Geographic Atrophy Treatment: Slowing Growth, Not Restoring Vision

For years, a diagnosis of geographic atrophy came with a specific, unwelcome kind of honesty: there was nothing to offer.

Anti-VEGF drugs treated the wet form of macular degeneration. The dry, atrophic form simply progressed.

Geographic atrophy is the advanced form of dry age-related macular degeneration, and it is now, for the first time, a treatable disease.

Two complement inhibitors have reached approval on the strength of trials that slowed the rate of atrophy expansion.

What they have not done – and this distinction matters enormously for how the treatment is discussed with patients – is restore vision already lost.

What Is Geographic Atrophy?

Geographic atrophy (GA) is a sharply demarcated area of loss of the retinal pigment epithelium, photoreceptors and choriocapillaris, representing the end-stage of dry age-related macular degeneration.

Two treatment-relevant features define the modern approach:

Lesions grow over time, with growth rate influenced by lesion size, location, multifocality and genetic factors
Once retinal tissue within a lesion is atrophic, that vision loss is permanent – treatment targets future growth, not existing damage

This second point is the single most important thing to communicate to a newly diagnosed patient, because it reframes what “treatment” can realistically deliver.

Epidemiology

Geographic atrophy is a major and growing cause of irreversible vision loss.

It affects a substantial proportion of patients with advanced age-related macular degeneration, and prevalence rises steeply with age
Bilateral involvement is common, though the two eyes often progress at different rates
Risk factors mirror those for AMD generally – age, smoking, family history and specific genetic variants including complement factor H and ARMS2
As populations age, geographic atrophy prevalence is projected to rise substantially over the coming decades

The scale of the unmet need is exactly why complement inhibition attracted such sustained investment despite a difficult trial history.

Pathophysiology

The complement system is now understood to be central to how atrophy develops and spreads.

Chronic low-grade inflammation and complement activation within the retinal pigment epithelium and choriocapillaris drive progressive cell loss
Drusen and complement deposits accumulate at the level of the RPE and Bruch membrane over years before atrophy becomes clinically apparent
Loss of RPE support leads to photoreceptor death, and loss of the choriocapillaris compounds the ischaemic insult
The alternative complement pathway, and specifically complement component 3 and complement factor C5, have emerged as the principal therapeutic targets

Targeting complement rather than VEGF reflects a fundamentally different disease mechanism – this is a chronic inflammatory and degenerative process, not a vascular leak.

Clinical Presentation

Symptoms

Gradual, often asymmetric central vision loss, frequently first noticed as difficulty reading in dim light
A scotoma that patients may describe as a blurred or missing patch rather than a sharp black spot
Preserved peripheral vision even in advanced disease, since GA is a macular process
Slow progression over years rather than the days-to-weeks course of wet AMD

Examination and Imaging Findings

A well-demarcated area of RPE loss on fundus examination, with underlying choroidal vessels visible through the atrophic patch
Fundus autofluorescence showing a hypoautofluorescent lesion with a variable hyperautofluorescent junctional zone, the region felt to reflect stressed RPE at highest risk of future involvement
OCT showing loss of the RPE band, outer retinal atrophy and increased choroidal signal transmission beneath the lesion
Drusen and pigmentary change typically present in the surrounding retina, reflecting the underlying AMD

Multimodal imaging – autofluorescence combined with OCT – is now standard for both diagnosis and for monitoring the lesion growth that guides treatment decisions.

Diagnostic Evaluation

Establishing the Diagnosis

Dilated fundus examination and colour fundus photography
Fundus autofluorescence to delineate lesion borders precisely
OCT to confirm outer retinal and RPE loss and exclude coexistent neovascular disease

Assessing Risk of Progression

Baseline lesion size and location relative to the fovea
Lesion configuration – multifocal lesions tend to progress faster than a single confluent lesion
Serial imaging over time to establish an individual growth rate before considering treatment

Excluding Neovascular Conversion

OCT and, where needed, OCT angiography to detect subclinical choroidal neovascularisation, which can develop within or adjacent to atrophic lesions and changes management substantially

Distinguishing GA from occult or non-exudative neovascular membranes matters practically, since the two are managed with entirely different drug classes.

Management

Complement Inhibitor Therapy

Pegcetacoplan, a C3 inhibitor, and avacincaptad pegol, a C5 inhibitor, are given as monthly or bimonthly intravitreal injections
Pivotal trials demonstrated a statistically significant reduction in the rate of lesion growth compared with sham injection, in the range of roughly 15 to 20 percent depending on the agent, regimen and follow-up duration
Neither agent has been shown to improve visual acuity, and both carry a small but real risk of progression to neovascular AMD during treatment, requiring monitoring for conversion
Patient selection favours lesions positioned where slowing growth is most likely to preserve functionally important vision – extrafoveal lesions with intact foveal sparing are a common target

Supportive Management

AREDS2 formulation supplementation, which reduces progression from intermediate to advanced AMD but has not been shown to slow established GA growth
Smoking cessation, which remains the single most impactful modifiable risk factor across the AMD spectrum
Low vision rehabilitation and referral to visual aids services, which remain central to functional outcome regardless of drug therapy
Monitoring of the fellow eye, since progression is frequently asymmetric

The treatment decision here is unusually dependent on shared decision-making – a monthly injection burden for a modest reduction in growth rate, with no promise of visual improvement, is a trade-off patients must weigh for themselves.

Differential Diagnosis

Conditions that can mimic geographic atrophy include:

Pattern dystrophies, including adult-onset vitelliform lesions – typically earlier onset and different autofluorescence patterns
Stargardt disease – earlier onset with a characteristic flecked appearance and dark choroid on fluorescein angiography
Toxic maculopathy from hydroxychloroquine – bull’s-eye pattern with a relevant drug history
Chloroquine or other drug-induced retinopathy
Choroideremia and other inherited chorioretinal atrophies, distinguished by earlier onset and characteristic peripheral involvement

Age at onset and the pattern of autofluorescence are usually enough to separate age-related GA from its inherited mimics.

Prognosis

Geographic atrophy remains a progressive disease even with treatment, and expectations need to be set accordingly.

Lesions continue to grow on complement inhibitor therapy, just more slowly than on sham treatment in trial populations
Central vision loss eventually occurs when growth reaches the fovea, regardless of treatment, though slower growth may delay that point
Peripheral vision is preserved throughout, and complete blindness from GA alone is rare
Long-term real-world data on functional benefit, and on the durability of the growth-rate reduction, are still accumulating

Geographic atrophy treatment is best understood as buying time rather than reversing disease – a meaningful first step, but one that leaves plenty of room for the next generation of therapy.

References

Heier JS, Lad EM, Holz FG, et al. Pegcetacoplan for the treatment of geographic atrophy (OAKS and DERBY). The Lancet. 2023.
Khanani AM, Patel SS, Staurenghi G, et al. Efficacy and safety of avacincaptad pegol (GATHER1, GATHER2). The Lancet. 2023.
Age-Related Eye Disease Study 2 Research Group. Lutein, zeaxanthin, and omega-3 fatty acids for AMD (AREDS2). JAMA. 2013.
Geographic Atrophy. EyeWiki, American Academy of Ophthalmology.
Age-Related Macular Degeneration, Geographic Atrophy. StatPearls, NCBI Bookshelf.