accept the rate or extent of anatomic progression of GA lesion enlargement, assessed by fundus autofluorescence (FAF) over multiple time points, as the standard for drug approval (11). This approach was discussed during the NEI/FDA Ophthalmic Clinical Trial Design and Endpoints Symposium (2006) and is supported by FAF’s ability to provide reproducible, quantitative measurements in studies of moderate duration (12,13). It was agreed that this structural endpoint could represent a clinically relevant outcome, even in the absence of documented changes in visual function. However, this emphasis on anatomical structure rather than functional vision creates a discrepancy between regulatory requirements and clinical relevance.

The recent Phase 3 GA clinical trials show that anatomical changes may not align with functional relevance, highlighting the need to reassess outcome measures in GA trials. In two phase 3 clinical trials leading up to the approval of pegcetacoplan, monthly treatment over 12 months showed a 22% reduction in GA lesion area growth in the OAKS trial and a 12% reduction in the DERBY trial (14). At 24 months, reductions from baseline were 22% and 19%, respectively (14). Additionally, the GALE extension study showed a continued reduction in GA growth rate between months 24 and 30, with up to a 45% reduction in GA growth rate over 30 months (15,16). Despite these structural benefits, there was no significant difference in functional outcomes between the pegcetacoplan and sham groups. Visual function measures, including best-corrected visual acuity (BCVA), Functional Reading Independence Index scores, monocular maximum reading speed, mean threshold sensitivity, and the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) distance activity subscale score, showed no meaningful improvement (14).

Similarly, in the GATHER1 trial, monthly avacincaptad pegol treatment reduced mean GA growth over 18 months by 28% in the 2 mg cohort and 30% in the 4 mg cohort compared to their respective sham groups (17). Additionally, the GATHER2 trial showed a 14% reduction in GA growth in the avacincaptad pegol 2 mg group compared to sham (18). Although significant structural differences were observed between treatment and control groups, visual functional outcomes were not statistically significant. For instance, in GATHER2 trial, there were no differences in BCVA or low-luminance VA between groups (18). Clinical trials for both pegcetacoplan and avacincaptad pegol showed a similar tendency where treatment benefits on structural outcomes were not followed by improvements in functional outcomes.

However, other outcome measures from the same clinical trials have been explored to better capture treatment effects and serve as improved outcome measures. A secondary analysis of the OAKS and DERBY trials by Fu et al. examined spectral-domain optical coherence tomography (SD-OCT) biomarkers in GA and found that several structural features, such as area of retinal pigment epithelium (RPE) loss and outer retinal atrophy (RORA), RPE loss, hypertransmission, photoreceptor degeneration (PRD), and PRD in isolation, were responsive to pegcetacoplan treatment (19). Moreover, changes in these OCT features were modestly but significantly associated with changes in BCVA from baseline to 24 months (Spearman’s rho: 0.07 to 0.17) (19). This study suggests that SD-OCT biomarkers not only capture structural outcomes in treatment response but also correlate with functional measures, indicating their potential to provide a more detailed view of the structure-function relationship.

In the GATHER2 trial, analysis of persistent vision loss—defined as a loss of 15 or more letters from baseline at two consecutive visits up to month 12—revealed a lower risk in the treatment group (3.1%) compared to sham (7.7%) (18). A post-hoc analysis of GATHER1 and GATHER2 also found a lower proportion of study eyes experienced losses of ≥10, 15, or 20 letters over 12 months relative to sham (20). For losses of ≥10 letters, the rates were 11.6% in the treatment group compared to 14.1% in the sham group, while for losses of ≥15 letters, the rates were 4.0% versus 7.6%, and for losses of ≥20 letters, 1.6% versus 4.5%, respectively (20). These findings suggest that categorical and time-to-event analyses focusing on the incidence of clinically significant vision loss may better capture patients’ real-world experience of vision decline than conventional functional measures such as BCVA.

