Geographic Atrophy Treatment: Pegcetacoplan and Avacincaptad Pegol Explained

Last updated: October 2026

For decades, geographic atrophy (GA) was the AMD we could only watch. Since 2023, two intravitreal complement inhibitors have been approved in the United States. They slow the growth of atrophy, but they do not restore vision, and European regulators declined both. A resident needs to know exactly what the trials showed, and what they did not.

What geographic atrophy is

• Definition: sharply demarcated loss of retinal pigment epithelium (RPE), photoreceptors and choriocapillaris. It is the advanced form of non-neovascular (dry) AMD.
• On OCT: the Classification of Atrophy Meetings (CAM) term is cRORA (complete RPE and outer retinal atrophy): a zone of choroidal hypertransmission and RPE loss at least 250 µm across, with overlying photoreceptor degeneration and no RPE tear.
• On fundus autofluorescence (FAF): dark (hypoautofluorescent) patches. Bright junctional patterns at the lesion edge predict faster growth.
• Natural history: lesions typically grow by roughly 1.5–2 mm² a year. They often spare the fovea at first, so acuity can stay deceptively good while reading and dim-light vision fail.
• Why complement? Genetic risk variants in CFH, C3 and CFB point to an overactive alternative complement pathway. AREDS2 supplements do not slow GA growth.

The two approved drugs at a glance

What the trials showed, and what they did not

• The primary endpoint was anatomical: growth of GA area on FAF. GATHER trials used square-root-transformed area, which reduces the influence of baseline lesion size.
• The effect grows with time. In the GALE extension of OAKS and DERBY (48 months in total), patients treated from the start preserved about 2.8–3.2 mm² of retina compared with projected sham (non-subfoveal lesions). In the GATHER2 open-label extension, continuous avacincaptad reduced growth by about 40% against projected sham over 3 years.
• No best-corrected visual acuity benefit was shown in the pivotal trials. This was the core of the European refusal: slowing lesion growth did not translate into a meaningful benefit in daily function.
• Functional signals are emerging, mostly from extensions and microperimetry. In GALE, patients treated early had about a 35% lower risk of progressing to absolute scotoma than those whose treatment started later. Treat these as supportive, not definitive.

Safety: what to watch for

How to counsel a patient with GA

• Explain the goal honestly: slowing loss, not restoring vision. Benefit accumulates over years of regular injections.
• The best candidates, where these drugs are available, are patients with non-subfoveal (extrafoveal) GA who still have useful central vision to protect, and who accept indefinite injections every 1–2 months.
• Both drugs are US-approved but are not authorised in Europe, and access elsewhere varies. Check current local availability before discussing them.
• Whatever the treatment decision, offer low-vision assessment, good lighting and magnification advice, an Amsler chart, and smoking cessation.

Viva pearls

• Pegcetacoplan blocks C3, which is upstream where all three complement pathways converge. Avacincaptad blocks C5, sparing C3b-mediated opsonisation.
• cRORA requires lesions of at least 250 µm. iRORA is the incomplete form.
• Extrafoveal and multifocal lesions grow faster than unifocal, subfoveal lesions.
• Know the regulatory split: the US approved both on anatomical benefit, while the EMA asked for functional benefit.

Related: the current anti-VEGF landscape, how to read an OCT and gradings and stagings.

Key sources

• EMA: Syfovre refusal of marketing authorisation
• Khanani AM et al. GATHER2 12-month results. Lancet 2023
• FDA expands Izervay dosing label (February 2025)
• 48-month OAKS/DERBY/GALE results (Ophthalmology Times)
• GATHER2 3-year open-label extension (AAO 2025)
• Pegcetacoplan three years after approval (Retina Today, manufacturer-sponsored)