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# Complement system modulation in age-related macular degeneration: navigating failures, building future successes

Aliénor Vienne-Jumeau, Elodie Bousquet, Francine Behar-Cohen

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Aliénor Vienne-Jumeau, Elodie Bousquet, Francine Behar-Cohen. Complement system modulation in age-related macular degeneration: navigating failures, building future successes. Current Opinion in Immunology, 2025, 96, 10.1016/j.coi.2025.102616. hal-05224883

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Review

# Complement system modulation in age-related macular degeneration: navigating failures, building future successes

Aliénor Vienne-Jumeau<fnref n="1" />,<fnref n="2" />, Elodie Bousquet<fnref n="3" />,<fnref n="4" /> and
Francine Behar-Cohen<fnref n="2" />,<fnref n="3" />,<fnref n="5" />

<figure><img src="image_3.png" /></figure>

Age-related macular degeneration (AMD) is a leading cause of irreversible central vision loss in elderly populations across developed countries. Complement system dysregulation has been implicated in AMD onset and evolution. Complement inhibition therapies have been authorized in the USA as the primary treatment for geographic atrophy, the dry form of AMD. They have shown moderate efficacy in slowing geographic atrophy lesion growth but have not demonstrated improvements in visual function. Challenges remain, including the optimal timing of intervention, delivery routes, safety concerns, the lack of sensitive biomarkers to assess efficacy and guide patient selection, and variability in therapeutic response.

Complement modulation represents a promising yet complex therapeutic avenue in AMD. Future success will require earlier intervention, precision medicine approaches integrating genetic and imaging biomarkers, and the exploration of combination or gene-based therapies.

## Addresses

Corresponding author: Behar-Cohen, Francine
(francine-behar@gmail.com)

Current Opinion in Immunology 2025, 96:102616

This review comes from a themed issue on **Complement**

Edited by **Chantal Dumastre-Perard** and **Marie-Agnes Durey**

Available online xxxx

https://doi.org/10.1016/j.coi.2025.102616

0952-7915/© 2025 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

## Introduction

Age-related macular degeneration (AMD) is a complex, multifactorial disease and the leading cause of irreversible central vision loss in elderly individuals in developed countries [1]. Its pathogenesis involves an interplay of environmental factors, such as smoking and the ingestion of a high-fat diet, alongside physiological factors like aging and genetic susceptibility [2]. The initial stage of the disease is characterized by material deposition (drusens) under the retinal pigment epithelium (RPE). While a few small peripheral drusen may occur in normal aging, central accumulation of larger drusen is characteristic of AMD. The disease progresses toward either neovascular ('wet' AMD) or non-neovascular ('dry' AMD) form that can evolve to geographic atrophy (GA), with progressive degeneration of the RPE, the choroid, and the outer retina (Figure 1). Notwithstanding the elevated disease burden, there are limited therapeutic options for GA, and no cure.

In the retina, the complement system contributes to immune surveillance and debris clearance, controls inflamming, and limits oxidative damage, but its dysregulation can drive retinal pathology [3]. Under physiological conditions, retinal cells secrete regulatory proteins, such as complement factor H (CFH) and related proteins to protect retinal tissue from uncontrolled complement activation, membrane attack complex (MAC; C5b-9)-mediated damage [4,5], oxidative stress-induced injury [3,6], and uncontrolled inflammation [7]. The aggregation of histological, genetic, and clinical data indicates that chronic, complement overactivation plays a pivotal role in disease onset, and its contribution to disease progression is the subject of active investigation [8,9]. However, the exact pathogenic mechanisms associated with complement-induced retinal degeneration remain incompletely understood [10,11].

The strong genetic link between complement dysregulation and AMD [12] has led to the development of therapeutic agents that target various components of the complement pathway. Pegcetacoplan and avacincaptad pegol have demonstrated the capacity to decelerate the progression of GA, leading to their approval by the Food and Drug Administration (FDA). Nevertheless, challenges persist with regard to the functional efficacy of these agents, their delivery routes, and the associated adverse effects [13,14].

<footnote n="1">¹Centre hospitalier national d'ophtalmologie des Quinze-Vings, Paris, France</footnote>

<footnote n="2">²Ophthalmopôle, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris, France</footnote>

<footnote n="3">³Centre de Recherche des Cordeliers, Université Paris Cité, INSERM U1138, Université Sorbonne Paris Cité, 75006 Paris, France</footnote>

<footnote n="4">⁴Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris, France</footnote>

<footnote n="5">⁵Department Ophthalmology Hôpital Foch, Suresnes, France</footnote>
<figure><img src="image_4.png" /><figcaption>Figure 1</figcaption></figure>