As such, exploring alternative outcome measures in GA trials may be essential to capture meaningful clinical changes. Commonly used endpoints, such as mean VA change from baseline, may not effectively capture meaningful clinical changes in GA. VA is a limited and often inadequate measure of treatment efficacy due to its narrow focus on central vision and poor correlation with lesion enlargement. Many GA patients retain near-normal VA until foveal involvement occurs, meaning vision loss often does not manifest until late in the disease, delaying detectable decline (1,21). As a result, using VA loss as a primary endpoint would require prolonged follow-up periods, which are impractical in clinical trial settings. Moreover, patients may temporarily compensate for scotomas using peripheral retinal islands, leading to natural fluctuations in VA (22). This variability makes VA change from baseline an insensitive and statistically noisy indicator of disease progression or therapeutic effect. Supporting this, the geographic atrophy progression (GAP) natural history study reported a highly variable VA decline of 6.2±15.6 letters over 12 months (23), which would require large sample sizes to detect meaningful differences when VA is used as an endpoint. In an effort to identify outcomes important to patients, clinicians, and researchers for future clinical trials, Krezel et al. conducted a Delphi study involving patients and experts, along with focus groups and interviews with patients, relatives, and care providers. They identified GA lesion size, best-corrected distance and near VA, low-luminance VA, reading speed, and patient-reported visual performance as core outcomes important in GA (24). Given the discordance between anatomical and functional endpoints, a multimodal assessment that combines structural imaging with multiple functional tests may be recommended to more accurately capture the disease’s impact (21,25). Therefore, we have explored other possible outcome measures for GA treatment trials.

Toward better outcome measures

Ideal outcome measures for GA trials should be clinically relevant, reflect the progression of GA, capture meaningful treatment benefits, allow response to treatment to be measured within a short timeframe, be reliably measurable, and be acceptable to regulatory agencies for drug approval. Here, we outline several potential outcome measures for GA trials (Table 2).

Functional assessments

Low luminance visual acuity (LLVA)

Objective functional assessments should ideally align with patients’ subjective experiences of visual function, such as difficulties with daily activities under low-light or nighttime conditions. Studies have shown that GA is associated with losses in LLVA, and that low luminance deficit can serve as a marker of future visual loss (26,27). LLVA losses are especially pronounced in cases of non-foveal GA, and progression of non-foveal GA may partly explain the worsening LLVA (28,29). Moreover, subretinal drusenoid deposits were closely linked to low luminance deficits, likely indicating rod photoreceptor dysfunction, and are associated with a more rapid rate of GA progression (29). As such, these findings suggest that LLVA may be a relevant functional metric for GA trials, especially in non-foveal GA. In practice, LLVA testing uses a standard VA chart viewed through a neutral density filter (commonly 2.0 log units) under photopic conditions. The test requires minimal additional equipment beyond a standard VA setup, making it straightforward for sites familiar with Early Treatment Diabetic Retinopathy Study (ETDRS) protocols. It is relatively easy for staff to administer, well-tolerated by patients, and yields reliable results when luminance is well controlled, supporting its use in multicenter clinical trials.

Reading speed

Reading speed is a functional measure closely tied to daily patient experiences and is significantly impaired in patients with GA. Künzel et al. found a strong correlation between reading speed and GA lesion size, with center-involving GA causing greater impairment compared to non-center-involving GA (30). Similarly, Varma et al. observed that both baseline GA lesion size and the magnitude of lesion growth were associated with a decline in mean reading speed over time (31). Moreover, Wu et al. studied four different reading speed measures: the reading speed of the fastest sentence read (RS1), mean reading speed of the three fastest sentences read (RS2), mean reading speed of sentences larger than the critical print size (RS3), and mean reading speed of the 10 largest print sizes [Reading Accessibility Index (ACC)] (32). They found that all four measures showed significant declines from baseline at 48, 72, and 96 weeks in GA patients (32). Notably, they observed that the mean reading speed derived from either the 10 print sizes used in everyday life or the fastest three sentences read was more effective than two widely used measures (RS1 and RS3) in capturing progressive functional decline in GA. These findings suggest that reading speed is a clinically relevant and sensitive assessment of everyday visual function in GA, although the FDA currently does not accept reading speed as a primary endpoint in clinical trials. From a practical standpoint, reading speed tests such as the MNREAD or Radner Reading Charts are simple, quick (3–5 minutes per eye), and inexpensive to administer. They require controlled illumination and standardized text distance but no specialized equipment. Results are reproducible when conditions are standardized; however, cultural and linguistic variations in reading materials may necessitate local adaptation, posing challenges for global multicenter implementation.

