Geographic atrophy (GA), the late-stage non-neovascular form of age-related macular degeneration (AMD), is one of the most important causes of irreversible central visual loss in older adults. It progressively erodes retinal pigment epithelium (RPE), photoreceptors, and choriocapillaris, with structural progression that is often measurable before patients appreciate the full functional consequences.

For years, eye care professionals have been frustrated by an asymmetry in practice: clinicians could diagnose GA accurately and monitor progression, yet they could offer little beyond risk-factor modification and low-vision support.

That position has now changed. Complement inhibitors have moved GA into an era of active treatment. Once disease slowing becomes possible, the value of detecting early GA, documenting lesion location, assessing the threat to the fovea and referring at the right time increases substantially. In other words, the optometrist’s role has expanded to recognition, risk stratification, counselling, and appropriate referral.

WHY THE INFLAMMATION STORY MATTERS

The clinicopathological work of Australian researchers, Shirley and John Sarks half a century ago, fundamentally shaped modern understanding of AMD. Their studies on drusen, ageing change, and the evolution of macular pathology demonstrated that AMD is not simply a passive degenerative event occurring in an ageing retina. Rather, it is associated with dynamic extracellular deposition, structural remodelling, and biological activity at the retinal pigment epithelium (RPE)-Bruch membrane complex, with the presence of inflammatory cells such as macrophages.1,2 Although these classic papers pre-dated the era of molecular therapeutics, they helped establish a conceptual foundation that is highly relevant to current therapy: AMD lesions are biologically active and the tissues surrounding drusen are participating in ongoing disease processes.

That line of thinking was strengthened when later work identified inflammatory proteins, complement components, and immune-complex-related material in drusen and adjacent tissues.3 Genetic discoveries then provided the decisive link. Variants involving complement regulation, particularly complement factor H and related pathways, showed that complement dysregulation is not simply an epiphenomenon but a central component of AMD susceptibility and pathobiology.4 The consequence is that the inflammatory model of AMD, once supported by pathology and tissue analysis, is now anchored in genetics, pre-clinical drug development, and therapeutic response.

Figure 1. Complement cascade illustrating the classical, lectin, and alternative pathways converging at C3, with downstream activation of C5 and formation of the membrane attack complex (MAC).7 Published with permission of Creative Commons.

HOW COMPLEMENT INHIBITORS WORK IN GA

Innate immunity is the body’s inborn firstline defence system and is distinct from adaptive immunity, which develops memory after exposure to a specific antigen. The complement cascade is a major arm of innate immunity. It can be activated through the classical, lectin, and alternative pathways, but all three ultimately converge on C3 and then proceed toward generation of C5a, C5b, and the membrane attack complex (MAC, C5b-9). In a healthy system, complement supports host defence, debris clearance, and homeostasis. In AMD, however, this tightly regulated system appears to become chronically dysregulated.

The retinal environment is especially vulnerable to this type of imbalance. The outer retina and RPE are metabolically active, exposed to oxidative stress, and dependent on efficient waste handling. If complement activation becomes excessive or insufficiently controlled, the result can be a sustained

inflammatory state rather than a protective one. This has several consequences that matter to GA. Complement fragments, such as C3a and C5a, can amplify inflammatory signalling. C5a may prime inflammasome activation. C5b contributes to MAC formation, which in turn can damage or kill RPE cells.5,6 Over time, those effects intersect with other drivers of AMD pathogenesis, including oxidative injury, mitochondrial dysfunction, lipid handling abnormalities, and age-related structural change in Bruch’s membrane.

That multifactorial context is important. Complement activation is not the whole story in GA. A single pathway cannot explain the entire disease. Yet the therapeutic success of complement inhibition strongly suggests that this pathway is clinically actionable. In that sense, the field has moved from biological plausibility to proof of principle.

Complement inhibition is expected to slow progression, not restore lost tissue: this point is important for patient counselling. Once RPE and photoreceptors are gone, the tissue cannot currently be regenerated. The value of treatment is therefore measured in reduced enlargement of atrophy, delayed foveal involvement, and delayed functional decline, rather than visual gain in the way we might expect with anti-VEGF therapy in neovascular AMD. This distinction must be made clearly in practice, because patients often equate ‘treatment available’ with ‘vision improvement expected’. In GA, the current goal is slowing disease and preserving functional vision for as long as possible, for tasks such as reading, driving, and cooking, to maintain independence.