Imaging (a–d) and histology (e,f) features of AMD. (a–d) Spectral domain optical coherence tomography (SD-OCT) B-scans and corresponding infrared fundus images. (a) Normal retina, (b) Intermediate AMD with subepithelial drusen (white arrows), (c) Advanced dry AMD or GA with thinning of the RPE cell layer, outer retina, and choriocapillaris causing hypertransmission of the signal (Braquet), (d) wet AMD with CNV (white arrow), visualized on SD-OCT angiography (inset). Toluidine blue semi-thin sections of a normal retina (e,f) showing the fovea (e) region and the RPE/choroid (f), the RPE/choroid of an intermediate AMD with subepithelial drusens (dark arrows) and the outer retina of a wet AMD with subepithelial CNV, subepithelial deposit of melanophages (white arrows) and severe disorganization of the outer retina with red blood cells invading the photoreceptor layer. Note the thinning of the choriocapillaris (star) in (g) compared to (e). Chor: choroid. GCL: ganglion cell layer; INL: inner nuclear layer, ONL: outer nuclear layer, IS: inner segment of the photoreceptor, OS: outer segment of the photoreceptor, cc: choriocapillaris. Bar = 50 µm.
This review provides an overview of the role of the complement system in AMD pathophysiology, with a particular focus on challenges in therapeutic development and prospects for strategies for overcoming current limitations.

## Role of complement dysregulation in age-related macular degeneration pathogenesis

### Role of complement in retinal pigment epithelium and choroid pathology

Complement activation may directly contribute to the formation and growth of drusens [5]. Drusens contain complement factors such as complement component 3 (C3), complement component 5 (C5), complement component 9 (C9), and the MAC, along with complement regulators like CFH and vitronectin (complement S-protein) [5,15] (Figure 2a,b). Oxidized lipids and other debris act as danger-associated molecular patterns that trigger complement activation via the alternative pathway, leading to recruitment of immune cells and further deposition of inflammatory mediators, further promoting drusen growth [16]. Besides, systemic complement activation may contribute to drusen formation, even outside the context of aging. The association between early-onset drusen and C3 glomerulopathy, including C3 glomerulonephritis, highlights the systemic nature of complement-mediated deposition diseases [17]. In the plasma of AMD patients, concentration of complement activation products are higher compared to healthy elderly [18].

Complement activation in RPE cells acts on choriocapillaris homeostasis. The MAC, formed by C5b9 complexes, allows extracellular Ca²⁺ influx and submembrane calcium increase, which may induce a hyperpolarizing shift in the inactivation curve of T-type channels, thereby reducing their activity. In RPE cells, this inhibition reduces the secretion vascular endothelial growth factor (VEGF) secretion, which is essential for maintaining the health and fenestration of the choriocapillaris [19]. In choroidal endothelial cells, beside MAC-induced cell death, increase expression of MMP-9 might contribute to reactive angiogenesis [20]. Such a mechanism may contribute to choroidal vascular atrophy in AMD [21]. The exact contribution of locally produced and circulating complement system components is not fully understood [11].

### Genetic studies show prominent role of complement dysregulation in age-related macular degeneration

Genetic evidence involves the complement system in both the development and progression of AMD [11]. Variants in several genes encoding complement components and regulators, including C2, C3, C9, complement factor B (CFB), complement factor I (CFI), complement factor D (CFD), CFH, and the complement factor F receptor 1-5 (CFHR1-5) gene cluster, have been associated with increased susceptibility to AMD (Table 1) [8,11,22-25]. Among these mutations,

the Y402H polymorphism in CFH, which acts as a critical inhibitor of the alternative complement pathway, is one of the most extensively studied [12]. This polymorphism in CFH impairs CFH's ability to bind glycosaminoglycans and strongly reduced affinity for C-reactive protein, that is elevated in the serum of AMD patients [26] and in the choroid of patients with homozygous CFH mutation [27], leading to insufficient suppression of complement activation in areas of oxidative damage [28]. This single polymorphism, along with a polymorphism on the ARMS2/HTRA1 gene, is estimated to account for up to 50% of the heritable risk for AMD (Figure 3a) [29].

The links between genetic predispositions in complement components and pathogenic mechanisms are complex and fully understood [11]. One mechanism associated with hyperactivation of the alternative complement pathway may progress MAC-induced cells death in RPE and choroidal endothelial cells. Deficiency in functional CFH, which is produced by RPE cells where it acts both as a secreted protein and intracellularly [6,30] could reduce RPE capacity to resist oxidative stress [31]. CFH binds oxidized phospholipids and malondialdehyde adducts, mitigating oxidative damage in RPE cells independently of complement regulation [6]. Besides, studies show that complement activation, whether during disease initiation or progression, can lead to different biological outcomes. The C3 gene variant R102G (rs2230199), identified as a significant risk factor for the development of AMD [32], protects from GA progression compared to noncarriers. This suggests that although complement dysregulation may initiate or accelerate early pathological processes, certain complement components might later exert protective effects such as promoting cellular debris clearance or modulating inflammation in ways that could counteract earlier damage and slow the progression of GA lesions [33]. Genetic variation in complement genes also influences clinical outcomes. For example, polymorphisms in C3, CFB, and CFH have been linked to variability in patient response to anti-VEGF therapy in neovascular AMD [34].

