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.

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. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article 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. Yousef Mesaed Al-Shammari, Yousef M. AlDhafiri^, Abdullah Kamal Ahmad, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7909324/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 20 Mar, 2026 Read the published version in International Ophthalmology → Version 1 posted 10 You are reading this latest preprint version Abstract 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. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Figure 15 Figure 16 1. Introduction Age-related macular degeneration (AMD) is a progressive disease characterized by degeneration of the central area of the retina and the leading cause of visual impairment and blindness in the elderly population worldwide ( 1 , 2 ). The retinal pigment epithelium (RPE) represents the central fulcrum of AMD pathogenesis. It is a key regulatory hub, integrating multiple cellular and molecular stimuli to maintain its own homeostasis while simultaneously transmitting signals to and from the surrounding retinal microenvironment. Ultimately, RPE dysfunction and degeneration constitute the irreversible, critical event that drives the progression of AMD ( 3 ). In AMD, vision loss is primarily caused by choroidal neovascularization (CNV), a VEGF-driven process central to the pathogenesis of neovascular AMD (nAMD) ( 4 ). AMD is defined into stages based on fundus lesions within the macula: early AMD (medium drusen, 63–125 µm, without pigmentary abnormalities), intermediate AMD (large drusen > 125 µm and/or any pigmentary abnormalities), and late AMD, which encompasses both neovascular AMD and geographic atrophy (GA) ( 5 ). Neovascular AMD, a late-stage subtype of the disease, is characterized by choroidal neovascularization with subretinal fluid leakage that distorts vision. It accounts for most severe AMD-related vision loss worldwide and substantially impacts quality of life and global economic productivity ( 6 ). Unlike non-neovascular AMD, which had no approved treatments until the recent introduction of intravitreal pegcetacoplan, nAMD outcomes showed improvement in recent years specialty after anti-VEGF ( 7 ). The treatment options for nAMD treatment include laser photocoagulation and photodynamic therapy. Repeated intravitreal anti-VEGF injections remain the gold standard ( 8 ). They work by inhibiting Vascular Endothelial Growth Factor-A (VEGF-A), a key driver of abnormal blood vessel growth (choroidal neovascularization) and leakage that causes vision loss. The primary goal is to stabilize and improve vision by reducing retinal fluid. These medications include ranibizumab (lucentis) and aflibercept (eylea) ( 9 ). A biosimilar is a biologic product highly comparable to an approved reference drug in chemical, physical, and biological characteristics, demonstrating equivalent safety, efficacy, and immunogenicity, while reducing treatment costs. Biosimilars are significantly cheaper to develop than the original innovator biologics, leading to an estimated reduction in treatment costs of more than 25%. In 2015, Razumab was the world's first biosimilar of ranibizumab (Lucentis) approved for use in ophthalmology and many more ophthalmic biosimilars are in the development ( 10 , 11 ). Overall, the evidence regarding anti-VEGF biosimilars in treating nAMD remains inconclusive. In this systematic review, we aim to make a better and more comprehensive understanding of the effect of anti-VEGF biosimilars by aggregating and analyzing all available evidence from multiple studies offering a consolidated, evidence-based foundation to guide treatment choices. 2. Methods This systematic review and meta-analysis was carried out following the PRISMA guidelines ( 12 ). 2.1 Search Strategy and Eligibility Criteria A systematic literature search was conducted to identify studies evaluating the efficacy and safety of anti-VEGF biosimilars in comparison with their reference biologics in treating nAMD. We searched PubMed, Scopus, and Cochrane library from inception through September 2025, using a combination of keywords and MeSH terms relevant to "anti-VEGF biosimilar" and "age-related macular degeneration". No language restrictions were applied. To ensure comprehensive coverage, we also manually reviewed the reference lists of included studies. All trials were phase 3, randomized, double-masked, multicenter clinical studies comparing a biosimilar anti-VEGF agent (either aflibercept or ranibizumab biosimilars) with the corresponding reference product (Eylea for aflibercept, Lucentis for ranibizumab). This design is considered the gold standard for demonstrating clinical equivalence. 2.2 Study Selection and Data Extraction Two independent reviewers screened the identified records by title and abstract, followed by a full-text review to assess eligibility based on the predefined criteria. Disagreements were resolved through discussion with a third reviewer until consensus was achieved. The same reviewers, using a standardized Excel form, extracted relevant data independently. Extracted variables included study design, female percentage, NCT, number of patients, mean age, BCVA score at baseline, follow-up duration, country and biosimilar name. The outcomes included the change of BCVA in the first 12 weeks (most of the vision gain from anti-VEGF therapy occurs in the first few months), the change in BCVA from baseline to the end of the trial, responders’ rates (the patients who gained ≥ 15 ETDRS letters, indicating a significant improvement in vision), ocular adverse events in the studied eye, serious adverse events in the studied eye and the incidence of Treatment-Emergent ADAs (how many patients developed anti-drug antibodies (ADAs) during the study after receiving the treatment). We used automeris.io to extract numerical information from charts. 2.3 Quality Assessment In this meta-analysis, the methodological quality of the included randomized controlled trials was evaluated using the Cochrane Risk of Bias 2 (ROB-2) tool. Two independent reviewers assessed each study across the five ROB-2 domains: randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result. Any disagreements between reviewers were resolved by consensus or consultation with a third reviewer. Overall, the methods ensured a systematic and reproducible assessment of risk of bias, contributing to the robustness of the meta-analysis findings. 2.4 Statistical Analysis All statistical analyses were conducted in R (version 4.1.2) using the metafor package (version 4.8-0) [14]. Continuous outcomes were summarized as mean difference (MDs) with 95% confidence intervals (CIs), calculated using the generic inverse variance method, while dichotomous variables were summarized using relative risk (RRs) with 95% confidence intervals (CIs), calculated using the generic inverse variance method. A random-effects model was applied to account for between-study variability. Heterogeneity was assessed with tau squared and quantified using the I² statistic, where I² >50% indicated moderate heterogeneity and I² >90% indicated substantial heterogeneity. Statistical significance was set at p < 0.05. Potential publication bias was explored visually using funnel plots. Sensitivity analyses were performed by sequentially omitting individual studies to evaluate the robustness of the pooled estimates. Meta-regression analyses were conducted to explore potential sources of heterogeneity by assessing the influence of study-level covariates on the pooled effect estimates. Subgrouping of the included studies into aflibercept biosimilars and ranibizumab biosimilars was conducted to detect any differences between these two biosimilars. 3. Results 3.1 Literature search results The comprehensive literature search initially identified a total of 154 studies across three major databases: PubMed (n = 79), Scopus (n = 52), and Cochrane (n = 23). Following the removal of duplicate records, 123 unique studies remained for further consideration. Title and abstract screening was then performed in accordance with the PRISMA guidelines, resulting in 40 studies eligible for full-text retrieval. After a rigorous full-text screening process, 10 studies published after June 2023 were identified and included in our study, in addition to the 7 studies included in the original review. Figure 1. 3.2 Characteristics of the included studies Our review included 17 RCTs, published between 2020 and 2025, involving 6,694 patients with nAMD. All the included studies were randomized, double blind parallel group, multicentral, phase 3 RCTs ( 13 – 29 ). These studies included many different biosimilars for ranibizumab and aflibercept with standardized medication doses (2 mg for aflibercept and aflibercept biosimilars and 0.5 mg for ranibizumab and ranibizumab biosimilars. Eight of the included studies were multinational ( 13 , 15 – 17 , 20 , 22 , 24 , 28 ), 4 were conducted in India ( 19 , 23 , 26 , 29 ) and 1 in Korea ( 18 ), China ( 14 ), Iran ( 21 ) and Finland ( 25 ). All studies restricted patients to those over 50 years of age. The means of age were close in the included studies, approximately 69 years of age. The sample sizes ranged from 152 ( 29 ) to 705 patients ( 13 ), while no study arm in any of the trials had fewer than 30 patients. The sex distribution did not exhibit a consistent trend, with some studies reporting a modest male predominance and others a modest female predominance. The mean baseline BCVA ranged from 42.5 to 61.7. And finally, the follow-up duration ranged from 12 weeks to 56 weeks with the 52 weeks and 48 weeks durations being the most common durations. Table 1 . Table 1 baseline characteristics of the included studies. Study ID Intervention Control NCT Country Study design Mean age intervention Mean age Control Number of Intervention Number of Control % female intervention % female control baseline BCVA intervention baseline BCVA control Follow-up Yoon et al. 2022 CKD-701 (0.5 mg) reference ranibizumab (0.5 mg) NCT04857177 Korea Phase 3 RCT 72.18 (8.09) 71.91 (8.79) 146 145 39.04 44.14 59.38(13.10) 60.19 (12.68) 48 weeks Li et al. 2024 QL1207 (2 mg) reference aflibercept (2 mg) NCT05345236 China Phase 3 RCT 67.4 (8.9) 67.1 (8.0) 185 181 34.1 30.4 56.1 (11.7) 56.1 (11.7) 48 weeks Kang et al. 2024 SCD411 (2 mg) reference aflibercept (2 mg) NCT04480463 multinational Phase 3 RCT 73.5 (8.0) 73.6 (8.6) 287 286 51.9 51.4 58.6 (10.8) 59.9 (10.6) 52 weeks Sadda et al. 2023 SB15 (2 mg) reference aflibercept (2 mg) NCT04450329 multinational Phase 3 RCT 