Geographic Atrophy: Pathophysiology, Diagnosis and Current and Emerging Treatments

Background: Geographic atrophy (GA) is an advanced, irreversible form of age-related macular degeneration (AMD) characterised by progressive loss of photoreceptors, retinal pigment epithelium (RPE) and choriocapillaris. It affects approximately 0.3–0.5% of the global population, with prevalence rising sharply with age and affecting 1 in 5 individuals aged 85 and above. GA disproportionately affects Caucasian populations and typically progresses from the perifoveal macula to involve the fovea within 1.5–2.4 years, resulting in profound central vision loss. Purpose: To summarise the pathophysiology, diagnosis and current and emerging therapeutic options for geographic atrophy, providing a mechanistic rationale for each treatment. Methods: This narrative review synthesises published clinical trials, systematic reviews and emerging pre-clinical and early-phase data pertaining to GA. Key databases including PubMed and ClinicalTrials.gov were reviewed. Studies were selected based on relevance to GA pathophysiology, diagnostic modalities and therapeutic outcomes. Results: Complement dysregulation, oxidative stress and accumulation of toxic metabolic byproducts represent the principal pathogenic drivers of GA. Intravitreal complement inhibitors represent the only currently approved pharmacological therapies. Pegcetacoplan (C3 inhibitor) reduced GA lesion growth by 16–29% in phase 2–3 trials (FILLY, OAKS, DERBY), whilst avacincaptad pegol (C5 inhibitor) reduced lesion growth by 14–28% (GATHER1, GATHER2). Neither agent demonstrated significant improvement in best corrected visual acuity, reading speed or functional independence. A 2025 post hoc analysis of AREDS/AREDS2 data demonstrated that oral antioxidant supplementation significantly slowed GA progression towards the central macula, suggesting a role in preserving foveal sparing, though no area-based benefit was confirmed in the prevalent GA cohort. Emerging gene therapies (JNJ-1887/AAVCAGsCD59) and stem-cell-based approaches (CPCB-RPE1) have demonstrated early-phase safety and preliminary signals of anatomical benefit, with phase 2–3 trials ongoing. Conclusion: Current approved therapies for GA offer modest anatomical benefit in slowing lesion enlargement but have not translated to meaningful functional gain. This discordance between anatomical and functional outcomes represents the central unmet need in GA management. Emerging gene and cell-based therapies have shown promising early data, although long-term safety and functional efficacy data remain limited. Future trials should incorporate functional independence and quality-of-life endpoints alongside conventional visual outcome measures to more accurately capture the patient-relevant impact of therapeutic interventions.