C3 VERSUS C5 INHIBITION

The current therapeutic landscape makes most sense when clinicians understand where different drugs sit within the cascade. Broadly speaking, the practical distinction is between upstream inhibition at the level of C3 and downstream inhibition at the level of C5.

C3 sits at the central point of convergence for the classical, lectin, and alternative pathways. Inhibiting C3, therefore, suppresses a large proportion of complement activity. Pegcetacoplan (Syfovre, Apellis Pharmaceuticals), the first approved intravitreal C3 inhibitor for GA, binds C3 and C3b and reduces downstream effector functions generated after C3 activation.8,9 Conceptually, this is an attractive strategy because it targets the cascade early and may curb amplification by the alternative pathway. The trade-off is that the upstream blockade is broader. Physiological complement functions upstream of C5 are also affected.

C5 inhibition is more selective. Avacincaptad pegol (ACP, Izervay, Astellas Pharma) is a pegylated ribonucleic acid (RNA) aptamer that specifically inhibits cleavage of C5 into C5a and C5b.5,6,10 This matters because C5a is a potent pro-inflammatory mediator and C5b initiates MAC formation. By blocking C5, avacincaptad pegol seeks to interrupt the terminal effector arm of complement-mediated tissue injury while preserving upstream complement activity. In simple clinical language, C5 inhibition tries to stop the damaging end-stage part of the cascade without shutting down everything that comes before it.

For optometrists, the practical takeaway is that ‘complement inhibition’ is not a single uniform intervention. Different drugs intervene at different levels, and those differences may influence both efficacy patterns and adverse-event profiles.

AVACINCAPTAD PEGOL AS A C5 INHIBITOR

In GATHER1, a randomised phase 2/3 sham-controlled study, ACP 2 mg reduced the mean rate of GA growth over 12 months by 27.4% versus sham using square-root-transformed fundus autofluorescence measurements; the 4 mg dose reduced growth by 27.8%.5 The extension report then showed continued benefit through 18 months, supporting the idea that the treatment effect is cumulative.11

GATHER2 was designed as the confirmatory Phase 3 study and is particularly relevant because it used the 2 mg dose that entered clinical practice. At 12 months, monthly avacincaptad pegol 2 mg slowed GA growth versus sham by 14% on the prespecified square-root-transformed analysis.6 As with several GA trials across the field, visual acuity endpoints showed less dramatic between-group separation over the initial timeframe, which is not surprising in a disease where anatomy may change before standard acuity metrics meaningfully diverge. Even so, the trial strengthened the core message that complement inhibition can slow lesion enlargement in a statistically significant way.

The two-year GATHER2 publication is particularly informative for clinical practice because it shows how treatment effect evolves over time. From baseline to year two, the mean rate of GA growth was 4.46 mm² with every-month dosing and 5.18 mm² with sham, representing a 14% difference. With year-two every-other-month dosing after initial monthly treatment, the difference versus sham was 19%.10 Piecewise analyses showed that treatment effects emerged by month six and increased over time, with the treatment difference more than doubling compared with year one.10 For clinicians, that is a meaningful point: if a patient is considering whether the burden of repeated intravitreal therapy is justified, the evidence suggests that the biological benefit accumulates over time.

Longer-term open-label extension data presented at the Macula Society (United States) in 2026 provide additional context, although, as conference data, they should be interpreted cautiously until the full peer-reviewed publication is available.12 In that extension study out to 3.5 years, continued monthly treatment was associated with a reported 40.5% reduction in GA lesion growth in the ACP-to-ACP every-month group, while eyes switching from sham to ACP showed a 37.1% reduction after crossover, reinforcing the message that earlier treatment is likely to confer greater cumulative benefit.12 These results are attractive because they speak directly to a real-world question: does earlier initiation matter? The answer appears to be yes.

Taken together, the GATHER program supports three clinically relevant conclusions. First, C5 inhibition with ACP slows anatomical progression of GA. Second, the effect appears to strengthen over time. Third, earlier initiation is likely to preserve more retinal tissue.

