The treatment of geographic atrophy (GA) has undergone rapid changes in the past 3 years. In 2023, both avacincaptad pegol (IZERVAY, Astellas Pharma) and pegcetacoplan (SYFOVRE, Apellis Pharmaceuticals) were approved for the treatment of GA secondary to dry age-related macular degeneration (AMD). Both therapies are intravitreal injections that target the complement cascade.
Avacincaptad pegol targets the complement factor C5 and is FDA-approved for monthly dosing in the United States. Pegcetacoplan targets the complement factor C3 and is FDA-approved for monthly or every-other-month (EOM) dosing in the United States.
Clinical trial data on intravitreal complement inhibitors for GA
Both drugs slow the progression of GA growth. Long-term data, extending up to 4 years for IZERVAY, show a 28% reduction in lesion growth in the monthly and 28% reduction in the EOM arms.1
Conversely, pegcetacoplan shows a 22% reduction in lesion growth in the monthly arm and an 18% reduction in the EOM arm at 2 years. In GATHER1, avacincaptad pegol showed a 28% reduction at 18 months. In GATHER2, avacincaptad pegol showed a decrease of 14% in the monthly arm at 1 year and 14% in the monthly arm at 2 years.2-9
Observed (raw) analysis by the sponsor reports 35% in GATHER1 at 12 months and 18% at 12 months in GATHER2, due to differences in statistical methodology.2-9
Diagnosis of geographic atrophy
Diagnosis of GA can be made by either fundus examination, optical coherence tomography (OCT) with or without near-infrared photography (NIR), and fundus autofluorescence (FAF). Fundus examination can show areas of GA, although these can be challenging to see clinically, especially in eyes with lighter pigmentation.
Figure 1: OCT imaging shows areas of choroidal hypertransmission, while corresponding NIR imaging shows well-defined areas of hyperreflectance.
Figure 1: Courtesy of Priya Vakharia, MD.
Figure 2: FAF imaging of hypoautofluorescence consistent with GA, with surrounding hyperautofluorescence suggestive of retinal pigment epithelium (RPE) dysfunction.
Figure 2: Courtesy of Priya Vakharia, MD.
More on the role of OCT in GA diagnosis
Optical coherence tomography has become a central imaging modality for detecting early structural changes associated with GA. Unlike FAF, which highlights metabolic alterations of the RPE, OCT provides high-resolution cross-sectional and en face visualization of retinal layers, enabling the identification of subtle pre-atrophic findings.10,11
The following OCT biomarkers can provide reliable evidence of the atrophic cascade before overt GA lesions are clinically visible, including:
- Incomplete RPE and outer retinal atrophy (iRORA)
- Complete RPE and outer retinal atrophy (cRORA)
- Hyperreflective foci
- Choroidal hypertransmission
These structural hallmarks have been codified by the Classification of Atrophy Meetings (CAM) group, establishing OCT as the standard tool for staging atrophic lesions in non-neovascular AMD. By identifying early atrophic changes, OCT enables clinicians to diagnose GA at its earliest stages, when interventions to slow progression may have the most significant impact.10,11
Using OCT to predict the risk of GA progression
Beyond diagnosis, OCT plays a vital role in predicting which eyes with intermediate AMD are at risk of developing GA and in monitoring its subsequent enlargement. Longitudinal studies have shown that iRORA lesions detected on OCT often progress to cRORA within 1 to 2 years, and the presence of intraretinal hyperreflective foci or baseline extrafoveal atrophy further accelerates progression.11
Quantitative OCT metrics, such as sub-RPE illumination area and changes in retinal layer thickness, correlate strongly with lesion growth and visual function decline, making them robust predictors of disease trajectory. OCT’s ability to capture repeatable, layer-specific measurements also facilitates the study of lesion enlargement rates, which are known to vary by lesion size, multifocality, and location.
This predictive capacity is particularly relevant now that complement inhibitors have become available, as clinicians seek to identify which patients may benefit most from timely treatment.10,11
Figure 3: GA OCT macular thickness map.
Figure 3: Courtesy of David RP Almeida, MD, MBA, PhD.
In addition to its clinical applications, OCT has proven valuable in the design and interpretation of GA clinical trials. OCT-derived lesion measurements have shown strong correlation with FAF-based GA assessments, validating OCT as a surrogate endpoint for disease monitoring.
Importantly, OCT provides a less invasive, more comfortable, and widely available imaging option compared with FAF, making it an attractive modality for both research and routine care.10,11
As machine-learning-enhanced segmentation and automated quantification continue to improve, OCT is poised to play an even larger role in the early diagnosis, risk stratification, and longitudinal management of patients with intermediate AMD at risk of developing GA.