73.7 (8.05) 74.3 (8.09) 224 225 52.7 58.7 59.5 (10.60) 58.9 (11.19) 56 weeks Bordon et al. 2024 SDZ-AFL (2 mg) reference aflibercept (2 mg) NCT04864834 multinational Phase 3 RCT 75.8 (7.82) 75.7 (7.72) 243 240 56.4 56.7 59.7 (10.05) 59.4 (10.37) 52 weeks Loewenstein et al. 2023 XSB-001 (0.5 mg( reference ranibizumab (0.5 mg) NCT03805100 multinational Phase 3 RCT 74.5 (8.7) 73.8 (8.3) 292 290 57.5 54.1 61.7 (8.1) 61.5 (8.2) 52 weeks Singh et al. 2022 Lupin’s biosimilar reference ranibizumab (0.5 mg) India Phase 3 RCT 67.2 (10.29) 67.2 (10.52) 101 101 36.63 41.58 12 weeks Woo et al. 2020 SB11 (0.5 mg) reference ranibizumab (0.5 mg) NCT03150589 multinational Phase 3 RCT 74.1 (8.5) 351 354 57.2 58.3 (10.6) 58.3 (10.6) 52 weeks Karkhaneh et al. 2024 P041 (2 mg) reference aflibercept (2 mg) NCT05587062 Iran Phase 3 RCT 68.64 (6.88) 68.26 (6.24) 84 84 30.95 44.05 49.58 (13.82) 54.11 (13.60) 52 weeks Agostini et al. 2025 AVT06 (2 mg) reference aflibercept (2 mg) NCT05155293 multinational Phase 3 RCT 73.7 (9.11) 74.3 (8.04) 205 205 50.2 56.6 55.0 (12.07) 54.2 (12.38) 48 weeks Ghosh et al. 2024 Sun’s ranibizumab reference ranibizumab (0.5 mg) India Phase 3 RCT 65.50 (9.78) 67.96 (9.25) 107 54 42.1 37.0 44.32 (12.78) 42.37 (11.44) 16 weeks Hamouz et al. 2025 QL1205 (0.5 mg) reference ranibizumab (0.5 mg) multinational Phase 3 RCT 70.5 (9.47) 72.2 (8.73) 308 308 49.0 52.3 55.6 (11.86) 55.1 (12.19) 48 weeks Holz et al. 2021 FYB201 (0.5 mg) reference ranibizumab (0.5 mg) NCT02611778 Finland Phase 3 RCT 72.8 (8.5) 74.1 (8.5) 238 239 56.7 56.1 48 weeks Apsangikar et al. 2021 Biosimilar (0.5 mg) reference ranibizumab (0.5 mg) India Phase 3 RCT 106 53 24 weeks UMIN000030010 Biosimilar (0.5 mg) reference ranibizumab (0.5 mg) Japan Phase 3 RCT 74.4 (7.5) 74.1 (7.3) 176 175 52 weeks Friedman et al. 2025 ABP 938 (2 mg) reference aflibercept (2 mg) NCT04270747 multinational Phase 3 RCT 76.0 (7.9) 76.0 (8.0) 288 288 52.4 59.4 58.9 (10.68) 57.6 (11.74) 48 weeks Rana et al. 2024 Biosimilar (0.5 mg) reference ranibizumab (0.5 mg) India Phase 3 RCT 65.8 (9.04) 68.8 (10.10) 114 38 42.1 42.1 42.5 (11.42) 46.5 (11.65) 12 weeks 3.3 Quality assessment The methodological quality of the included randomized controlled trials was evaluated using the Cochrane Risk of Bias 2 (ROB-2) tool. Most studies were judged to have a low risk of bias across all five domains: bias arising from the randomization process (D1), bias due to deviations from intended interventions (D2), bias due to missing outcome data (D3), bias in measurement of the outcome (D4), and bias in selection of the reported result (D5). Four studies (Kang et al. 2024, Woo et al. 2020, Agostini et al. 2025, and Ghosh et al. 2024) were assessed as having “some concerns,” mainly in D1 or D5, indicating possible but not critical limitations ( 13 , 17 , 22 , 23 ). Importantly, no study was rated as having a high risk of bias in any domain. Overall, the body of evidence can be considered robust, with a low likelihood that bias substantially influenced the pooled estimates. The domain-specific risk of bias judgments is presented in Fig. 2 . 3.4 Outcomes 3.4.1 The change of BCVA from baseline to week 12 Our analysis of 12 studies including 4,524 nAMD patients demonstrated no clinically meaningful difference in BCVA outcomes between anti-VEGF biosimilars and their reference biologics in the first 12 weeks (Fig. 3 : MD = -0.42, 95% CI [-1.01; 0.18], P = 0.17). Moderate-high heterogeneity was detected (tau 2 : 0.49, I 2 : 48.47%). The sensitivity analysis revealed no significant differences when excluding any of the included studies, as none of the included studies was considered influential. The subgrouping of the included studies into aflibercept biosimilars and ranibizumab biosimilars revealed no statically significant differences too. Our analysis demonstrated no clinically meaningful difference in BCVA outcomes between aflibercept biosimilars and reference aflibercept in the first 12 weeks (Fig. 4 : MD = -0.3, 95% CI [-0.96; 0.37], P = 0.38, I 2 = 0.00%). Also, our analysis demonstrated no clinically meaningful difference in BCVA outcomes between ranibizumab biosimilars and reference ranibizumab in the first 12 weeks (Fig. 5 : MD = -0.52, 95% CI [-1.49; 0.46], P = 0.3, I 2 = 68.06%). We performed meta-regression to explore the potential effect of the mean age, female percentage, baseline BCVA and follow-up duration on the improvement of BCVA outcomes and the heterogeneity across studies. The results of the regression demonstrated that mean age, baseline BCVA and follow-up duration did not demonstrate statistically significant association with the improvement of BCVA outcomes (follow-up: slope = -0.038, 95% CI [-0.09; 0.01], P = 0.16, age: slope = -0.17, 95% CI [-0.38; 0.04], P = 0.11 and baseline BCVA: slope = -0.07, 95% CI [-0.24; 0.11], P = 0.46). Also, these moderators did not significantly explain the heterogeneity as it remained high after including these moderators (follow-up: I 2 = 46.32%, age: I 2 = 45.40% and baseline BCVA: I 2 = 53.90%). While the female percentage demonstrated a statistically significant association with the improvement of BCVA outcomes (slope = -0.0853, 95% CI [-0.14; -0.03], P = 0.002) and significantly explained the heterogeneity as it became very low after including this moderator (I 2 = 13.38%). Egger’s test indicated no evidence of significant publication bias (p = 0.40). Visual inspection of the funnel plot revealed a reasonably symmetrical distribution of studies. The trim-and-fill analysis suggested that no studies were missing, supporting the robustness of the findings. (supplements: Funnel 1). 3.4.2 The change of BCVA from baseline to the end of the trial Our analysis of 15 studies including 5,965 nAMD patients demonstrated no clinically meaningful difference in the BCVA outcomes between anti-VEGF biosimilars and their reference biologics (Fig. 6 : MD = -0.32, 95% CI [-0.85; 0.20], P = 0.23). Low-moderate heterogeneity was detected (tau 2 : 0.29, I 2 : 28.62%). The sensitivity analysis revealed no significant differences when excluding any of the included studies, as none of the included studies was considered influential. The subgrouping of the included studies into aflibercept biosimilars and ranibizumab biosimilars revealed some different findings. Our analysis demonstrated no clinically meaningful difference in BCVA outcomes between aflibercept biosimilars and reference aflibercept (Fig. 7 : MD = 0.03, 95% CI [-0.88; 0.94], P = 0.95, I 2 = 38.89%). But our analysis demonstrated that ranibizumab biosimilars showed a significantly lesser improvement in the BCVA outcomes reference ranibizumab (Fig. 8 : MD = -0.63, 95% CI [-1.18; -0.07], P = 0.03, I 2 = 0.00%). We performed meta-regression to explore the potential effect of the mean age, female percentage, baseline BCVA and follow-up duration on the improvement of BCVA outcomes and the heterogeneity across studies. The results of the regression demonstrated that mean age, baseline BCVA, female percentage and follow-up duration did not demonstrate statistically significant association with the improvement of BCVA outcomes (follow-up: slope = -0.028, 95% CI [-0.08; 0.02], P = 0.28, age: slope = -0.10, 95% CI [-0.31; 0.09], P = 0.31, female percentage: slope = -0.03, 95% CI [-0.10; 0.04], P = 0.37 and baseline BCVA: slope = -0.04, 95% CI [-0.20; 0.12], P = 0.63). Also, these moderators did not significantly explain the heterogeneity as it remained high after including these moderators (follow-up: I 2 = 31.27%, age: I 2 = 31.56%, female percentage: I 2 = 31.46% and baseline BCVA: I 2 = 34.26%). Egger’s test indicated no evidence of significant publication bias (p = 0.66). Visual inspection of the funnel plot revealed a reasonably symmetrical distribution of studies. The trim-and-fill analysis suggested that no studies were missing, supporting the robustness of the findings. (supplements: Funnel 2). 3.4.3 The responders’ rate (≥ 15-letter gain) Our analysis of 11 studies including 4,333 nAMD patients demonstrated no clinically meaningful difference in the responders’ rates between anti-VEGF biosimilars and their reference biologics (Fig. 9 : RR = 1.06, 95% CI [0.93; 1.22], P = 0.36). Low-moderate heterogeneity was detected (tau 2 : 0.02, I 2 : 30.76%). The sensitivity analysis revealed no significant differences when excluding any of the included studies, as none of the included studies was considered influential. The subgrouping of the included studies into aflibercept biosimilars and ranibizumab biosimilars revealed no statically significant differences too. Our analysis demonstrated no clinically meaningful difference in the responders’ rates between aflibercept biosimilars and reference aflibercept (Fig. 10 : RR = 1.11, 95% CI [0.86; 1.42], P = 0.42, I 2 = 55.97%). Also, our analysis demonstrated no clinically meaningful difference in the responders’ rates between ranibizumab biosimilars and reference ranibizumab in the first 12 weeks (Fig. 11 : RR = 1.02, 95% CI [0.89; 1.18], P = 0.74, I 2 = 0.00%). We performed meta-regression to explore the potential effect of the mean age, female percentage, baseline BCVA and follow-up duration on the responders’ rates and the heterogeneity across studies. The results of the regression demonstrated that baseline BCVA, female percentage and follow-up duration did not demonstrate statistically significant association with the responders’ rates (follow-up: slope = 0.0, 95% CI [-0.01; 0.01], P = 0.91, female percentage: slope = -0.01, 95% CI [-0.03; 0.001], P = 0.07 and baseline BCVA: slope = -0.02, 95% CI [-0.04; 0.01], P = 0.20). The female percentage, mean age and baseline BCVA significantly explained the heterogeneity across studies (age: I 2 = 3.44%, female percentage: I 2 = 4.47% and baseline BCVA: I 2 = 18.05%), while the follow-up duration did not significantly explain the heterogeneity across studies (I 2 = 37.42%.) Finally, the mean age demonstrated a statistically significant association with the responders’ rates (slope = -0.04, 95% CI [-0.08; -0.0002], P = 0.049). Egger’s test indicated no evidence of significant publication bias (p = 0.3). Visual inspection of the funnel plot revealed some asymmetrical distribution of studies. The trim-and-fill analysis suggested that 2 studies were missing from the left side of the funnel plot, which did not significantly influence the results of the responders’ rate (RR = 1.02, P = 0.83, I 2 = 38.14%), supporting the robustness of the findings. (supplements: Funnel 3 & 4). 