### Role of the complement in geographic atrophy onset and progression

While the involvement of the complement system in the onset of advanced AMD is well established, genetic studies have not consistently demonstrated association with GA progression. Analyses from large cohorts, including AREDS1, AREDS2, and others, including a genome-wide association study, found no significant association between CFH alleles and GA expansion [35,36]. Only two smaller studies reported a possible link between CFH and GA progression [37,38]. These findings highlight a disconnect between genetic risk for disease onset and factors influencing disease progression.
<figure><img src="image_5.png" /><figcaption>Figure 2</figcaption></figure>

Localization of complement components and regulators in the retina/choroid under normal conditions and in AMD, with a schematic overview of AMD pathogenesis. (a) In the healthy retina, key complement regulators — CFH, complement factor I (CFI), CD46, CD55, and CD59 — are distributed across the RPE, choroid, and photoreceptors. These molecules maintain immune homeostasis and inhibit excessive complement activation. (b) In the AMD retina, complement activation products, including C3a, C5a, C3b, C5b, the MAC, and terminal components C6–C9, are detected within drusen and surrounding the RPE. Red labels highlight complement components and accumulation sites associated with AMD pathology, while black and gray labels denote complement regulators and their preserved localization. (c) Schematic representation of AMD pathogenesis, illustrating the interplay between complement dysregulation, oxidative stress, and RPE-choroid dysfunction.
<table><caption>Table 1</caption><caption>Summary of genetic risk and protective factors associated with polymorphisms in complement system components.</caption><thead><tr><th>Gene</th><th>Polymorphism (rsID)</th><th>Polymorphism (amino acid change)</th><th>Cellular effect</th><th>Domain</th><th>Risk/protection</th></tr></thead><tbody><tr><td rowspan="8">CFH</td><td>rs1061170</td><td>Y402H</td><td>Tyrosine to histidine</td><td>Heparin and CRP-binding domain</td><td>Risk</td></tr><tr><td>rs2274700</td><td>A473A</td><td>Synonymous</td><td>SCR domain (silent)</td><td>Risk</td></tr><tr><td>rs1410996</td><td>—</td><td>Intronic</td><td>Intronic</td><td>Protective</td></tr><tr><td>rs800292</td><td>I62V</td><td>Isoleucine to valine</td><td>SCR1 domain</td><td>—</td></tr><tr><td>rs121913059</td><td>R1210C*</td><td>Arginine to cysteine</td><td>SCR20</td><td>Risk</td></tr><tr><td>rs121913063</td><td>N1050Y*</td><td>Asparagine to tyrosine</td><td>SCR18</td><td>Protective</td></tr><tr><td>rs121913061</td><td>D130N*</td><td>Aspartic acid to asparagine</td><td>SCR3</td><td>Risk</td></tr><tr><td>rs10922109</td><td>—</td><td>Intronic</td><td>Intronic</td><td>Risk</td></tr><tr><td>rs570618 (in high LD with rs1061170)</td><td>—</td><td>Intronic</td><td>Intronic</td><td>Risk</td></tr><tr><td>CFHR1/3</td><td>Deletion</td><td>—</td><td>Absence of CFHR1 and CFHR3 proteins</td><td>Genomic deletion</td><td>Protective</td></tr><tr><td>CFHR5</td><td>rs6677604</td><td>—</td><td>Intronic</td><td>Intronic</td><td>Protective</td></tr><tr><td rowspan="2">C2</td><td>rs9332739</td><td>E318D</td><td>Glutamic acid to aspartic acid</td><td>Exon 7 (protein-coding region)</td><td>Protective</td></tr><tr><td>rs547154 (in high LD with rs9332739)</td><td>—</td><td>Intronic</td><td>Intronic</td><td>Protective</td></tr><tr><td rowspan="2">CFB</td><td>rs641153</td><td>R32Q</td><td>Arginine to glutamine</td><td>Ba domain</td><td>Protective</td></tr><tr><td>rs4151667</td><td>L9H</td><td>Leucine to histidine</td><td>Signal peptide</td><td>Protective</td></tr><tr><td rowspan="4">C3</td><td>rs2230199</td><td>R102G</td><td>Arginine to glycine</td><td>MG1 domain</td><td>Risk</td></tr><tr><td>rs1047286</td><td>—</td><td>Synonymous</td><td>Exon (silent)</td><td>Risk</td></tr><tr><td>rs147859257</td><td>K155Q*</td><td>Lysine to glutamine</td><td>MG2 domain</td><td>Risk</td></tr><tr><td>rs147859271</td><td>R735W*</td><td>Arginine to tryptophan</td><td>MG6 domain</td><td>Risk</td></tr><tr><td rowspan="4">CFI</td><td>rs10033900</td><td>—</td><td>Promoter region</td><td>Promoter region</td><td>Protective</td></tr><tr><td>rs12144939</td><td>G119R*</td><td>Missense</td><td>SP domain</td><td>Risk</td></tr><tr><td>rs141853578</td><td>P553S*</td><td>Proline to serine</td><td>SP domain</td><td>Risk</td></tr><tr><td>rs146444258</td><td>A240G*</td><td>Alanine to glycine</td><td>SP domain</td><td>Risk</td></tr><tr><td rowspan="2">C9</td><td>rs34882957</td><td>P167S*</td><td>Proline to serine</td><td>MACPF domain</td><td>Risk</td></tr><tr><td>rs62358361</td><td>—</td><td>Intronic</td><td>Intronic</td><td>Risk</td></tr></tbody></table>

