Abstract / Summary
Background/Objectives: Geographic atrophy (GA), an advanced form of dry age-related macular degeneration (AMD), causes irreversible central vision loss and has limited treatment options. Complement dysregulation plays a pivotal role in GA pathogenesis. This systematic review synthesizes the efficacy, safety, tolerability, and pharmacokinetics of approved and investigational complement-targeting therapies, alongside emerging drug delivery systems and gene-based approaches. Methods: Following PRISMA guidelines, PubMed, Embase, and Cochrane were searched and studies screened against predefined eligibility criteria. Risk of bias and pharmacokinetic quality were assessed using the Newcastle–Ottawa Scale and ClinPK Statement checklist, respectively. Results: Thirty-one studies evaluating C3, C5, factor D, and factor B inhibitors; recombinant factor H; soluble CD59 gene therapy; and an indirect anti-amyloid-β strategy were analyzed. Only two agents are FDA-approved: pegcetacoplan (C3 inhibitor) and avacincaptad pegol (C5 inhibitor). They both significantly, albeit modestly, slowed GA lesion growth. However, both increased the risk of exudative AMD conversion and required frequent intravitreal injections. Other complement targets showed limited efficacy or failed to meet clinical endpoints. Pharmacokinetic data, largely derived from serum measurements and model-based predictions, suggest that intravitreal half-life and injection volume dose limitations may complicate the translational development of complement inhibitors. Conclusions: Current evidence indicates a modest, agent-, dose-, and regimen-dependent slowing of GA anatomical progression. Clinically meaningful visual function benefit has not been firmly established, although post hoc analyses suggest possible benefits for photoreceptor structure and vision-related risk. Gene therapy and advanced intraocular delivery systems have emerged as potential strategies, but further research must determine whether they can provide sustained, multitarget, patient-centered treatment with acceptable ocular and systemic safety.