3.4.4 The incidence of Treatment-Emergent ADAs Our analysis of 11 studies including 4,627 nAMD patients demonstrated no clinically meaningful difference in the incidence of Treatment-Emergent ADAs between anti-VEGF biosimilars and their reference biologics (Fig. 12 : RR = 0.89, 95% CI [0.67; 1.17], P = 0.40). Very low heterogeneity was detected (tau 2 : 0.0, I 2 : 0.00%). The sensitivity analysis revealed no significant differences when excluding any of the included studies, as none of the included studies was considered influential. The subgrouping into aflibercept biosimilars and ranibizumab biosimilars (Fig. 13 , Fig. 14 ) and meta-regression on the mean age, female percentage, baseline BCVA and follow-up duration of the included studies revealed no statically significant differences. Egger’s test indicated no evidence of significant publication bias (p = 0.4). Visual inspection of the funnel plot revealed some asymmetrical distribution of studies. The trim-and-fill analysis suggested that 1 study was missing from the right side of the funnel plot, which did not significantly influence the results of the incidence of Treatment-Emergent ADAs (RR = 0.91, P = 0.51, I 2 = 0.00%), supporting the robustness of the findings. (supplements: Funnel 5 & 6). 3.4.5 Ocular and serious ocular adverse effects of the studied eye Our analysis demonstrated no clinically meaningful difference in the incidence of ocular adverse events in the studied eye between anti-VEGF biosimilars and their reference biologics (Fig. 15 : RR = 0.99, 95% CI [0.91; 1.08], P = 0.86, I 2 = 0.02%). Also, our analysis demonstrated no clinically meaningful difference in the incidence of serious ocular adverse events in the studied eye between anti-VEGF biosimilars and their reference biologics (Fig. 16: RR = 1.06, 95% CI [0.81; 1.40], P = 0.67, I 2 = 0.02%). Very low heterogeneity was detected in both ocular adverse events and serious ocular adverse events. The sensitivity analysis revealed no significant differences when excluding any of the included studies in both ocular adverse events and serious ocular adverse events. The subgrouping into aflibercept biosimilars and ranibizumab biosimilars (Fig. 17, Fig. 18 ) and meta-regression on the mean age, female percentage, baseline BCVA and follow-up duration of the included studies revealed no statically significant differences. 4. Discussion This systematic review provides the most recent evidence regarding the efficacy and safety of anti-VEGF in treating nAMD. nAMD is an aggressive form of AMD and one of the leading causes of irreversible central vision loss in people over 50 years. The gold standard for nAMD treatment is anti-VEGF therapy, but it is one of the most expensive chronic treatments in ophthalmology. Biosimilars are entering the market specifically to lower costs and expand access as an alternative for the reference. Aflibercept and ranibizumab are both anti-VEGF therapies for nAMD, but they differ in structure and treatment schedule. Aflibercept is a recombinant fusion protein that acts as a trap binding VEGF-A, VEGF-B, and placental growth factor, whereas ranibizumab is a monoclonal antibody fragment that selectively binds VEGF-A. Aflibercept is typically dosed every 8 weeks after a 3-dose loading phase, reducing the injection burden, while ranibizumab is often given monthly but can also follow treat-and-extend or less frequent maintenance regimens based on disease activity ( 13 , 14 , 18 ). Across all included trials, anti-VEGF therapy was administered via intravitreal injection at the reference product dose (0.5 mg ranibizumab biosimilars; 2.0 mg aflibercept biosimilars). Most studies used three monthly loading doses, followed by either fixed dosing (monthly or every 2 months) or switched to giving injections only when fluid or vision changes were found during eye scans. Thus, differences in outcomes across studies are unlikely to be explained by differences in route or dosing, but rather by population characteristics and maintenance regimen ( 13 – 29 ). Our analysis demonstrated no clinically meaningful difference in BCVA outcomes between anti-VEGF biosimilars and their reference biologics, neither in the first 12 weeks (MD = -0.42, P = 0.17, I 2 = 48%) nor to the end of the trial (MD =-0.32, P = 0.23, I 2 = 29%). Most of the included studies showed the same conclusion, suggesting that the findings are robust and consistent across different cases. Mean age, follow-up and BCVA score at baseline did not significantly influence the change of BCVA score or explain the heterogeneity detected across studies, but interestingly studies with a higher female percentage tend to have a lesser improvement in the BCVA score in the first 12 weeks (slope = -0.0853, P = 0.002). Also, the subgrouping of studies into aflibercept biosimilars and ranibizumab biosimilars demonstrated that the effect of aflibercept biosimilars was significantly superior, as aflibercept biosimilars were not significantly different than their reference, while ranibizumab biosimilars were significantly inferior to their reference. Noticeably, all trials reported that most BCVA gain occurred within the first 8–12 weeks in all trials in all anti-VEGF biosimilars kinds, corresponding to the loading phase. Our findings support the concept that early response is a reliable surrogate for long-term efficacy and may guide clinicians in identifying poor responders who might benefit from treatment modification or switching strategies ( 13 – 29 ). Our analysis demonstrated no clinically meaningful difference in the responders’ rate between anti-VEGF biosimilars and their reference biologics (RR = 1.06, P = 0.36, I 2 = 30%). All included studies showed the same conclusion, suggesting that the findings are robust and consistent across different cases. Female percentage, follow-up subgrouping into aflibercept biosimilars and ranibizumab biosimilars and BCVA score at baseline did not significantly influence the responders’ rate, while the mean age demonstrated a statistically significant association with the responders’ rates (slope = -0.04, P = 0.049). Our analysis demonstrated no clinically meaningful difference in the incidence of Treatment-Emergent ADAs between anti-VEGF biosimilars and their reference biologics (RR = 0.89, P = 0.40, I 2 = 0.00%). All trials confirmed that the immunogenicity of ranibizumab and aflibercept biosimilars was minimal and clinically irrelevant, as the proportion of patients who developed treatment-emergent anti-drug antibodies was low (1–6%). This finding should reassure clinicians that switching from the reference product to a biosimilar does not increase the risk of immune-mediated loss of efficacy or safety concerns. Our analysis demonstrated no clinically meaningful difference in the incidence of ocular adverse events (RR = 0.99, P = 0.86, I 2 = 0.02%) and serious ocular adverse events (RR = 1.06, P = 0.67, I 2 = 0.02%) in the studied eye between anti-VEGF biosimilars and their reference biologics. The most commonly reported mild adverse events were conjunctival hemorrhage, eye pain or discomfort after injection and increased intraocular pressure shortly after injection, while endophthalmitis, retinal detachment and intraocular hemorrhage were the most common serious ocular adverse events, even though the incidence rates were very low. These findings confirmed that biosimilars did not pose additional ocular or systemic risks compared with their reference products. These findings were important for clinicians who may hesitate to switch stable patients to a biosimilar due to safety concerns. Long-term real-world data will still be valuable to monitor for very rare events. Our findings were consistent with the most recent Cochrane review of anti-VEGF biosimilars in nAMD, which pooled data from nine randomized trials including more than 3,800 eyes. That review confirmed that biosimilars match their reference products in terms of visual acuity gain at 8–12 weeks, prevention of vision loss at one year, and reduction in retinal thickness, with no clinically meaningful differences. Importantly, rates of ocular and systemic adverse events were similar between groups, and the incidence of treatment-emergent anti-drug antibodies was low and comparable. Taken together, these results reinforce that biosimilars deliver equivalent efficacy, safety, and immunogenicity to their originators, supporting their adoption as cost-saving alternatives in routine practice. Nonetheless, as the Cochrane authors highlighted, long-term data and real-world switching studies remain limited, and future research should address these evidence gaps to strengthen clinician confidence further ( 30 ). Clinical Relevance: The equivalence in efficacy, safety, and immunogenicity between biosimilars and their reference drugs has major clinical and public health implications. Anti-VEGF therapy represents one of the highest ongoing costs in ophthalmology, with patients often requiring lifelong injections. The availability of lower cost biosimilars can significantly reduce the financial burden on healthcare systems, improve patient access to timely treatment, and reduce undertreatment driven by cost constraints. Wider use of biosimilars could therefore translate into better population-level visual outcomes while optimizing resource utilization. Future Directions: Although our meta-analysis confirmed that biosimilars were equivalent to reference drugs in efficacy, safety, and immunogenicity, important evidence gaps remained. Future studies should evaluate long-term outcomes beyond one year to confirm the durability of visual gains and continued safety, including the risk of rare adverse events. More real-world studies are also needed to assess treatment patterns under treat-and-extend regimens, adherence, and outcomes after switching from originator to biosimilar therapy. Additionally, health-economic analyses quantifying cost savings and the impact on access to care will be crucial to inform policy decisions and optimize the use of biosimilars in routine practice. Conclusion This meta-analysis of 17 randomized controlled trials including 6,694 patients with neovascular age-related macular degeneration demonstrates that ranibizumab and aflibercept biosimilars provide equivalent efficacy, safety, and immunogenicity compared with their reference biologics. Visual acuity gains were comparable across groups, with most improvement achieved during the first 8–12 weeks of treatment. The incidence of anti-drug antibodies was low and not associated with loss of efficacy or increased adverse events, and the rates of ocular and systemic adverse events were similar between biosimilars and originators. These findings support the clinical adoption of anti-VEGF biosimilars as safe and effective, cost-saving alternatives that could improve access to therapy and reduce undertreatment. Future research should focus on long-term outcomes, real-world switching data, and health-economic analyses to guide sustainable implementation in routine practice. Declarations Author Contribution Author Contributions.Y.M.A.