SCR: short consensus repeat; CRP: C-reactive protein; MACPF: membrane attack complex/perforin; LD: linkage dis-equilibrium; SP: serine protease.

This table provides an overview of the impact of genetic variants in key complement proteins. Certain polymorphisms are associated with increased susceptibility to disease, while others confer a protective effect.

* rare variant. R1210C, N1050Y: high-penetrance mutations associated with familial AMD.

The recent efficacy of complement-targeting therapies, such as pegcetacoplan and avacincaptad pegol in slowing GA progression, suggests that complement activation still plays a pathogenic role at this stage, even if not tightly linked to inherited genetic variation. This discrepancy may reflect the growing contribution of acquired, local complement dysregulation, such as age-related oxidative stress, mitochondrial dysfunction, or impaired clearance mechanisms beyond what is captured by germline genetics alone [33,39]. Among these factors, anaphylatoxins C3a and C5a could play an important role by promoting the degranulation of mast cell, abundant in the choroid [40], and increased in AMD eyes compared to controls [21]. Additionally, experimental models have shown that mast cell stabilizers or inhibitors of chymase can attenuate choroidal neovascularization (CNV) and

RPE degeneration [41,40]. As such, genetic markers may be more predictive of disease susceptibility than progression, underscoring the need for biomarkers or imaging features to guide treatment decisions in GA.

This lack of reliable prognostic indicators presents a major obstacle to nontargeted and nonpersonalized therapeutic strategies, as clinicians are currently unable to identify which patients are most likely to experience rapid disease progression or to benefit from specific interventions. The functional impact of multiple genetic variants across different complement components further complicates patient stratification based solely on genetic profiles. A better characterization of these mechanisms is therefore also essential to guide therapeutic decisions and optimize the management of AMD (Figure 2c).
<figure><img src="image_6.png" /><figcaption>Figure 3</figcaption></figure>

Overview of complement system activation pathways, genetic variants associated with AMD and therapeutic interventions. These schematic illustrate the three major complement activation pathways — classical, lectin, and alternative — which converge on the central component C3 and progress through the formation of C3 and C5 convertases to generate the terminal MAC. (a) Regulatory proteins that inhibit or modulate these cascades are indicated, as well as genetic variants implicated in AMD pathogenesis (highlighted in green boxes). Red arrows mark key amplification loops, while pink elements represent complement inhibitors. Several complement regulators and modulators carry risk or protective polymorphisms in AMD, contributing to dysregulated complement activation and chronic inflammation in the retina. (b) Therapeutic targets are indicated in green, with arrows pointing to their molecular site of action within the cascade. Therapies are color-coded according to their clinical status: approved (bold green), ongoing (black), and failed (gray).
<table><caption>**Table 2**

Summary of failed complement-targeted therapies in GA.</caption><thead><tr><th>Drug</th><th>Target</th><th>Sponsor</th><th>Trial phase/ID</th><th>Outcome</th></tr></thead><tbody><tr><td>Lampalizumab</td><td>Factor D (alternative pathway)</td><td>Genentech/Roche</td><td>Phase III – Chroma and Spectri<br>Phase II – COMPLETE (NCT00935883)</td><td>No significant reduction in GA lesion growth; trials failed to meet primary end points.<br>Well tolerated but did not significantly slow GA progression.</td></tr><tr><td>Eculizumab</td><td>C5 (terminal pathway)</td><td>Alexion</td><td>Phase II – COMPLETE (NCT01527500)</td><td>No anatomical or visual benefit observed compared to sham.</td></tr><tr><td>Tesidolumab (LFG316)</td><td>C5 (terminal pathway)</td><td>Novartis</td><td>Phase II – NCT02515942</td><td>No significant effect on GA progression, both as monotherapy and in combination.</td></tr><tr><td>CLG561</td><td>Properdin (alternative pathway)</td><td>Novartis</td><td>Phase II – NCT01603043</td><td>Trial terminated early due to intraocular deposits and formulation issues.</td></tr><tr><td>POT-4 (AL-78898A)</td><td>C3 (central component)</td><td>Alcon</td><td>Phase II – NCT04643886</td><td>Well tolerated with biomarker evidence of complement regulation (CFH elevation, C3a and Ba reduction); development discontinued after early trials; no efficacy data on GA progression.</td></tr><tr><td>GEM103</td><td>CFH (alternative pathway)</td><td>Gemini Therapeutics</td><td>Phase IIa – ReGAtta (NCT04643886)</td><td>Did not meet primary end point of statistically significant reduction in GA lesion growth; favorable safety profile with no increase in CNV; development discontinued after Merck declined licensing option.</td></tr><tr><td>NGM621</td><td>Complement C3 (central component)</td><td>NGM Biopharmaceuticals</td><td>Phase II – CATALINA (NCT04465955)</td><td>Phase II trial initiated to assess safety and efficacy in GA; development discontinued following disappointing data; no further development plans announced.</td></tr><tr><td>IONIS-FB-LRx</td><td>Complement factor B (alternative pathway)</td><td>Ionis Pharmaceuticals/Roche</td><td>Phase II – GOLDEN (NCT03815825)</td><td></td></tr></tbody></table>