PEGCETACOPLAN AS A C3 INHIBITOR

In the Phase 3 OAKS and DERBY trials, 1,258 patients with GA secondary to AMD were randomised 2:2:1:1 to monthly pegcetacoplan, every-other-month pegcetacoplan, monthly sham, or every-other-month sham, with sham arms pooled for analysis. At 12 months, OAKS showed reductions in GA lesion growth of 21% with monthly dosing and 16% with every-other-month dosing versus sham; DERBY showed corresponding reductions of 12% and 11%. By 24 months, these effects had strengthened to 22% and 18% in OAKS, and 19% and 16% in DERBY, supporting the view that benefit with complement inhibition accumulates over time.8

Longer-term follow-up from the GALE open-label extension extends that signal. In the overall GALE population, pegcetacoplan was associated with reductions in GA growth versus projected sham of 24% with monthly dosing, and 23% with every-other-month dosing through 48 months. Over months 24 to 48 alone, the reductions were 28% for both regimens. In non-subfoveal GA, the 48-month reductions were larger, at 32% with monthly dosing and 27% with every-other-month dosing. These longer-term data are important because they reinforce two practical messages: First, lesion location matters, with non-subfoveal eyes showing greater absolute potential for tissue preservation; second, earlier and continued treatment appears to preserve more retina over time. The GALE dataset also reported strong retention, with 79% of participants completing 24 months of extension follow-up.9

SAFETY OUTCOMES: CLINICAL TRIALS, AND REAL WORLD

Patients need to understand that the benefits of slowing disease progression must be balanced against the risks of treatment. Overall, both pegcetacoplan and avacincaptad pegol require monitoring for macular neovascularisation and standard intravitreal injection complications. The main distinction is that pegcetacoplan has an established post-marketing signal for retinal vasculitis and a clearer trial and labelling signal for ischaemic optic neuropathy and intraocular

inflammation, whereas avacincaptad pegol has, to date, shown comparatively low rates of serious inflammatory events in clinical trials, extension studies, product information, and early real-world reports.6,10,12-19

Retinal Vasculitis Retinal vasculitis is the most important rare safety signal to acknowledge for pegcetacoplan. Early real-world experience, including the American Society of

Retinal Specialists Research and Safety in Therapeutics (ReST) Committee report, identified retinal vasculitis after pegcetacoplan, often after the first injection, with many cases demonstrating an occlusive component and some associated with severe vision loss. This adverse event, not seen in clinical trials but rarely observed in routine clinical practice, is now reflected in prescribing information and routine clinical discussions. By contrast, no retinal vasculitis was reported over two years in GATHER2 with avacincaptad pegol, no retinal vasculitis was reported in the open-label extension, and early real-world series have similarly not identified this complication.10,12,14,17-19

Endophthalmitis Endophthalmitis is an uncommon but recognised intravitreal injection risk with both agents. In pegcetacoplan studies, endophthalmitis occurred in fewer than 1% of treated patients. With avacincaptad pegol, there were no cases over 12 months in GATHER2, one case over two years in GATHER2, and one case in the extension study among sham-to-treatment switchers. These data are more consistent with routine intravitreal injection procedure risk than with a drug-specific safety signal.6,10,12,14,17

Ischaemic Optic Neuropathy In pegcetacoplan labelling derived from OAKS and DERBY, ischaemic optic neuropathy was reported in 1.7% of monthly-treated eyes, 0.2% of every-other-month-treated eyes, and 0% of sham-treated eyes. This has remained part of the pegcetacoplan safety discussion in extension and postmarketing analyses. For avacincaptad pegol, no ischaemic optic neuropathy was reported over two years in GATHER2, and none in the extension study.6,10,12,17,19

Intraocular Inflammation Intraocular inflammation has also been reported more prominently with pegcetacoplan than with avacincaptad pegol. In OAKS and DERBY, intraocular inflammation was reported in 4% of monthly-treated eyes, 2% of every-other-month-treated eyes, and less than 1% of sham-treated eyes. With avacincaptad pegol, there were no intraocular inflammation events at 12 months in GATHER2; over two years there was one non-serious event; and in the open-label extension, five anterior intraocular inflammation events were reported across 4,203 injections, none serious, and none associated with retinal vasculitis.6,10,12,17