A closer look at FAF
By providing a noninvasive means of visualizing lipofuscin accumulation in the RPE, FAF has become an essential tool in the diagnosis and monitoring of GA. Areas of hypoautofluorescence correspond to established atrophy, while regions of increased hyperautofluorescence at the margins of GA often indicate stressed or dysfunctional RPE that may precede expansion of atrophy.
Several studies have confirmed the utility of FAF in tracking lesion growth, with distinct autofluorescence patterns at the junctional zone serving as important predictors of disease course.12,13
Figure 4: FAF image of banded GA OS.
Figure 4: Courtesy of David RP Almeida, MD, MBA, PhD.
Identifying FAF patterns associated with faster GA progression
Holz et al., in a prospective multicenter natural history study published in the American Journal of Ophthalmology, demonstrated that eyes with banded or diffuse FAF patterns had significantly faster rates of GA progression than eyes with focal or no abnormalities (median 1.77 to 1.81 mm2/year vs. 0.38 to 0.81 mm2/year).
Notably, the diffuse trickling pattern was associated with the most aggressive progression (median 3.02 mm2/year), highlighting the prognostic value of detailed FAF phenotyping.13
Simplified FAF-based classification schemes have also been developed to aid reproducibility in both clinical and research settings. One such method stratifies eyes by the extent of rim area focal hyperautofluorescence (RAFH) within a 500µm margin surrounding GA lesions.
Eyes with extensive RAFH (≥ 67%) were shown to progress nearly twice as quickly as those with little or no hyperautofluorescence (≤ 33%), underscoring the direct relationship between baseline FAF abnormalities and subsequent enlargement of atrophy.12
Because increased autofluorescence reflects excessive lipofuscin load and RPE stress, these imaging biomarkers have strong physiologic plausibility as predictors of disease activity.
Taken together, FAF imaging not only improves diagnostic precision but also allows clinicians to stratify patients by risk, select appropriate candidates for clinical trials, and anticipate the pace of visual decline, thereby enhancing personalized care for patients with GA.12,13
Ideal candidate for GA therapies
The goal of therapy is to slow the progression of GA growth. Therefore, the ideal patient is likely the one with extrafoveal GA who is experiencing progression of their GA, but still retains good vision. This patient could benefit the most from early treatment.
However, the decision to treat GA is nuanced and depends on multiple factors, including fellow eye status, medical comorbidities, age, and goals of care. While nonfoveal patients may benefit the most from treatment, they may also not be symptomatic, leading to a dichotomy in perceived urgency.
Patients with foveal involvement can still benefit from treatment if they retain eccentric fixation or have functional vision that they wish to preserve. It is important to note that neither pegcetacoplan nor avacincaptad pegol met their primary endpoints for functional benefit in their registration trials; however, both have undergone post-hoc analyses that suggest a level of functional benefit from treatment.
Patient education on GA therapies to optimize results
Patient education is key in the treatment of GA. First and foremost, patients have to understand that they have GA and that the disease may progress over time.
At the first visit, I sit down with the patient and their family members and do my best to explain their ocular condition in simple terms. I print out the patient’s FAF photos and provide them with a handout regarding GA for review at home with their family.
I typically do not initiate treatment on the first visit, as I want to ensure that the patient has had sufficient time to review all our materials and can make an informed decision.
After this, I remind them that the use of pegcetacoplan or avacincaptad pegol will only help to slow the progression of GA and requires compliant therapy to achieve maximal treatment results. We walk through the injection protocol and reasonable expectations, along with plans for topical anesthesia.
Lastly, they are informed of the risks associated with therapy, namely the risk of conversion to neovascular AMD and the risk of endophthalmitis, inflammation, and rare reports of retinal vasculitis (the latter primarily observed with pegcetacoplan at a rate of 1 in 4,000 as a first-injection phenomenon). I remind patients that they should call us if they experience any issues with their injections.
In conclusion
The management of GA has entered a new era with the advent of complement inhibitors, providing clinicians with the first pharmacologic tools to slow disease progression.
While both avacincaptad pegol and pegcetacoplan have demonstrated meaningful reductions in lesion growth, patient selection and counseling remain critical to optimize outcomes.
OCT has emerged as an indispensable modality for both early detection and prediction of progression, enabling clinicians to identify high-risk patients who may benefit most from timely intervention.
Ultimately, the integration of advanced imaging and evidence-based therapies enables eyecare professionals to achieve optimal patient selection, guiding patients through personalized decisions about treatment to preserve vision and quality of life.