## Current therapeutic landscape and challenges in complement-based therapy

The complement cascade offers several points of intervention, from upstream C3 inhibition to downstream C5 or MAC blockade. Despite considerable effort, clinical translation has faced major hurdles.

### Clinical trials with negative or inconclusive outcomes

A range of therapeutics targeting these steps has been tested, with varying levels of success. Table 2 summarizes the major clinical trials that failed to meet efficacy endpoints. Figure 3b illustrates the complement cascade alongside targeted drug checkpoints and regulatory nodes, highlighting the complexity of complement modulation.

### FDA-approved molecules

Two molecules have received FDA approval for the treatment of GA: pegcetacoplan (APL-2) and avacincaptad pegol (Zimura). Pegcetacoplan (APL-2) is a pegylated peptide that binds to C3 and inhibits its activation, thereby blocking the complement cascade upstream. In the phase 2 trial, monthly and every-other-month intravitreal injections of pegcetacoplan led to a 29% and 20% reduction in GA lesion growth, respectively, compared to sham treatment at 12 months [13]. In the OAKS phase 3 trial but not in the DERBY phase 3 trial, pegcetacoplan significantly reduced GA lesion growth at 12 months. Both trials showed significant reduction of GA growth at 24 months compared to sham (19–22% for monthly injections and 16–18% for every-other-month injections), without significant differences in visual function [42]. Incidence of new-onset exudative AMD, serious ocular adverse events, and dropout rates were higher in the pegcetacoplan arms than in the sham group [42]. The FDA but not the European Medical Agency approved the treatment (Syfovre™) as the first treatment for GA. Avacincaptad pegol (Zimura) binds to C5, inhibiting the generation of C5a and MAC formation. In the Phase 2/3 GATHER1 trial, monthly administration reduced GA progression by approximately 27% at 12 months [14]. These results were confirmed in the GATHER2 trial [43], which led to FDA approval in 2023. European Medical Agency did not approve any of these drugs because neither pegcetacoplan nor avacincaptad pegol demonstrated improvements in visual function or quality of life compared to sham.

This raises questions about the sensitivity of current functional end points, which may not capture subtle but significant structural changes. Alternatively, autofluorescence, commonly used as a structural marker, may not reliably indicate functional capacity. New imaging techniques, such as adaptive optics transscleral flood imaging, enable *in vivo* visualization of RPE cell morphology and allow for the quantification of RPE density
and structural alterations [44]. These advances may
prove valuable in refining imaging biomarkers.

**Other investigational agents**

NGM621 (monoclonal antibody against C3) [45], GEM103 (recombinant human CFH replacement protein) [46], IONIS-FB-LRx (antisense oligonucleotide designed to reduce hepatic production of CFB) [47], tesidolumab (LFG316, C5 inhibitor) [48], and lampalizumab (CFD inhibitor) [49], although well tolerated in phase 1 studies, showed limited efficacy and did not progress to later phases. Eculizumab, a systemic C5 inhibitor previously approved for other complement-mediated diseases, was also evaluated for GA, but the trial was discontinued due to lack of efficacy [50].

**Safety challenges**

Inhibition of factors that are at the beginning of the cascade (e.g., at the level of C3 or CFB) might be more efficient by blocking several downstream effectors. However, this approach also carries a higher risk of compromising beneficial complement activation, particularly those involved in host defense and tissue homeostasis. Broad-spectrum complement inhibition may increase susceptibility to bacterial infections, leading to complications like endophthalmitis [51]. Additionally, cases of retinal vasculitis have been reported following intravitreal administration of complement inhibitors like pegcetacoplan [42]. In contrast, downstream inhibition that selectively blocks MAC formation and C5a-mediated inflammation preserves earlier complement functions, such as opsonization and immune surveillance.

