Geographic Atrophy

Geographic atrophy is an advanced form of dry AMD in which patches of retinal pigment epithelium and photoreceptors have atrophied. These areas of macula have irreversible vision loss. Atrophic patches may begin outside the foveal center and then enlarge toward reading vision. For many years, management focused on monitoring, low-vision support, and watching for wet AMD. Since 2023, pegcetacoplan (Syfovre) and avacincaptad pegol (Izervay) have provided a treatment option that can slow lesion growth, although they do not restore lost vision.

What Geographic Atrophy Looks Like

On a dilated fundoscopic exam, GA appears as one or more well-demarcated, sharp-edged areas where the retinal pigment epithelium has atrophied. Through these atrophic windows, the underlying choroidal blood vessels become visible. The lesions are usually multifocal, gradually coalescing over years, often beginning in the perifoveal region and eventually involving the fovea itself.

GA is best documented and tracked with:

• Fundus autofluorescence - atrophic areas appear dark; the leading edge often shows a hyperautofluorescent rim that is associated with disease progression
• OCT - shows the absence of RPE, photoreceptor loss, and increased reflectivity from the underlying choroid
• Fundus photography - for long-term comparison

Progression

GA expands at a typical rate of approximately 1.5-2.5 mm² of new atrophy per year (mean roughly 2.0), with substantial individual variability driven by lesion configuration, autofluorescence pattern, and genotype. The pattern matters:

• Foveal-sparing GA can preserve central acuity for years even as the surrounding GA advances
• Foveal involvement produces substantial central vision loss
• Bilateral disease is common; the second eye is at increased risk over time

Functional impact is greater than visual acuity often suggests - reading speed, contrast sensitivity, and low-light vision are typically affected before Snellen acuity drops, because the perifoveal atrophy compromises rod-rich tissue surrounding the fovea, which is critical for dim-light and contrast performance.

Causes and Risk Factors

GA is the end-stage of dry AMD. Risk factors are the same:

• Age over 65
• Smoking - the strongest modifiable risk factor
• Family history and genetic markers (CFH, ARMS2)
• European ancestry
• Cardiovascular disease and hypertension

Pathologically, GA reflects chronic dysregulation of the complement system at the retinal level, with progressive RPE death and overlying photoreceptor loss.

Treatment

Complement Inhibitors (FDA-Approved 2023)

Two intravitreal injections are now available:

Pegcetacoplan (Syfovre)

• A complement C3 inhibitor
• FDA-approved for either monthly or every-other-month dosing (every 25 to 60 days); both regimens were studied in pivotal trials
• Slowed GA lesion growth by approximately 14-22% over 24 months across the OAKS and DERBY trials, with the magnitude depending on dosing frequency and trial. Visual-acuity endpoints did not show a statistically significant treatment benefit
• FDA-approved February 2023

Avacincaptad Pegol (Izervay)

• A complement C5 inhibitor
• Administered every 4 weeks (monthly)
• GATHER1 (2 mg, 18-month) showed approximately a 27% reduction in GA lesion growth versus sham; GATHER2 (12-month primary endpoint) showed approximately a 14% reduction. Like pegcetacoplan, no statistically significant benefit on visual-acuity endpoints was demonstrated
• FDA-approved August 2023

Both drugs slow expansion but do not improve vision and do not stop progression entirely. The decision to start is individualized, weighing:

• The current rate of progression
• The proximity of GA to the fovea
• The patient's tolerance for monthly or near-monthly intravitreal injections
• The cost
• The increased risk of converting to wet AMD with treatment - pivotal trials reported neovascular conversion in approximately 6-12% of treated eyes (compared with roughly 2-4% on sham), with rates higher with monthly than every-other-month dosing
• Reported risks of intraocular inflammation, rare occlusive retinal vasculitis (mostly with pegcetacoplan, typically after the first injection), and isolated post-marketing reports of ischemic optic neuropathy

Other Management

• Stop smoking - one of the most important modifiable risk steps for AMD
• AREDS2 vitamins - demonstrated benefit in intermediate AMD and in unilateral advanced AMD (to reduce the risk of progression in the fellow eye). AREDS2 supplementation does not slow growth of established GA lesions
• Self-monitoring with Amsler grid for early detection of conversion to wet AMD
• Regular eye exams at the interval recommended by the retina specialist, often every 6-12 months when not receiving injections and more often during treatment
• Low vision rehabilitation - particularly valuable as central vision declines

Frequently Asked Questions

Is geographic atrophy the same as wet AMD?

No. GA is the end-stage of dry AMD - atrophy of retinal tissue. Wet AMD is the form caused by abnormal blood vessel growth and is treated with anti-VEGF injections. The two can coexist.

Will the complement inhibitors restore my vision?

No. They slow the expansion of existing atrophy. Vision already lost in atrophied areas does not return. The benefit of treatment is preservation of vision in the not-yet-atrophied parts of the retina, particularly when GA is approaching the fovea.

How do I decide whether to start treatment?

The decision involves several factors: how close GA is to the fovea, how fast it is progressing, the burden of monthly or every-25-to-60-day injections depending on the drug, and the willingness to accept risks such as wet AMD conversion or intraocular inflammation. Many patients with foveal-sparing GA threatening central vision consider treatment; some patients with already-foveal involvement may find the trade-offs less attractive.

Can my central vision be preserved long-term?

Many patients with foveal-sparing GA preserve good central vision for years, sometimes longer, even before complement inhibitors became available. With the new treatments, the expansion rate is slower, which may extend the time before central vision is lost.

What if I cannot do monthly injections?

Pegcetacoplan's U.S. label allows dosing once every 25 to 60 days, while avacincaptad pegol is labeled monthly. Patient preference and treatment burden are part of the discussion. For patients who do not start or continue treatment, ongoing monitoring and low vision rehabilitation remain important.

References