Microperimetry

Microperimetry provides a unique anatomical-functional correlation in GA by mapping retinal sensitivity at specific locations, allowing researchers to track vision changes as the disease progresses (33). Wu et al. demonstrated that defect-mapping microperimetry can capture deep visual sensitivity losses, showing that the extent of GA within the central macula explains much of the variance in retinal locations where stimuli are not perceived (R²=0.90) (34). Notably, the probability of missing stimuli increases at the margins of GA lesions, highlighting the critical sensitivity of perilesional and junctional zones to disease progression. Similarly, Saeed et al. found that longitudinal changes in GA lesion size, assessed by microperimetry over multiple visits, closely correlated with functional declines both globally and locally (35). This confirms that the spatial progression of atrophy directly translates into worsening visual function at corresponding retinal sites. Increased overlap between microperimetry test locations and expanding GA regions significantly elevated the probability of visual sensitivity loss over time, emphasizing the method’s value for monitoring disease progression (35).

Further supporting microperimetry’s utility, Chang et al. assessed different macular sensitivity outcomes, finding that perilesional macular sensitivity (average of points adjacent to absolute scotomatous points) and responding macular sensitivity (average of all non-scotomatous points) are more sensitive endpoints than mean macular sensitivity for tracking functional decline over time in GA (36). These findings underscore microperimetry’s relevance in precisely tracking functional changes that mirror structural progression. Moreover, the importance of microperimetry is further emphasized by Mukherjee et al.’s study (37). They found that absolute scotomas aligned more closely with choroidal hypertransmission on OCT than with GA areas defined by FAF, suggesting that OCT may offer better insight into visual function than FAF alone (37). However, some discordance for both structural features was still present, highlighting the need to perform microperimetry alongside structural imaging. While microperimetry may be a valuable tool in assessing visual function in GA trials, current tests require a significant time commitment from both the patient and examiner. Test sessions typically last 5–20 minutes per eye, during which patient fixation and cooperation are essential. Although reproducibility is high within experienced centers, variability can occur across study sites. The time and technical expertise required make large-scale trial integration challenging, though emerging rapid-testing protocols may improve accessibility. Developing faster, more reproducible, and accessible methods is essential to enable broader use of microperimetry in GA trials.

Patient-reported outcome measures (PROM)

The NEI-VFQ-25 remains the most used PROM in GA clinical research, offering valuable insights into how the GA affects patients’ daily lives. Nielsen et al. found that GA significantly impairs quality of life across all 12 NEI-VFQ-25 subscales, with the greatest difficulties reported in near activities, general vision, mental health, and role difficulties (38). These findings underscore the broad and meaningful impact GA has on both functional and psychosocial well-being. Despite this sensitivity to patient experience, there were no reported improvements in NEI-VFQ-25 scores in the OAKS and DERBY phase 3 trials evaluating pegcetacoplan, highlighting the ongoing challenge of demonstrating functional or quality-of-life benefits from current therapies within clinical trial timelines (14). This gap reflects the slow pace at which functional changes may occur in GA and underscores the difficulty in capturing meaningful patient-experienced outcomes, even when anatomical progression is demonstrated. Consequently, while PROM like the NEI-VFQ-25 provide critical qualitative context, they have yet to fulfill the role of regulatory endpoints due to their limited responsiveness in short-term studies.