Furthermore, complement inhibition, particularly at
upstream nodes such as C3 or C5, has been associated
with an increased incidence of CNV in several clinical
trials. In the phase 3 OAKS and DERBY trials evaluating
pegcetacoplan, an increased incidence of new-onset
exudative AMD was reported [42]. Notably, the devel-
opment of CNV appeared more common among patients
with neovascular AMD in the fellow eye [52]. This pa-
thological angiogenesis highlights a paradox where
therapeutic attempts to slow GA progression may inad-
vertently convert nonexudative AMD into exudative
AMD. As a result, it may become necessary to combine
complement inhibitors with anti-VEGF agents to
counterbalance the risk of CNV development and
manage both atrophic and neovascular processes si-
multaneously.

**Reasons for failures and limitations**

The lack of efficacy in some trials may be attributed to
suboptimal study designs that did not fully account for

the complexities of GA progression. Initiating treatment
in later stages of the disease may limit the potential
benefits of complement inhibition. Moreover, the het-
erogeneity of AMD and genotype-phenotype variability
complicate both trial design and clinical application.
While risk alleles in complement genes such as CFH
and C3 are strongly associated with disease onset, their
correlation with GA progression is inconsistent. This
variability suggests that not all patients may derive equal
benefit from complement inhibition therapies. Besides,
the absence of other robust biomarkers to stratify re-
sponders from nonresponders further hampers the clin-
ical efficacy of complement-targeted treatments.
Identifying such biomarkers is essential for optimizing
patient selection and improving therapeutic outcomes.

**Future directions and emerging strategies**

**Personalized medicine based on genetic profiling, molecular biomarkers, and imaging data**

Polygenic risk scores (PRS), which combine multiple
genetic susceptibility loci, are emerging as promising
tools to better assess individual risk for AMD. In the
future, these scores could help identify high-risk in-
dividuals earlier, while sparing low-risk individuals from
invasive or costly interventions that are unlikely to offer
significant benefit [53]. When combined with retinal
imaging biomarkers, PRS could further enhance pre-
dictive accuracy. Molecular biomarkers, such as chy-
mase, along with systemic markers of oxidative stress,
could provide an additional level of patient stratification.
This integration supports a precision medicine approach,
where treatment is tailored not just to a patient's genetic
profile but also to the specific stage and presentation of
their AMD and their systemic proteomic profile.

**Delivery approaches**

Sustained local delivery methods such as gene therapy, viral or nonviral, and long-acting implants are under investigation as means to reduce treatment burden and enhance therapeutic efficacy. Particularly in a disease where different complement modulators may be required at various stages, a nonviral, nonpermanent gene therapy approach could be especially advantageous [54]. In parallel, genome editing technologies, such as CRISPR/Cas9, are opening new avenues for localized, durable manipulation of the complement system [55]. Finally, combination with systemic complement modulators could be explored.

**Exploring earlier intervention in preatrophic stages**

Recent data support the use of earlier anatomical end-
points in clinical trials before extensive atrophy sets in.
High-resolution OCT could help monitor disease pro-
gression at the preatrophic stage, making it a valuable
tool for evaluating the impact of early interventions. Emerging modalities capable of identifying and monitoring RPE alterations before they become evident on conventional imaging may also enable earlier risk stratification and help define optimal therapeutic windows for intervention [56].

## Conclusion

Despite intensive work, therapies that target the complement system for AMD, especially GA, have only shown limited success so far. The modest effectiveness of the current treatments highlights several ongoing challenges: there is a gap between genetic risk factors and how the disease progresses, the intricacies of complement biology, and the need for better trial end points. It is becoming clear that waiting until the later stages of the disease might not be enough to stop significantly the decline in both structure and function. Looking ahead, targeting treatments earlier, perhaps even before atrophy sets in, could lead to more significant improvements.

Additionally, the diverse nature of AMD calls for a move toward personalized medicine, which would involve using PRS, molecular biomarkers, and advanced imaging biomarkers to help choose the right patients and treatment plans. The integration of these multimodal data sources will be critical for effective stratification, an area where artificial intelligence and, in particular, machine learning are expected to play a pivotal role by enabling the analysis and interpretation of complex, high-dimensional data sets. Innovations in local delivery methods, like gene therapy and implants, along with combination therapies that tackle both inflammation and neurodegeneration, could also improve results. Finally, we urgently need more effective functional end points and validated biomarkers to track how well treatments are working and to predict their benefits.

## Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Papers of particular interest, published within the period of review, have been highlighted as:

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7. Sándor N, Schneider AE, Matola AT, et al.: The human factor H protein family - an update. *Front Immunol* 2024, **15**:1135490, https://doi.org/10.3389/fimmu.2024.1135490

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This review underscores the efficacy of integrating genomics with multi-omics approaches (transcriptomics, proteomics, epigenomics, etc.) in enhancing our comprehension of the pathogenesis of AMD. The majority of AMD-associated genes are expressed in non-neuronal cells, such as RPE and choroidal cells. Expression Quantitative Trait Locus and protein Quantitative Trait Locus studies are instrumental in identifying causal genes, particularly within the complement system. iPSC-derived RPE cells and synthetic haplotypes represent emerging tools for the validation of functional variants. The insights gained from systems genomics are contributing to the advancement of personalised medicine strategies and the guidance of clinical trials based on polygenic risk scores and molecular profiling.

