Clinical Efficacy and Safety of Anti-vascular Biosimilars Compared to Reference Anti-vascular for neovascular age-related macular degeneration: A Systematic Review, Meta-Analysis and Meta-regression.

Abstract

<title>Abstract</title> Background Neovascular age-related macular degeneration (nAMD) is a leading cause of irreversible vision loss in older adults and is commonly treated with intravitreal anti-VEGF agents such as ranibizumab and aflibercept. These therapies are highly effective but expensive, imposing a significant burden on patients and healthcare systems. Biosimilars offer a lower-cost alternative, but concerns remain regarding their clinical equivalence and safety. Purpose To systematically evaluate the efficacy, safety, and immunogenicity of ranibizumab and aflibercept biosimilars compared with their reference biologics in the treatment of neovascular age-related macular degeneration (nAMD). Methods We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing biosimilar anti-VEGF agents with reference ranibizumab or aflibercept. A comprehensive search of PubMed, Scopus, and Cochrane Library (inception–September 2025) was performed following PRISMA guidelines. Outcomes included change in best-corrected visual acuity (BCVA) at 12 weeks and study endpoint, ≥ 15-letter responder rates, treatment-emergent anti-drug antibodies (ADAs), and ocular/serious ocular adverse events. Risk of bias was assessed using the Cochrane ROB-2 tool. Results Seventeen phase 3 RCTs including 6,694 patients were analyzed. Pooled results showed no clinically meaningful differences in BCVA improvement at 12 weeks (MD = -0.42, p = 0.17) or at study endpoint (MD =-0.32, p = 0.23) between biosimilars and reference biologics. Responder rates (≥ 15-letter gain) were comparable (RR = 1.06, p = 0.36), as were rates of treatment-emergent ADAs (RR = 0.89, p = 0.40) and ocular adverse events (RR = 0.99, p = 0.86). Subgroup analysis revealed no significant differences for aflibercept biosimilars versus reference aflibercept; however, ranibizumab biosimilars showed slightly reduced BCVA gains at study endpoint (RR = 0.53, p = 0.02). Heterogeneity was generally low to moderate, and no significant publication bias was detected. Conclusion Our analysis showed that ranibizumab and aflibercept biosimilars provide equivalent efficacy, safety, and immunogenicity compared with their reference biologics. Future research should focus on long-term outcomes, real-world switching data, and health-economic analyses to guide sustainable implementation in routine practice.