According to the 2024 American Academy of Ophthalmology (AAO) Age-Related Macular Degeneration (AMD) Preferred Practice Pattern (PPP), bevacizumab (Avastin) is a full-length monoclonal antibody that binds all isoforms of vascular endothelial growth factor (VEGF). It is Food and Drug Administration (FDA)-approved only for intravenous oncology use but widely used off-label as an intravitreal injection (1.25 mg) for neovascular age-related macular degeneration (nAMD). The key supporting literature includes the landmark CATT trial, which found bevacizumab and ranibizumab had comparable visual acuity improvements with monthly dosing at 1 and 2 years (Table 1), and the IVAN trial (Table 2), which confirmed similar efficacy outcomes. A 2018 meta-analysis of over 8,000 eyes also found bevacizumab and ranibizumab had equivalent efficacy for best-corrected visual acuity (BCVA). Notably, the CATT study did identify a higher rate of serious systemic adverse events with bevacizumab compared to ranibizumab (24% vs. 19% at 2 years), though two Cochrane systematic reviews concluded any safety difference between agents is minimal. Informed consent regarding bevacizumab's off-label status is required. Regarding biosimilars, the PPP confirms that FDA-approved biosimilars for both ranibizumab (Byooviz, Cimerli) and aflibercept 2 mg have demonstrated no clinically meaningful differences from their reference products in safety or efficacy, with one comparative trial required for approval. Importantly, the PPP states that the choice of biologic product — reference, biosimilar, or interchangeable — should be that of the treating ophthalmologist and the patient, as patients may respond more favorably to one biologic over another. [1]
A 2022 review discussed the emerging role of anti-VEGF biosimilars in ophthalmology, emphasizing their potential to reduce treatment costs while maintaining comparable efficacy, safety, and immunogenicity to reference biologics. Biosimilars, unlike generic small-molecule drugs, are derived from living systems and are therefore highly similar but not identical to their reference products due to inherent manufacturing variability. Regulatory approval in the United States and European Union relies on a stepwise, totality-of-evidence approach incorporating analytical characterization, pharmacokinetic similarity, preclinical data when applicable, and clinical studies evaluating safety, immunogenicity, and efficacy. If no clinically meaningful differences are demonstrated, biosimilars may receive approval for multiple indications via extrapolation, even in the absence of direct clinical trials in each indication. At the time of publication, ophthalmic biosimilars included ranibizumab-nuna (Byooviz) and ranibizumab-eqrn (Cimerli), while additional biosimilars targeting ranibizumab, aflibercept, and bevacizumab were in various stages of clinical development. Notably, no bevacizumab biosimilars had been approved for ophthalmic use, despite several bevacizumab biosimilars, bevacizumab-bvzr (Zirabev), bevacizumab-awwb (Mvasi), Abevmy, Alymsys/Oyavas, Aybintio, and Onbevzi, being approved in the United States and/or European Union for oncologic indications. During periods of bevacizumab shortage, some payers proposed substituting oncology-approved biosimilars for intravitreal use; however, ophthalmology societies opposed this practice due to the absence of ophthalmic-specific evaluation and concerns regarding formulation differences, including excipients that may carry potential retinal toxicity risk and the lack of intravitreal safety data. Broader implementation of biosimilars was also highlighted as a strategy to increase access and reduce healthcare expenditures, with real-world oncology experience demonstrating meaningful cost savings and downstream improvements in treatment availability and system-level resource allocation. [2]
A 2026 review article aimed to evaluate the safety and efficacy of biosimilar VEGF agents in managing retinopathy of prematurity. The review meticulously compiled data from five studies, encompassing 382 eyes, that focused on the intravitreal administration of VEGF biosimilars in preterm infants. Results from the systematic review highlighted a favorable safety profile for biosimilar anti-VEGF agents, with an overall adverse event rate of 0.5%. Among the studies, bevacizumab biosimilars were evaluated in 217 eyes, reporting a pooled treatment success rate of 65% (95% confidence interval [CI] 58% to 71%), while ranibizumab biosimilars were assessed in 118 eyes, demonstrating a success rate of 46% (95% CI 2% to 95%). Surgical intervention was required in 1% of the cases, affecting five eyes in total, with four from the bevacizumab group and one from the ranibizumab group. The findings suggest the potential of biosimilars as cost-effective alternatives to current treatments, particularly in resource-constrained settings. Nonetheless, the authors advocate for further randomized controlled trials to rigorously compare these biosimilars to their reference biologics, paving the way for improved clinical outcomes. [3]
A 2007 literature review examined the efficacy and safety of off-label intravitreal bevacizumab for neovascular ocular diseases. The synthesis of data from these sources included information on more than 3,500 patients treated with intravitreal bevacizumab for various conditions, such as neovascular AMD, diabetic retinopathy, pathological myopia, neovascular glaucoma, and macular edema due to diabetes, retinal vein occlusion, or uveitis. Statistically significant improvements were noted in visual acuity, along with reductions in retinal thickness and choroidal neovascularization. Tolerance to intravitreal bevacizumab was favorable over the short term, with adverse events occurring at rates of 0.21% or less across a registry encompassing 7113 injections. The findings from these uncontrolled studies suggest a beneficial effect of intravitreal bevacizumab in neovascular AMD for durations ranging from three months to one year. However, the need for controlled trials to better define the safety, efficacy, and optimal treatment regimens remains critical. [4]
A 2019 Cochrane systematic review and meta-analysis analyzed 16 randomized Controlled Trials (RCTs) enrolling 6,347 participants to evaluate bevacizumab and other anti-VEGF agents for neovascular AMD. For bevacizumab specifically, two RCTs compared it directly to control and 10 head-to-head RCTs compared bevacizumab to ranibizumab. Compared to control, bevacizumab-treated participants were 7.8 times more likely to gain 15 or more letters of visual acuity at one year (RR 7.80, 95% CI 2.44-24.98, high-certainty evidence). When compared directly to ranibizumab across eight RCTs (n=3,144), bevacizumab demonstrated equivalent efficacy at one year for gaining 15 or more letters (RR 0.95, 95% CI 0.81-1.12; high-certainty evidence), preventing loss of fewer than 15 letters (RR 1.00, 95% CI 0.98-1.02; high-certainty evidence), and mean change in visual acuity (MD -0.5 letters, 95% CI -1.5 to 0.5; high-certainty evidence). The small difference in central retinal thickness reduction favoring ranibizumab (MD -11.6 μm) was deemed clinically insignificant. Bevacizumab was less costly (USD 490 vs. USD 18,590 per year in Comparison of Age-Related Macular Degeneration Treatments Trials [CATT]). At two years, 36% of bevacizumab-treated participants experienced at least one serious adverse event versus 30% in ranibizumab groups (RR 1.20, 95% CI 1.05-1.37), though absolute event numbers remained small. The authors conclude that bevacizumab and ranibizumab are equally effective for neovascular AMD, with bevacizumab representing a substantially lower-cost option, while acknowledging it remains off-label for ophthalmic use. [5]