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20. Zeng S, Whitmore SS, Sohn EH, et al.: Molecular response of chorioretinal endothelial cells to complement injury: implications for macular degeneration. *J Pathol* 2016, **238**:446-456, https://doi.org/10.1002/path.4669

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26. Seddon JM, Gensler G, Milton RC, et al.: Association between C-reactive protein and age-related macular degeneration. *JAMA* 2004, **291**:704-710, https://doi.org/10.1001/jama.291.6.704

27. Johnson PT, Betts KE, Radeke MJ, et al.: Individuals homozygous for the age-related macular degeneration risk-conferring variant of complement factor H have elevated levels of CRP in the choroid. *Proc Natl Acad Sci* 2006, **103**:17456-17461, https://doi.org/10.1073/pnas.0606234103

28. Toomey CB, Johnson LV, Bowes Rickman C: Complement factor H in AMD: bridging genetic associations and pathobiology. *Prog Retin Eye Res* 2018, **62**:38-57, https://doi.org/10.1016/j.preteyeres.2017.09.001

29. Klein RJ, Zeiss C, Chew EY, et al.: Complement factor H polymorphism in age-related macular degeneration. *Science* 2005, **308**:385-389, https://doi.org/10.1126/science.1109557

30. Armento A, Honisch S, Panagiotakopoulou V, et al.: Loss of complement factor H impairs antioxidant capacity and energy metabolism of human RPE cells. *Sci Rep* 2020, **10**:10320, https://doi.org/10.1038/s41598-020-67292-z

The study demonstrates that the endogenous form of factor H (CFH) contributes to the maintenance of metabolic and oxidative homeostasis in retinal pigment epithelial (RPE) cells. Researchers silenced CFH in hTERT-RPE1 cells. This resulted in the accumulation of C3, an increase in oxidative stress sensitivity, a disruption of energy metabolism (with a reduction in glycolysis and mitochondrial respiration), an elevation of lipid peroxidation, and a decrease in cell viability.

31. Bertram KM, Baglole CJ, Phipps RP, Libby RT: Molecular regulation of cigarette smoke induced-oxidative stress in human retinal pigment epithelial cells: implications for age-related macular degeneration. *Am J Physiol Cell Physiol* 2009, **297**:C1200-C1210, https://doi.org/10.1152/ajpcell.00126.2009

32. Spencer KL, Olson LM, Anderson BM, et al.: C3 R102G polymorphism increases risk of age-related macular degeneration. *Hum Mol Genet* 2008, **17**:1821-1824, https://doi.org/10.1093/hmg/ddn075

33. Keenan TDL: Geographic atrophy in age-related macular degeneration: a tale of two stages. *Ophthalmol Sci* 2023, **3**:100306, https://doi.org/10.1016/j.xops.2023.100306

34. Cui J, Lu H, Wang S, et al.: Genotypes of SNPs of key genes regulate susceptibility and drug sensitivity to neovascular AMD in the human population. *BMJ Open Ophthalmol* 2025, **10**:e001872, https://doi.org/10.1136/bmjophth-2024-001872

35. Klein ML, Ferris FL, Francis PJ, et al.: Progression of geographic atrophy and genotype in age-related macular degeneration, e1, *Ophthalmology* 2010, **117**:1554-1559, https://doi.org/10.1016/j.ophtha.2009.12.012

36. Grassmann F, Harsch S, Brandl C, et al.: Assessment of novel genome-wide significant gene loci and lesion growth in geographic atrophy secondary to age-related macular degeneration. *JAMA Ophthalmol* 2019, **137**:867-876, https://doi.org/10.1001/jamaophthalmol.2019.1318

37. Caire J, Recalde S, Velazquez-Villoria A, et al.: Growth of geographic atrophy on fundus autofluorescence and polymorphisms of CFH, CFB, C3, FHR1-3, and ARMS2 in age-related macular degeneration. *JAMA Ophthalmol* 2014, **132**:528-534, https://doi.org/10.1001/jamaophthalmol.2013.8175

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39. Keenan TD, Agrón E, Domalpally A, et al.: Progression of geographic atrophy in age-related macular degeneration: ARED52 Report Number 16. *Ophthalmology* 2018, **125**:1913-1928, https://doi.org/10.1016/j.ophtha.2018.05.028

40. Bousquet E, Zhao M, Thillaye-Goldenberg B, et al.: Choroidal mast cells in retinal pathology: a potential target for intervention. *Am J Pathol* 2015, **185**:2083-2095, https://doi.org/10.1016/j.ajpath.2015.04.002

41. Mcharg S, Booth L, Perveen R, et al.: Mast cell infiltration of the choroid and protease release are early events in age-related macular degeneration associated with genetic risk at both chromosomes 1q32 and 10q26. *Proc Natl Acad Sci USA* 2022, **119**:e2118510119, https://doi.org/10.1073/pnas.2118510119

42. Heier JS, Lad EM, Holz FG, et al.: 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. *Lancet Lond Engl* 2023, **402**:1434-1448, https://doi.org/10.1016/S0140-6736(23)01520-9.