Macular Neovascularisation Macular neovascularisation is a recognised complication with both complement inhibitors. For pegcetacoplan, neovascular AMD or choroidal neovascularisation was reported by month 24 in 12% of monthly-treated eyes, 7% of every-other-month-treated eyes, and 3% of controls. For avacincaptad pegol, choroidal neovascularisation was reported in 7% of treated eyes versus 4% of sham at 12 months, and in 11.6% versus 9.0% over two years in GATHER2. These rates do not preclude treatment, but they reinforce the need for ongoing surveillance and, where required, separate anti-VEGF therapy.6,10,17

Raised Intraocular Pressure Raised intraocular pressure (IOP) is usually manageable, but it deserves separate mention because both pegcetacoplan and avacincaptad pegol are administered in a 0.1 mL intravitreal volume, which is greater than the 0.05 mL volume commonly used for intravitreal anti-VEGF injections in routine practice. This larger injection volume may contribute to transient post-injection IOP rises in some eyes. In OAKS and DERBY, increased IOP was reported in 2% of monthly pegcetacoplan-treated eyes, 3% of every-other-month-treated eyes, and less than 1% of sham-treated eyes. With avacincaptad pegol, increased IOP occurred in 9% of treated eyes versus 1% of sham through 12 months in pooled GATHER data. Disc optical coherence tomography (OCT) can be helpful to monitor for glaucomatous changes. IOP lowering treatment can be considered if required.6,14-17

WHAT THIS MEANS FOR OPTOMETRISTS

For the optometrist, the emergence of treatment has altered the clinical purpose of GA recognition. The central question is no longer simply, “Does this patient have atrophy?”. It is now, “How advanced is it, how close is it to threatening central vision, how quickly may it be progressing, and is referral likely to change the patient’s medium-term visual trajectory?”.

High-Resolution Imaging That places renewed value on multimodal imaging. OCT is essential for recognising complete RPE and outer retinal atrophy (cRORA) and for identifying earlier structural precursors such as incomplete retinal pigment epithelial and outer retinal atrophy (iRORA). Emerging AI-assisted technology for measuring GA progression on en face OCT images requires the images to be captured at high-resolution. Fundus autofluorescence remains highly useful for delineating lesion extent and following enlargement over time. It can also help differentiate inherited retinal disease. Colour photography is no longer sufficient on its own if the aim is treatment-era triage rather than descriptive diagnosis. The practical threshold for referral will vary with local pathways, but extrafoveal GA, threatened foveal involvement, documented enlargement, and symptomatic decline should all lower the threshold for referral. Royal Australian and New Zealand College of Ophthalmologists (RANZCO) National AMD referral guidelines can assist with pathway development (ranzco.edu/wp-content/uploads/2024/04/RANZCO-Referral-Pathway-for-AMD-Management-17APR2024.pdf ).

Patient Counselling Counselling also needs to evolve. Patients should understand that treatment aims to preserve vision for longer, not recover vision already lost. They should also understand that the burden of care may resemble other retinal treatment pathways: repeated intravitreal injections, ongoing imaging, and continued surveillance for neovascular conversion. There are also potential risks with regular intravitreal treatment. Some will accept that trade-off readily; others will prioritise injection burden, safety, travel or quality-of-life considerations differently. The optometrist can add enormous value here by explaining the rationale clearly before the retinal consultation, improving patient understanding of treatment options.

Early Disease Recognition The product information for avacincaptad pegol and pegcetacoplan specifies use in adult patients with GA secondary to AMD with an intact fovea and when central vision is threatened by lesion growth.16,17 That wording reinforces the importance of lesion location. In practice, the optometrist who identifies non-foveal GA approaching the centre may be the clinician who creates the window for treatment that preserves functional vision.

Early recognition matters more now than it did in the observation-only era. Precise imaging matters. Referral timing matters. Clear patient counselling matters. The treatment landscape will continue to evolve, but the fundamental shift has already happened: GA is now a condition in which earlier diagnosis can create therapeutic opportunity.

This article is sponsored by Astellas Pharma.

Adjunct Professor Hemal Mehta is a macular disease specialist and clinical researcher focused on bringing emerging therapies to patients. As Co-Director of Clinical Trials Research at Strathfield Retina Clinic, he has served as principal or sub-investigator on more than 50 retinal trials. He is a Medical Retina Section Editor for the journal Eye and a member of the RANZCO Therapeutics Committee. He also works on the Sarks Archive at the University of Notre Dame Australia, co-supervising PhD students studying AMD disease mechanisms.

References available at mivision.com.au.