Emerging structural endpoints

An emerging structural outcome measure in GA research is the proximity of GA lesions to the foveal center, which may better reflect the impact of therapeutic interventions on vision than total lesion area alone. Keenan et al. analyzed data from the AREDS and AREDS2 studies and found that slowing the proximity-based progression of GA toward the fovea was significantly associated with slower rates of VA decline, even when the overall area of GA was not changing significantly (39). In AREDS, patients randomized to antioxidant supplementation exhibited a significantly slower proximity-based progression towards the central macula compared to placebo (51 vs. 73 µm/year, P=0.01), and in AREDS2, a similar effect was observed for those who received lutein/zeaxanthin compared to those who didn’t receive the treatment (80 vs. 114 µm/year, P=0.01). Moreover, this reduction in proximity-based GA progression was accompanied by lower rates of VA loss (−2.1 vs. −4.2 letters/year, P=0.007). These findings suggest that tracking lesion proximity to the fovea, rather than just absolute lesion size, may serve as a more functionally relevant and sensitive endpoint in GA clinical trials, capturing the risk to central vision and the potential for functional preservation conferred by treatments.

Challenges and ethical considerations in GA trials

Despite the recent FDA approval of pegcetacoplan and avacincaptad pegol for slowing the progression of GA, clinical trials have yet to demonstrate corresponding improvements in functional vision outcomes. This disconnect between structure and the ability of existing functional tests to detect corresponding functional change, where anatomical lesion growth is slowed without observable visual benefit, poses significant challenges for trial design, endpoint selection, and regulatory evaluation. Participants, often elderly and with comorbidities, are asked to commit to frequent treatments, exposing them to potential side effects, despite not experiencing meaningful functional benefits over short to moderate follow-up periods. These factors may need to be considered, particularly in a population vulnerable to high dropout rates and treatment fatigue. As a result, identifying outcome measures that capture early treatment effects while reflecting patient-perceived benefit remains a central unmet need in GA therapeutic development.

The strength of our review lies in a comprehensive examination of the latest phase 3 GA clinical trial data alongside observational studies, uniquely integrating recent FDA approvals with emerging multidimensional outcome measures that extend beyond traditional structural endpoints, such as LLVA, microperimetry, reading speed, and patient-reported outcomes. By synthesizing functional, structural, and patient-centered perspectives, this review provides a holistic framework for GA trial endpoints. The paper addresses the disconnect between anatomical improvements and functional gains, highlighting an important research gap. However, variability in trial design, endpoint definitions, and follow-up durations limits direct comparisons across studies. Furthermore, PROM, though crucial for capturing patient experience, remains underrepresented and often demonstrates limited sensitivity in short-term studies. Functional assessments such as microperimetry, while promising, face challenges related to reproducibility and scalability across trial sites. These factors highlight areas for methodological improvements and emphasize the necessity of developing core outcome sets and standard trial reporting to enhance evidence quality, clinical decision-making, and regulatory evaluation. Additionally, the emerging nature of many newer outcome measures means their validation and regulatory acceptance remain incomplete. Despite these limitations, the review offers insights and a foundation for future GA trial designs aimed at better capturing meaningful treatment benefits.

Conclusions

Current clinical trials for GA therapies, including those that led to the FDA approval of pegcetacoplan and avacincaptad pegol, have demonstrated significant reductions in the rate of lesion growth. However, these structural improvements have not been consistently accompanied by gains in visual function, highlighting a disconnect between anatomical changes and functional outcomes. This underscores the urgent need to identify and validate outcome measures that are both clinically meaningful and responsive within typical trial timeframes. To fully capture the therapeutic impact of GA treatments, future studies may incorporate a combination of structural measures (e.g., proximity-based GA progression and SD-OCT metrics), sensitive functional assessments (e.g., LLVA, reading speed, and microperimetry), and PROM. Such a comprehensive framework will be critical for evaluating treatment efficacy, informing regulatory pathways, and ultimately aligning clinical outcomes with patient experiences.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aes.amegroups.com/article/view/10.21037/aes-25-39/rc

Peer Review File: Available at https://aes.amegroups.com/article/view/10.21037/aes-25-39/prf

Funding: This study was supported by NIH Vision Core grant (P30-EY01583–26) and Research to Prevent Blindness (New York, New York).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aes.amegroups.com/article/view/10.21037/aes-25-39/coif). G.S.Y. serves as an unpaid editorial board member of Annals of Eye Science from June 2024 to December 2026. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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