These pivotal phase 3 trials evaluated pegcetacoplan, a complement C3 inhibitor, in over 1,200 patients with GA. Both monthly and every-other-month regimens showed a significant reduction in GA lesion growth compared to sham treatment, especially in extrafoveal lesions. However, an increased incidence of exudative age-related macular degeneration (AMD) was observed, raising safety considerations. The results support pegcetacoplan's approval as the first GA treatment to slow atrophic progression.

43. Khanani AM, Patel SS, Staurenghi G, et al.: Efficacy and safety of avacincaptad pegol in patients with geographic atrophy (GATHER2): 12-month results from a randomised, double-masked, phase 3 trial. *Lancet Lond Engl* 2023, **402**:1449-1458, https://doi.org/10.1016/S0140-6736(23)01583-0.

GATHER2 assessed avacincaptad pegol, a C5 inhibitor, in 448 patients with GA. Monthly injections significantly slowed GA growth at 12 months compared to sham. The safety profile was acceptable, although some cases of exudative AMD occurred. The results reinforce the role of complement pathway inhibition in GA and offer an alternative to pegcetacoplan with potentially different safety and efficacy profiles.

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45. Wykoff CC, Hershberger V, Eichenbaum D, et al.: Inhibition of complement factor 3 in geographic atrophy with NGM621: phase 1 dose-escalation study results. *Am J Ophthalmol* 2022, **235**:131-142, https://doi.org/10.1016/j.ajo.2021.08.018

46. Khanani AM, Maturi RK, Bagheri N, et al.: A phase I, single ascending dose study of GEM103 (recombinant human complement factor H) in patients with geographic atrophy.
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47. Mahmoudzadeh R, Hinkle JW, Hsu J, Garg SJ: Emerging treatments for geographic atrophy in age-related macular degeneration. Curr Opin Ophthalmol 2021, 32:294-300, https:// doi.org/10.1097/ICU.0000000000000746

48. Kim BJ, Mastellos DC, Li Y, et al.: Targeting complement components C3 and C5 for the retina: key concepts and lingering questions. Prog Retin Eye Res 2021, 83:100936, https:// doi.org/10.1016/j.preteyeres.2020.100936

49. Holz FG, Sadda SR, Busbee B, et al.: Efficacy and safety of lampalizumab for geographic atrophy due to age-related macular degeneration: chroma and spectri phase 3 randomized clinical trials. JAMA Ophthalmol 2018, 136:666-677, https://doi.org/10.1001/jamaophthalmol.2018.1544

50. Yehoshua Z, de Amorim Garcia Filho CA, Nunes RP, et al.: Systemic complement inhibition with eculizumab for geographic atrophy in age-related macular degeneration: the COMPLETE study. Ophthalmology 2014, 121:693-701, https://doi. org/10.1016/j.ophtha.2013.09.044

51. Tzoumas N, Riding G, Williams MA, Steel DH: Complement inhibitors for age-related macular degeneration. Cochrane Database Syst Rev 2023, 2023:CD009300, https://doi.org/10.1002/ 14651858.CD009300.pub3

52. Dascalu AM, Grigorescu CC, Serban D, et al.: Complement inhibitors for geographic atrophy in age-related macular degeneration-a systematic review. J Pers Med 2024, 14:990, https://doi.org/10.3390/jpm14090990

53. Jaskoll S, Kramer A, Elbaz-Hayoun S, et al.: Genotype-phenotype correlations and genetic risk assessment in age-related macular degeneration. Adv Exp Med Biol 2025, 1468:21-25, https://doi.org/10.1007/978-3-031-76550-6_4.

This paper explores the relationship between specific AMD-associated genetic polymorphisms (e.g., CFH, ARMS2) and clinical phenotypes, including GA and neovascular progression. It advocates for integrating genetic profiling into personalized risk prediction and treatment stratification, especially as targeted therapies and gene-based approaches advance.

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55. Salman A, Song WK, Storm T, et al.: CRISPR targeting of SNPs associated with age-related macular degeneration in ARPE-19 cells: a potential model for manipulating the complement system. Gene Ther 2025, 32:132-141, https://doi.org/10.1038/ s41434-025-00522-z

56. Laforest T, Künzi M, Kowalczuk L, et al.: Transscleral optical phase imaging of the human retina. Nat Photonics 2020, 14:439-445, https://doi.org/10.1038/s41566-020-0608-y