-S. conceived and designed the study and supervised the project. Y.M.A.-S., A.K.A., B.B.A., M.A.A.-A., and R.M.A.-N. performed the literature search, study selection, data extraction, and risk-of-bias assessment. Y.M.A.-D. and R.M.A.-N. conducted the statistical analyses and prepared the figures and tables. Y.M.A.-S. drafted the manuscript. All authors interpreted the results, revised the manuscript critically for important intellectual content, and approved the final version. Y.M.A.-S. is the guarantor of the work.Initials key:Y.M.A.-S. = Yousef Mesaed Al-Shammari;Y.M.A.-D. = Yousef M. AlDhafiri;A.K.A. = Abdullah Kamal Ahmad;B.B.A. = Basel Bader Alkharraz;M.A.A.-A. = Mohammed Ahmad Al-Awadhi;R.M.A.-N. = Rahed Mesaed Alnabhan. References Wong WL, Su X, Li X, Cheung CMG, Klein R, Cheng CY, et al. 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Supplementary Files supplements.docx Cite Share Download PDF Status: Published Journal Publication published 20 Mar, 2026 Read the published version in International Ophthalmology → Version 1 posted Editorial decision: Revision requested 04 Feb, 2026 Reviews received at journal 03 Feb, 2026 Reviewers agreed at journal 02 Feb, 2026 Reviews received at journal 19 Dec, 2025 Reviewers agreed at journal 08 Dec, 2025 Reviewers agreed at journal 03 Dec, 2025 Reviewers invited by journal 01 Dec, 2025 Editor assigned by journal 22 Oct, 2025 Submission checks completed at journal 22 Oct, 2025 First submitted to journal 20 Oct, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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5","display":"","copyAsset":false,"role":"figure","size":95460,"visible":true,"origin":"","legend":"\u003cp\u003eThe pooled effect of ranibizumab biosimilars in BCVA outcomes compared to their reference biologics in the first 12 weeks.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7909324/v1/1d21d3456da80dfccdddffd2.png"},{"id":97370567,"identity":"2cbea195-7b81-485d-a75f-8590c66f9b9c","added_by":"auto","created_at":"2025-12-03 16:27:36","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":186467,"visible":true,"origin":"","legend":"\u003cp\u003eThe pooled effect of anti-VEGF biosimilars in BCVA outcomes compared to their reference biologics.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-7909324/v1/65812203f7befd6623bd2fcc.png"},{"id":97344708,"identity":"d3d4727d-3124-42c8-9f6c-6ec31a18a43c","added_by":"auto","created_at":"2025-12-03 11:41:23","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":94589,"visible":true,"origin":"","legend":"\u003cp\u003eThe pooled effect of aflibercept biosimilars in BCVA outcomes compared to their reference biologics.\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-7909324/v1/aa60ea3a45098dbdc5fe3e9f.png"},{"id":97370666,"identity":"d37ae1c6-24e8-47cb-a929-94295e8057c1","added_by":"auto","created_at":"2025-12-03 16:27:45","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":135437,"visible":true,"origin":"","legend":"\u003cp\u003eThe pooled effect of ranibizumab biosimilars in BCVA outcomes compared to their reference biologics.\u003c/p\u003e","description":"","filename":"8.png","url":"https://assets-eu.researchsquare.com/files/rs-7909324/v1/18b0248fd50c48aade657e9f.png"},{"id":97344679,"identity":"f0d6dfb9-fc2b-4da7-af79-da6fab4c4b28","added_by":"auto","created_at":"2025-12-03 11:41:21","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":168064,"visible":true,"origin":"","legend":"\u003cp\u003eThe pooled effect of anti-VEGF biosimilars in the responders’ rate compared to their reference biologics.\u003c/p\u003e","description":"","filename":"9.png","url":"https://assets-eu.researchsquare.com/files/rs-7909324/v1/d970f82d07445f914d63917f.png"},{"id":97370330,"identity":"c098a1c4-6ab9-4d91-acc6-625472ac29da","added_by":"auto","created_at":"2025-12-03 16:27:10","extension":"png","order_by":10,"title":"Figure 10","display":"","copyAsset":false,"role":"figure","size":95441,"visible":true,"origin":"","legend":"\u003cp\u003eThe pooled effect of aflibercept biosimilars in the responders’ rate compared to their reference biologics.\u003c/p\u003e","description":"","filename":"10.png","url":"https://assets-eu.researchsquare.com/files/rs-7909324/v1/482fb2b00266c53460bae080.png"},{"id":97344681,"identity":"e9a23e32-b3b6-4627-b6e6-2e14ab327d63","added_by":"auto","created_at":"2025-12-03 11:41:22","extension":"png","order_by":11,"title":"Figure 11","display":"","copyAsset":false,"role":"figure","size":95012,"visible":true,"origin":"","legend":"\u003cp\u003eThe pooled effect of ranibizumab biosimilars in the responders’ rate compared to their reference biologics.\u003c/p\u003e","description":"","filename":"11.png","url":"https://assets-eu.researchsquare.com/files/rs-7909324/v1/cffba45bfc42aedfbaefed1b.png"},{"id":97344701,"identity":"4bd51c6d-6af6-4a36-9f52-336a3a78e1e4","added_by":"auto","created_at":"2025-12-03 11:41:22","extension":"png","order_by":12,"title":"Figure 12","display":"","copyAsset":false,"role":"figure","size":146494,"visible":true,"origin":"","legend":"\u003cp\u003eThe pooled effect of anti-VEGF biosimilars in the incidence of Treatment-Emergent ADAs compared to their reference biologics.\u003c/p\u003e","description":"","filename":"12.png","url":"https://assets-eu.researchsquare.com/files/rs-7909324/v1/b3ce7b064956eb359c48467f.png"},{"id":97344717,"identity":"559e6cad-5810-47e5-943d-a7b5a35d2462","added_by":"auto","created_at":"2025-12-03 11:41:23","extension":"png","order_by":13,"title":"Figure 13","display":"","copyAsset":false,"role":"figure","size":86783,"visible":true,"origin":"","legend":"\u003cp\u003eThe pooled effect of aflibercept biosimilars in the incidence of Treatment-Emergent ADAs compared to their reference biologics.\u003c/p\u003e","description":"","filename":"13.png","url":"https://assets-eu.researchsquare.com/files/rs-7909324/v1/65c1cddc9a7d25ed18a86bcb.png"},{"id":97370586,"identity":"2a532dd3-5e4a-4c8f-8106-5948bac847c6","added_by":"auto","created_at":"2025-12-03 16:27:39","extension":"png","order_by":14,"title":"Figure 14","display":"","copyAsset":false,"role":"figure","size":95053,"visible":true,"origin":"","legend":"\u003cp\u003eThe pooled effect of ranibizumab biosimilars in the incidence of Treatment-Emergent ADAs compared to their reference biologics.\u003c/p\u003e","description":"","filename":"14.png","url":"https://assets-eu.researchsquare.com/files/rs-7909324/v1/a13c7f902bc92b0e4452e711.png"},{"id":97344672,"identity":"1ac8f429-772c-4520-87f8-ff21eb651fb5","added_by":"auto","created_at":"2025-12-03 11:41:21","extension":"png","order_by":15,"title":"Figure 15","display":"","copyAsset":false,"role":"figure","size":199841,"visible":true,"origin":"","legend":"\u003cp\u003eThe pooled effect of anti-VEGF biosimilars in the incidence of ocular adverse events compared to their reference biologics.\u003c/p\u003e","description":"","filename":"15.png","url":"https://assets-eu.researchsquare.com/files/rs-7909324/v1/b353b7cf43a0b4ab333ea4bf.png"},{"id":97344727,"identity":"93c5b184-aa43-4d13-b796-1e51b0beb76e","added_by":"auto","created_at":"2025-12-03 11:41:23","extension":"png","order_by":16,"title":"Figure 16","display":"","copyAsset":false,"role":"figure","size":190749,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure 15: \u003c/strong\u003eThe pooled effect of anti-VEGF biosimilars in the incidence of serios ocular adverse events compared to their reference biologics.\u003c/p\u003e","description":"","filename":"16.png","url":"https://assets-eu.researchsquare.com/files/rs-7909324/v1/3e1d3010331d4515349526c1.png"},{"id":105223338,"identity":"0505bd66-3067-4c0c-9bfe-0686ee39be70","added_by":"auto","created_at":"2026-03-23 16:04:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2759863,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7909324/v1/efa0ec68-e7c1-4958-9c96-5e9385a371f4.pdf"},{"id":97369854,"identity":"4e3fb4f5-4f4d-4d02-be7e-c919992b3464","added_by":"auto","created_at":"2025-12-03 16:25:56","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":55561,"visible":true,"origin":"","legend":"","description":"","filename":"supplements.docx","url":"https://assets-eu.researchsquare.com/files/rs-7909324/v1/9b1da5cc05bd50c55e3e7141.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"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.","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eAge-related macular degeneration (AMD) is a progressive disease characterized by degeneration of the central area of the retina and the leading cause of visual impairment and blindness in the elderly population worldwide (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The retinal pigment epithelium (RPE) represents the central fulcrum of AMD pathogenesis. It is a key regulatory hub, integrating multiple cellular and molecular stimuli to maintain its own homeostasis while simultaneously transmitting signals to and from the surrounding retinal microenvironment. Ultimately, RPE dysfunction and degeneration constitute the irreversible, critical event that drives the progression of AMD (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). In AMD, vision loss is primarily caused by choroidal neovascularization (CNV), a VEGF-driven process central to the pathogenesis of neovascular AMD (nAMD) (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAMD is defined into stages based on fundus lesions within the macula: early AMD (medium drusen, 63\u0026ndash;125 \u0026micro;m, without pigmentary abnormalities), intermediate AMD (large drusen\u0026thinsp;\u0026gt;\u0026thinsp;125 \u0026micro;m and/or any pigmentary abnormalities), and late AMD, which encompasses both neovascular AMD and geographic atrophy (GA) (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Neovascular AMD, a late-stage subtype of the disease, is characterized by choroidal neovascularization with subretinal fluid leakage that distorts vision. It accounts for most severe AMD-related vision loss worldwide and substantially impacts quality of life and global economic productivity (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Unlike non-neovascular AMD, which had no approved treatments until the recent introduction of intravitreal pegcetacoplan, nAMD outcomes showed improvement in recent years specialty after anti-VEGF (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe treatment options for nAMD treatment include laser photocoagulation and photodynamic therapy. Repeated intravitreal anti-VEGF injections remain the gold standard (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). They work by inhibiting Vascular Endothelial Growth Factor-A (VEGF-A), a key driver of abnormal blood vessel growth (choroidal neovascularization) and leakage that causes vision loss. The primary goal is to stabilize and improve vision by reducing retinal fluid. These medications include ranibizumab (lucentis) and aflibercept (eylea) (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eA biosimilar is a biologic product highly comparable to an approved reference drug in chemical, physical, and biological characteristics, demonstrating equivalent safety, efficacy, and immunogenicity, while reducing treatment costs. Biosimilars are significantly cheaper to develop than the original innovator biologics, leading to an estimated reduction in treatment costs of more than 25%. In 2015, Razumab was the world's first biosimilar of ranibizumab (Lucentis) approved for use in ophthalmology and many more ophthalmic biosimilars are in the development (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eOverall, the evidence regarding anti-VEGF biosimilars in treating nAMD remains inconclusive. In this systematic review, we aim to make a better and more comprehensive understanding of the effect of anti-VEGF biosimilars by aggregating and analyzing all available evidence from multiple studies offering a consolidated, evidence-based foundation to guide treatment choices.