Comparative Evaluation of Pegcetacoplan and Placebo on the Progression of Geographic Atrophy in Dry Age-related Macular Degeneration: A Systematic Review and Meta-analysis of Randomised Controlled Trials

Abstract

Introduction: As a late-stage dry Age-related Macular Degeneration (AMD), Geographic Atrophy (GA) historically, has had few effective therapeutic options, but pegcetacoplan (marketed as Syfovre) was recently approved by the Food and Drug Administration (FDA) for this indication in 2023. Pegcetacoplan inhibits C3 component of the complement system and reduces downstream inflammation and damage to the retina. Aim: To examine the efficacy and safety of pegcetacoplan, a complement C3 inhibitor, in slowing GA progression by targeting complement dysregulation, compared with placebo. Materials and Methods: The present systematic review and meta-analysis were performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered in International Prospective Register of Systematic Reviews (PROSPERO) (CRD42024625783). A systematic search of MEDLINE, EMBASE, Scopus, Web of Science, ProQuest and Cumulative Index to Nursing and Allied Health Literature (CINAHL) from inception to December 2024 was conducted. Randomised controlled trials (RCT) in English language evaluating intravitreal pegcetacoplan in GA secondary to dry AMD were included. Eligibility criteria for screening were RCTs of pegcetacoplan versus placebo/sham reporting efficacy {change in GA area and Best-Corrected Visual Acuity (BCVA)} and safety outcomes {Treatment-Emergent Adverse Events (TEAE), Serious Adverse Events (SAE), and Macular Neovascularisation (MNV)}. Data were extracted and risk of bias was assessed independently by two reviewers, using the RAYYAN tool and the Cochrane Risk of Bias 2 (RoB 2) Tool and any disagreement on study inclusion was resolved through discussion and consensus with a third author. We quantitatively combined studies with similar participants, interventions, outcomes and methods using meta-analysis. Mean Differences (MDs) and Odds Ratios (OR) with 95% Confidence Intervals (CI) were computed using fixed and random-effects models in RStudio (v4.2.1) with the meta package, while heterogeneity was assessed using Cochran’s Q (Chi-squared), Tau-squared and I² statistic. Results: Seven eligible publications were included in the systematic review. Pegcetacoplan significantly slowed GA progression compared to placebo at 12 months (MD: -0.199; 95% CI: -0.372; -0.026; p=0.0236) and 24 months (MD: -0.760; 95% CI: -1.014; -0.507, p<0.001) respectively. No significant improvement in BCVA was observed at 12 and 24 months. Pegcetacoplan was associated with a 36% increase in TEAEs (OR: 1.36; 95% CI: 1.03; 1.81; p=0.03) and 53% increase in TEAEs (OR: 1.53; 95% CI: “1.04; 2.26”; p=0.03) at 12 months and 24 months respectively. No significant differences in SAEs at 12 months. Pegcetacoplan was associated with an approximately three-fold higher odds of MNV at 12 months (OR: 2.99; 95% CI: “1.12; 7.96”; p=0.029) and 24 months (OR: 3.17; 95% CI: “1.50; 6.73”; p=0.0026), respectively. Conclusion: Pegcetacoplan considerably slows the progression of GA at 12 and 24 months in patients with dry AMD, but no significant improvement in visual acuity was observed. Treatment was associated with increased risk of TEAEs and MNV, but not SAEs, supporting a favourable but carefully balanced benefit-risk profile that merits further long-term evaluation. The magnitude and long-term durability of treatment effects should be interpreted with caution given the evidence available is based on a small number of underlying trial cohorts and further independent studies are warranted.