GA is an advanced form of age-related macular degeneration (AMD) characterized by progressive retinal pigment epithelium (RPE) and photoreceptor loss, leading to irreversible vision loss.
Until recently, no effective treatments existed, making GA management.
FDA-Approved Treatments:
Pegcetacoplan: First FDA-approved treatment (February 2023) for GA, a complement C3 inhibitor administered via intravitreal injection.
Avacincaptad pegol: A C5 inhibitor, also approved for GA, showing complement inhibition as a key mechanism to slow GA progression.
High-yield: Know that these drugs target the complement pathway, a critical pathway in GA pathogenesis.
Clinical Trial Data:
Pegcetacoplan (DERBY and OAKS trials, phase 3):
Reduced GA growth by 16–22% over 24 months.
Absolute GA area reductions: 0.90 mm² and 0.74 mm² (OAKS); 0.75 mm² and 0.63 mm² (DERBY).
Primary endpoint: Mean change in GA lesion area (anatomical, not functional), a testable point for exams.
Avacincaptad pegol (GATHER 1 and 2):
Reduced GA growth by 27% and 14% over 12 months.
Absolute difference: 0.056 mm² in mean GA growth compared to sham.
Limitations:
Trials did not distinguish between new lesion formation vs. existing lesion expansion, despite potentially different mechanisms.
No significant improvement in predefined visual function endpoints (e.g., visual acuity, microperimetry), though post hoc analyses suggested some functional benefits (hypothesis-generating only).
Mechanistic Insights:
Complement inhibition: Likely more effective for preventing new GA lesions (early-stage) than slowing existing lesion progression.
Genetic risk factors (highly testable):
ARMS2 and HTRA1: Increase risk for both GA incidence and expansion.
CFH: Affects GA incidence only.
C3: Raises GA risk but associated with slower expansion.
Safety Concerns:
Neovascularization: ~12% of pegcetacoplan-treated patients developed neovascular AMD, requiring additional anti-VEGF therapy.
Occlusive retinal vasculitis: Rare (1 per 10,000 injections) but serious; listed as an adverse effect for pegcetacoplan, not yet for avacincaptad pegol.
Frequent intravitreal injections: Increase risk of complications, a key concern for patient counseling on exams.
Regulatory Controversy:
FDA approval: Criticized for lacking scientific advisory committee input and relying on anatomical endpoints rather than functional outcomes.
EMA rejection (pegcetacoplan, September 2024):
Cited insufficient functional benefits and safety risks from frequent injections.
Microperimetry recognized as the best functional measure for GA but showed no significant benefit in prespecified outcomes.
Avacincaptad pegol: Application withdrawn by Astellas Pharma (October 2024) after EMA discussions, highlighting regulatory skepticism.
High-yield: Understand differences in FDA vs. EMA priorities (FDA prioritizes access, EMA emphasizes patient-centered benefit-risk balance).
Clinical Challenges:
Unlike anti-VEGF therapies (clear functional benefits like fluid reduction), GA treatments lack observable functional improvements, complicating efficacy assessment in practice.
Counseling patients: Physicians must discuss approved and unapproved treatments, including risks and limited functional benefits.
Future Directions:
Explore alternative targets: mitochondrial dysfunction, hypoxia-related factors, toxic visual cycle byproducts, and inflammation.
Trials should integrate anatomical and functional outcomes (e.g., microperimetry as a primary endpoint) to better assess clinical benefit.
Differential Diagnosis:
GA vs. neovascular AMD: GA lacks hemorrhage/exudation; confirmed by OCT/FAF showing atrophy without fluid.
Other atrophic maculopathies: Stargardt disease, central areolar choroidal dystrophy (distinguished by genetics, age of onset).
Citation Address of the Uploaded Paper
Jia H, Sun X. Slowing Geographic Atrophy—Hopeful Progress or Uncertain Benefit. JAMA Ophthalmology. 2025;143(4):267-268. doi:10.1001/jamaophthalmol.2024.6490. Corresponding author: Xiaodong Sun, MD, PhD, Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Rd, Shanghai 200080, China (xdsun@sjtu.edu.cn).