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cp\u003eThis systematic review and meta-analysis was carried out following the PRISMA guidelines (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Search Strategy and Eligibility Criteria\u003c/h2\u003e\u003cp\u003eA systematic literature search was conducted to identify studies evaluating the efficacy and safety of anti-VEGF biosimilars in comparison with their reference biologics in treating nAMD. We searched PubMed, Scopus, and Cochrane library from inception through September 2025, using a combination of keywords and MeSH terms relevant to \"anti-VEGF biosimilar\" and \"age-related macular degeneration\". No language restrictions were applied. To ensure comprehensive coverage, we also manually reviewed the reference lists of included studies.\u003c/p\u003e\u003cp\u003eAll trials were phase 3, randomized, double-masked, multicenter clinical studies comparing a biosimilar anti-VEGF agent (either aflibercept or ranibizumab biosimilars) with the corresponding reference product (Eylea for aflibercept, Lucentis for ranibizumab). This design is considered the gold standard for demonstrating clinical equivalence.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Study Selection and Data Extraction\u003c/h2\u003e\u003cp\u003eTwo independent reviewers screened the identified records by title and abstract, followed by a full-text review to assess eligibility based on the predefined criteria. Disagreements were resolved through discussion with a third reviewer until consensus was achieved.\u003c/p\u003e\u003cp\u003eThe same reviewers, using a standardized Excel form, extracted relevant data independently. Extracted variables included study design, female percentage, NCT, number of patients, mean age, BCVA score at baseline, follow-up duration, country and biosimilar name. The outcomes included the change of BCVA in the first 12 weeks (most of the vision gain from anti-VEGF therapy occurs in the first few months), the change in BCVA from baseline to the end of the trial, responders\u0026rsquo; rates (the patients who gained\u0026thinsp;\u0026ge;\u0026thinsp;15 ETDRS letters, indicating a significant improvement in vision), ocular adverse events in the studied eye, serious adverse events in the studied eye and the incidence of Treatment-Emergent ADAs (how many patients developed anti-drug antibodies (ADAs) during the study after receiving the treatment). We used automeris.io to extract numerical information from charts.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Quality Assessment\u003c/h2\u003e\u003cp\u003eIn this meta-analysis, the methodological quality of the included randomized controlled trials was evaluated using the Cochrane Risk of Bias 2 (ROB-2) tool. Two independent reviewers assessed each study across the five ROB-2 domains: randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result. Any disagreements between reviewers were resolved by consensus or consultation with a third reviewer. Overall, the methods ensured a systematic and reproducible assessment of risk of bias, contributing to the robustness of the meta-analysis findings.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Statistical Analysis\u003c/h2\u003e\u003cp\u003eAll statistical analyses were conducted in R (version 4.1.2) using the metafor package (version 4.8-0) [14]. Continuous outcomes were summarized as mean difference (MDs) with 95% confidence intervals (CIs), calculated using the generic inverse variance method, while dichotomous variables were summarized using relative risk (RRs) with 95% confidence intervals (CIs), calculated using the generic inverse variance method. A random-effects model was applied to account for between-study variability. Heterogeneity was assessed with tau squared and quantified using the I\u0026sup2; statistic, where I\u0026sup2; \u0026gt;50% indicated moderate heterogeneity and I\u0026sup2; \u0026gt;90% indicated substantial heterogeneity. Statistical significance was set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Potential publication bias was explored visually using funnel plots. Sensitivity analyses were performed by sequentially omitting individual studies to evaluate the robustness of the pooled estimates. Meta-regression analyses were conducted to explore potential sources of heterogeneity by assessing the influence of study-level covariates on the pooled effect estimates. Subgrouping of the included studies into aflibercept biosimilars and ranibizumab biosimilars was conducted to detect any differences between these two biosimilars.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e3.1 Literature search results\u003c/h2\u003e\u003cp\u003eThe comprehensive literature search initially identified a total of 154 studies across three major databases: PubMed (n\u0026thinsp;=\u0026thinsp;79), Scopus (n\u0026thinsp;=\u0026thinsp;52), and Cochrane (n\u0026thinsp;=\u0026thinsp;23). Following the removal of duplicate records, 123 unique studies remained for further consideration. Title and abstract screening was then performed in accordance with the PRISMA guidelines, resulting in 40 studies eligible for full-text retrieval. After a rigorous full-text screening process, 10 studies published after June 2023 were identified and included in our study, in addition to the 7 studies included in the original review. Figure\u0026nbsp;1.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e3.2 Characteristics of the included studies\u003c/h2\u003e\u003cp\u003e Our review included 17 RCTs, published between 2020 and 2025, involving 6,694 patients with nAMD. All the included studies were randomized, double blind parallel group, multicentral, phase 3 RCTs (\u003cspan additionalcitationids=\"CR14 CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). These studies included many different biosimilars for ranibizumab and aflibercept with standardized medication doses (2 mg for aflibercept and aflibercept biosimilars and 0.5 mg for ranibizumab and ranibizumab biosimilars. Eight of the included studies were multinational (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e), 4 were conducted in India (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e) and 1 in Korea (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e), China (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), Iran (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) and Finland (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). All studies restricted patients to those over 50 years of age. The means of age were close in the included studies, approximately 69 years of age. The sample sizes ranged from 152 (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e) to 705 patients (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), while no study arm in any of the trials had fewer than 30 patients. The sex distribution did not exhibit a consistent trend, with some studies reporting a modest male predominance and others a modest female predominance. The mean baseline BCVA ranged from 42.5 to 61.7. And finally, the follow-up duration ranged from 12 weeks to 56 weeks with the 52 weeks and 48 weeks durations being the most common durations. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ebaseline characteristics of the included studies.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"15\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c15\" colnum=\"15\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudy ID\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIntervention\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eControl\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNCT\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCountry\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eStudy design\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMean age intervention\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMean age Control\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNumber of Intervention\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNumber of Control\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\"\u003e\u003cp\u003e% female intervention\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c12\"\u003e\u003cp\u003e% female control\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c13\"\u003e\u003cp\u003ebaseline BCVA intervention\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c14\"\u003e\u003cp\u003ebaseline BCVA control\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c15\"\u003e\u003cp\u003eFollow-up\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYoon et al. 2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCKD-701 (0.5 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ereference ranibizumab (0.5 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNCT04857177\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eKorea\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePhase 3 RCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e72.18 (8.09)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e71.91 (8.79)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e146\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e145\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e39.