Abstract

Importance: Dry Age-related Macular Degeneration (AMD) affects approximately 8 million individuals in the United States alone, representing the leading cause of irreversible vision loss in developed countries. Intermediate AMD presents a critical therapeutic gap where patients currently have limited options beyond nutritional supplementation, while Geographic Atrophy (GA) progresses relentlessly despite the psychological and functional burden on affected individuals.
Observations: This narrative review summarizes evidence from pivotal phase III clinical trials evaluating three therapeutic approaches: nutritional supplementation (AREDS2, N=4,203), complement inhibition (OAKS/DERBY/GALE for pegcetacoplan, N=1,258; GATHER1/2 for avacincaptad pegol, N=734) and photobiomodulation (LIGHTSITE III, N=100). Complement inhibitors demonstrate 17-35% reduction in GA growth rates, with efficacy varying substantially by lesion location: 36-42% reduction for extrafoveal lesions versus 19-21% for subfoveal lesions. Both complement inhibitors carry risk of exudative conversion (6.7-12% cumulative over 2 years) requiring ongoing surveillance. Photobiomodulation data from a single trial suggest potential for modest functional benefit (treatment group gained 5.4 letters from baseline vs 3.0 letters in sham; between-group difference 2.4 letters, P<0.0001). In a secondary analysis with limited conversion events (6 eyes total), photobiomodulation was associated with reduced new GA onset (OR 9.4, P=0.024). Independent validation studies are essential before definitive conclusions can be drawn.
Conclusion and relevance: Current evidence supports stage-specific therapeutic considerations, with an important conceptual distinction between structural preservation (slowing GA expansion) and functional rescue (improving visual acuity). Complement inhibitors provide the first evidence-based intervention for established GA, with optimal efficacy in non-subfoveal lesions. Photobiomodulation represents a potentially promising intervention for intermediate AMD targeting functional outcomes, though its evidence base remains preliminary. Both approaches require ongoing evaluation to define optimal patient selection, treatment sequencing, and long-term outcomes. Shared decision-making with patients regarding treatment burden, expected benefits, and risks remains paramount.

Keywords:Age-related macular degeneration; Dry AMD; Geographic atrophy; Intermediate AMD; Complement system; C3 inhibition; C5 inhibition; Pegcetacoplan; Avacincaptad pegol; Photobiomodulation; Mitochondrial dysfunction; AREDS2; Nutritional supplementation; Structural preservation; Functional rescue; Best-corrected visual acuity; Fundus autofluorescence; Exudative conversion; Subfoveal lesions; Extrafoveal lesions