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e44.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e\u003cp\u003e59.38(13.10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e\u003cp\u003e60.19 (12.68)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e48 weeks\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLi et al. 2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eQL1207 (2 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ereference aflibercept (2 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNCT05345236\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eChina\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePhase 3 RCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e67.4 (8.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e67.1 (8.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e185\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e181\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e34.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e30.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e\u003cp\u003e56.1 (11.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e\u003cp\u003e56.1 (11.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e48 weeks\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKang et al. 2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSCD411 (2 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ereference aflibercept (2 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNCT04480463\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003emultinational\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePhase 3 RCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e73.5 (8.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e73.6 (8.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e287\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e286\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e51.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e51.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e\u003cp\u003e58.6 (10.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e\u003cp\u003e59.9 (10.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e52 weeks\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSadda et al. 2023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSB15 (2 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ereference aflibercept (2 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNCT04450329\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003emultinational\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePhase 3 RCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e73.7 (8.05)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e74.3 (8.09)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e224\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e225\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e52.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e58.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e\u003cp\u003e59.5 (10.60)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e\u003cp\u003e58.9 (11.19)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e56 weeks\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBordon et al. 2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSDZ-AFL (2 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ereference aflibercept (2 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNCT04864834\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003emultinational\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePhase 3 RCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e75.8 (7.82)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e75.7 (7.72)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e243\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e240\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e56.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e56.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e\u003cp\u003e59.7 (10.05)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e\u003cp\u003e59.4 (10.37)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e52 weeks\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLoewenstein et al. 2023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eXSB-001 (0.5 mg(\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ereference ranibizumab (0.5 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNCT03805100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003emultinational\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePhase 3 RCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e74.5 (8.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e73.8 (8.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e292\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e290\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e57.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e54.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e\u003cp\u003e61.7 (8.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e\u003cp\u003e61.5 (8.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e52 weeks\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSingh et al. 2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLupin\u0026rsquo;s biosimilar\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ereference ranibizumab (0.5 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eIndia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePhase 3 RCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e67.2 (10.29)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e67.2 (10.52)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e101\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e101\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e36.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e41.58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e12 weeks\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWoo et al. 2020\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSB11 (0.5 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ereference ranibizumab (0.5 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNCT03150589\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003emultinational\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePhase 3 RCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e74.1 (8.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e351\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e354\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e57.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e\u003cp\u003e58.3 (10.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e\u003cp\u003e58.3 (10.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e52 weeks\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKarkhaneh et al. 2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eP041 (2 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ereference aflibercept (2 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNCT05587062\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eIran\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePhase 3 RCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e68.64 (6.88)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e68.26 (6.24)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e30.95\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e44.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e\u003cp\u003e49.58 (13.82)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e\u003cp\u003e54.11 (13.60)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e52 weeks\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAgostini et al. 2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAVT06 (2 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ereference aflibercept (2 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNCT05155293\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003emultinational\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePhase 3 RCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e73.7 (9.11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e74.3 (8.04)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e205\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e205\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e50.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e56.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e\u003cp\u003e55.0 (12.07)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e\u003cp\u003e54.2 (12.38)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e48 weeks\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGhosh et al. 2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSun\u0026rsquo;s ranibizumab\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ereference ranibizumab (0.5 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eIndia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePhase 3 RCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e65.50 (9.78)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e67.96 (9.25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e107\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e42.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e37.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e\u003cp\u003e44.32 (12.78)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e\u003cp\u003e42.37 (11.44)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e16 weeks\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHamouz et al. 2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eQL1205 (0.5 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ereference ranibizumab (0.5 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003emultinational\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePhase 3 RCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e70.5 (9.47)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e72.2 (8.73)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e308\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e308\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e49.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e52.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e\u003cp\u003e55.6 (11.86)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e\u003cp\u003e55.1 (12.19)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e48 weeks\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHolz et al. 2021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFYB201 (0.5 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ereference ranibizumab (0.5 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNCT02611778\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFinland\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePhase 3 RCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e72.8 (8.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e74.1 (8.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e238\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e239\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e56.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e56.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e48 weeks\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eApsangikar et al. 2021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBiosimilar (0.5 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ereference ranibizumab (0.5 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eIndia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePhase 3 RCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e106\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e24 weeks\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUMIN000030010\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBiosimilar (0.5 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ereference ranibizumab (0.5 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eJapan\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePhase 3 RCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e74.4 (7.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e74.1 (7.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e176\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e175\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e52 weeks\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFriedman et al. 2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eABP 938 (2 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ereference aflibercept (2 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNCT04270747\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003emultinational\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePhase 3 RCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e76.0 (7.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e76.0 (8.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e288\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e288\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e52.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e59.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e\u003cp\u003e58.9 (10.68)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e\u003cp\u003e57.6 (11.74)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e48 weeks\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRana et al. 2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBiosimilar (0.5 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ereference ranibizumab (0.5 mg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eIndia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePhase 3 RCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e65.8 (9.04)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e68.8 (10.10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e114\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e42.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e42.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e\u003cp\u003e42.5 (11.42)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e\u003cp\u003e46.5 (11.65)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e12 weeks\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e3.3 Quality assessment\u003c/h2\u003e\u003cp\u003eThe methodological quality of the included randomized controlled trials was evaluated using the Cochrane Risk of Bias 2 (ROB-2) tool. Most studies were judged to have a low risk of bias across all five domains: bias arising from the randomization process (D1), bias due to deviations from intended interventions (D2), bias due to missing outcome data (D3), bias in measurement of the outcome (D4), and bias in selection of the reported result (D5). Four studies (Kang et al. 2024, Woo et al. 2020, Agostini et al. 2025, and Ghosh et al. 2024) were assessed as having \u0026ldquo;some concerns,\u0026rdquo; mainly in D1 or D5, indicating possible but not critical limitations (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Importantly, no study was rated as having a high risk of bias in any domain. Overall, the body of evidence can be considered robust, with a low likelihood that bias substantially influenced the pooled estimates. The domain-specific risk of bias judgments is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e3.4 Outcomes\u003c/h2\u003e\u003cdiv id=\"Sec12\" class=\"Section3\"\u003e\u003ch2\u003e3.4.1 The change of BCVA from baseline to week 12\u003c/h2\u003e\u003cp\u003eOur analysis of 12 studies including 4,524 nAMD patients demonstrated no clinically meaningful difference in BCVA outcomes between anti-VEGF biosimilars and their reference biologics in the first 12 weeks (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003e: MD = -0.42, 95% CI [-1.01; 0.18], P\u0026thinsp;=\u0026thinsp;0.17). Moderate-high heterogeneity was detected (tau\u003csup\u003e2\u003c/sup\u003e: 0.49, I\u003csup\u003e2\u003c/sup\u003e: 48.47%). The sensitivity analysis revealed no significant differences when excluding any of the included studies, as none of the included studies was considered influential.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe subgrouping of the included studies into aflibercept biosimilars and ranibizumab biosimilars revealed no statically significant differences too. Our analysis demonstrated no clinically meaningful difference in BCVA outcomes between aflibercept biosimilars and reference aflibercept in the first 12 weeks (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e: MD = -0.3, 95% CI [-0.96; 0.37], P\u0026thinsp;=\u0026thinsp;0.38, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.00%). Also, our analysis demonstrated no clinically meaningful difference in BCVA outcomes between ranibizumab biosimilars and reference ranibizumab in the first 12 weeks (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e5\u003c/span\u003e: MD = -0.52, 95% CI [-1.49; 0.46], P\u0026thinsp;=\u0026thinsp;0.3, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;68.06%).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eWe performed meta-regression to explore the potential effect of the mean age, female percentage, baseline BCVA and follow-up duration on the improvement of BCVA outcomes and the heterogeneity across studies. The results of the regression demonstrated that mean age, baseline BCVA and follow-up duration did not demonstrate statistically significant association with the improvement of BCVA outcomes (follow-up: slope = -0.038, 95% CI [-0.09; 0.01], P\u0026thinsp;=\u0026thinsp;0.16, age: slope = -0.17, 95% CI [-0.38; 0.04], P\u0026thinsp;=\u0026thinsp;0.11 and baseline BCVA: slope = -0.07, 95% CI [-0.24; 0.11], P\u0026thinsp;=\u0026thinsp;0.46). Also, these moderators did not significantly explain the heterogeneity as it remained high after including these moderators (follow-up: I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;46.32%, age: I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;45.40% and baseline BCVA: I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;53.90%). While the female percentage demonstrated a statistically significant association with the improvement of BCVA outcomes (slope = -0.0853, 95% CI [-0.14; -0.03], P\u0026thinsp;=\u0026thinsp;0.002) and significantly explained the heterogeneity as it became very low after including this moderator (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;13.38%).\u003c/p\u003e\u003cp\u003eEgger\u0026rsquo;s test indicated no evidence of significant publication bias (p\u0026thinsp;=\u0026thinsp;0.40). Visual inspection of the funnel plot revealed a reasonably symmetrical distribution of studies. The trim-and-fill analysis suggested that no studies were missing, supporting the robustness of the findings. \u003cb\u003e(supplements: Funnel 1).\u003c/b\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section3\"\u003e\u003ch2\u003e3.4.2 The change of BCVA from baseline to the end of the trial\u003c/h2\u003e\u003cp\u003eOur analysis of 15 studies including 5,965 nAMD patients demonstrated no clinically meaningful difference in the BCVA outcomes between anti-VEGF biosimilars and their reference biologics (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e6\u003c/span\u003e: MD = -0.32, 95% CI [-0.85; 0.20], P\u0026thinsp;=\u0026thinsp;0.23). Low-moderate heterogeneity was detected (tau\u003csup\u003e2\u003c/sup\u003e: 0.29, I\u003csup\u003e2\u003c/sup\u003e: 28.62%). The sensitivity analysis revealed no significant differences when excluding any of the included studies, as none of the included studies was considered influential.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe subgrouping of the included studies into aflibercept biosimilars and ranibizumab biosimilars revealed some different findings. Our analysis demonstrated no clinically meaningful difference in BCVA outcomes between aflibercept biosimilars and reference aflibercept (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e7\u003c/span\u003e: MD\u0026thinsp;=\u0026thinsp;0.03, 95% CI [-0.88; 0.94], P\u0026thinsp;=\u0026thinsp;0.95, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;38.89%). But our analysis demonstrated that ranibizumab biosimilars showed a significantly lesser improvement in the BCVA outcomes reference ranibizumab (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e8\u003c/span\u003e: MD = -0.63, 95% CI [-1.18; -0.07], P\u0026thinsp;=\u0026thinsp;0.03, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.00%).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eWe performed meta-regression to explore the potential effect of the mean age, female percentage, baseline BCVA and follow-up duration on the improvement of BCVA outcomes and the heterogeneity across studies. The results of the regression demonstrated that mean age, baseline BCVA, female percentage and follow-up duration did not demonstrate statistically significant association with the improvement of BCVA outcomes (follow-up: slope = -0.028, 95% CI [-0.08; 0.02], P\u0026thinsp;=\u0026thinsp;0.28, age: slope = -0.10, 95% CI [-0.31; 0.09], P\u0026thinsp;=\u0026thinsp;0.31, female percentage: slope = -0.03, 95% CI [-0.10; 0.04], P\u0026thinsp;=\u0026thinsp;0.37 and baseline BCVA: slope = -0.04, 95% CI [-0.20; 0.12], P\u0026thinsp;=\u0026thinsp;0.63). Also, these moderators did not significantly explain the heterogeneity as it remained high after including these moderators (follow-up: I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;31.27%, age: I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;31.56%, female percentage: I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;31.46% and baseline BCVA: I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;34.26%).\u003c/p\u003e\u003cp\u003eEgger\u0026rsquo;s test indicated no evidence of significant publication bias (p\u0026thinsp;=\u0026thinsp;0.66). Visual inspection of the funnel plot revealed a reasonably symmetrical distribution of studies. The trim-and-fill analysis suggested that no studies were missing, supporting the robustness of the findings. \u003cb\u003e(supplements: Funnel 2).\u003c/b\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section3\"\u003e\u003ch2\u003e3.4.3 The responders\u0026rsquo; rate (\u0026ge;\u0026thinsp;15-letter gain)\u003c/h2\u003e\u003cp\u003eOur analysis of 11 studies including 4,333 nAMD patients demonstrated no clinically meaningful difference in the responders\u0026rsquo; rates between anti-VEGF biosimilars and their reference biologics (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e9\u003c/span\u003e: RR\u0026thinsp;=\u0026thinsp;1.06, 95% CI [0.93; 1.22], P\u0026thinsp;=\u0026thinsp;0.36). Low-moderate heterogeneity was detected (tau\u003csup\u003e2\u003c/sup\u003e: 0.02, I\u003csup\u003e2\u003c/sup\u003e: 30.76%). The sensitivity analysis revealed no significant differences when excluding any of the included studies, as none of the included studies was considered influential.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe subgrouping of the included studies into aflibercept biosimilars and ranibizumab biosimilars revealed no statically significant differences too. Our analysis demonstrated no clinically meaningful difference in the responders\u0026rsquo; rates between aflibercept biosimilars and reference aflibercept (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e10\u003c/span\u003e: RR\u0026thinsp;=\u0026thinsp;1.11, 95% CI [0.86; 1.42], P\u0026thinsp;=\u0026thinsp;0.42, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;55.97%). Also, our analysis demonstrated no clinically meaningful difference in the responders\u0026rsquo; rates between ranibizumab biosimilars and reference ranibizumab in the first 12 weeks (Fig.\u0026nbsp;\u003cspan refid=\"Fig10\" class=\"InternalRef\"\u003e11\u003c/span\u003e: RR\u0026thinsp;=\u0026thinsp;1.02, 95% CI [0.89; 1.18], P\u0026thinsp;=\u0026thinsp;0.74, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.00%).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eWe performed meta-regression to explore the potential effect of the mean age, female percentage, baseline BCVA and follow-up duration on the responders\u0026rsquo; rates and the heterogeneity across studies. The results of the regression demonstrated that baseline BCVA, female percentage and follow-up duration did not demonstrate statistically significant association with the responders\u0026rsquo; rates (follow-up: slope\u0026thinsp;=\u0026thinsp;0.0, 95% CI [-0.01; 0.01], P\u0026thinsp;=\u0026thinsp;0.91, female percentage: slope = -0.01, 95% CI [-0.03; 0.001], P\u0026thinsp;=\u0026thinsp;0.07 and baseline BCVA: slope = -0.02, 95% CI [-0.04; 0.01], P\u0026thinsp;=\u0026thinsp;0.20). The female percentage, mean age and baseline BCVA significantly explained the heterogeneity across studies (age: I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;3.44%, female percentage: I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;4.47% and baseline BCVA: I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;18.05%), while the follow-up duration did not significantly explain the heterogeneity across studies (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;37.42%.) Finally, the mean age demonstrated a statistically significant association with the responders\u0026rsquo; rates (slope = -0.04, 95% CI [-0.08; -0.0002], P\u0026thinsp;=\u0026thinsp;0.049).\u003c/p\u003e\u003cp\u003eEgger\u0026rsquo;s test indicated no evidence of significant publication bias (p\u0026thinsp;=\u0026thinsp;0.3). Visual inspection of the funnel plot revealed some asymmetrical distribution of studies. The trim-and-fill analysis suggested that 2 studies were missing from the left side of the funnel plot, which did not significantly influence the results of the responders\u0026rsquo; rate (RR\u0026thinsp;=\u0026thinsp;1.02, P\u0026thinsp;=\u0026thinsp;0.83, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;38.14%), supporting the robustness of the findings. \u003cb\u003e(supplements: Funnel 3 \u0026amp; 4).\u003c/b\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section3\"\u003e\u003ch2\u003e3.4.4 The incidence of Treatment-Emergent ADAs\u003c/h2\u003e\u003cp\u003eOur analysis of 11 studies including 4,627 nAMD patients demonstrated no clinically meaningful difference in the incidence of Treatment-Emergent ADAs between anti-VEGF biosimilars and their reference biologics (Fig.\u0026nbsp;\u003cspan refid=\"Fig11\" class=\"InternalRef\"\u003e12\u003c/span\u003e: RR\u0026thinsp;=\u0026thinsp;0.89, 95% CI [0.67; 1.17], P\u0026thinsp;=\u0026thinsp;0.40). Very low heterogeneity was detected (tau\u003csup\u003e2\u003c/sup\u003e: 0.0, I\u003csup\u003e2\u003c/sup\u003e: 0.00%). The sensitivity analysis revealed no significant differences when excluding any of the included studies, as none of the included studies was considered influential.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe subgrouping into aflibercept biosimilars and ranibizumab biosimilars (Fig.\u0026nbsp;\u003cspan refid=\"Fig12\" class=\"InternalRef\"\u003e13\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig13\" class=\"InternalRef\"\u003e14\u003c/span\u003e) and meta-regression on the mean age, female percentage, baseline BCVA and follow-up duration of the included studies revealed no statically significant differences.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eEgger\u0026rsquo;s test indicated no evidence of significant publication bias (p\u0026thinsp;=\u0026thinsp;0.4). Visual inspection of the funnel plot revealed some asymmetrical distribution of studies. The trim-and-fill analysis suggested that 1 study was missing from the right side of the funnel plot, which did not significantly influence the results of the incidence of Treatment-Emergent ADAs (RR\u0026thinsp;=\u0026thinsp;0.91, P\u0026thinsp;=\u0026thinsp;0.51, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.00%), supporting the robustness of the findings. \u003cb\u003e(supplements: Funnel 5 \u0026amp; 6).\u003c/b\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section3\"\u003e\u003ch2\u003e3.4.5 Ocular and serious ocular adverse effects of the studied eye\u003c/h2\u003e\u003cp\u003eOur analysis demonstrated no clinically meaningful difference in the incidence of ocular adverse events in the studied eye between anti-VEGF biosimilars and their reference biologics (Fig.\u0026nbsp;\u003cspan refid=\"Fig15\" class=\"InternalRef\"\u003e15\u003c/span\u003e: RR\u0026thinsp;=\u0026thinsp;0.99, 95% CI [0.91; 1.08], P\u0026thinsp;=\u0026thinsp;0.86, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.02%). Also, our analysis demonstrated no clinically meaningful difference in the incidence of serious ocular adverse events in the studied eye between anti-VEGF biosimilars and their reference biologics (Fig.\u0026nbsp;16: RR\u0026thinsp;=\u0026thinsp;1.06, 95% CI [0.81; 1.40], P\u0026thinsp;=\u0026thinsp;0.67, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.02%). Very low heterogeneity was detected in both ocular adverse events and serious ocular adverse events. The sensitivity analysis revealed no significant differences when excluding any of the included studies in both ocular adverse events and serious ocular adverse events.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe subgrouping into aflibercept biosimilars and ranibizumab biosimilars (Fig.\u0026nbsp;17, \u003cb\u003eFig.\u0026nbsp;18\u003c/b\u003e) and meta-regression on the mean age, female percentage, baseline BCVA and follow-up duration of the included studies revealed no statically significant differences.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis systematic review provides the most recent evidence regarding the efficacy and safety of anti-VEGF in treating nAMD. nAMD is an aggressive form of AMD and one of the leading causes of irreversible central vision loss in people over 50 years. The gold standard for nAMD treatment is anti-VEGF therapy, but it is one of the most expensive chronic treatments in ophthalmology. Biosimilars are entering the market specifically to lower costs and expand access as an alternative for the reference.\u003c/p\u003e\u003cp\u003eAflibercept and ranibizumab are both anti-VEGF therapies for nAMD, but they differ in structure and treatment schedule. Aflibercept is a recombinant fusion protein that acts as a trap binding VEGF-A, VEGF-B, and placental growth factor, whereas ranibizumab is a monoclonal antibody fragment that selectively binds VEGF-A. Aflibercept is typically dosed every 8 weeks after a 3-dose loading phase, reducing the injection burden, while ranibizumab is often given monthly but can also follow treat-and-extend or less frequent maintenance regimens based on disease activity (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAcross all included trials, anti-VEGF therapy was administered via intravitreal injection at the reference product dose (0.5 mg ranibizumab biosimilars; 2.0 mg aflibercept biosimilars). Most studies used three monthly loading doses, followed by either fixed dosing (monthly or every 2 months) or switched to giving injections only when fluid or vision changes were found during eye scans. Thus, differences in outcomes across studies are unlikely to be explained by differences in route or dosing, but rather by population characteristics and maintenance regimen (\u003cspan additionalcitationids=\"CR14 CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eOur analysis demonstrated no clinically meaningful difference in BCVA outcomes between anti-VEGF biosimilars and their reference biologics, neither in the first 12 weeks (MD = -0.42, P\u0026thinsp;=\u0026thinsp;0.17, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;48%) nor to the end of the trial (MD =-0.32, P\u0026thinsp;=\u0026thinsp;0.23, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;29%). Most of the included studies showed the same conclusion, suggesting that the findings are robust and consistent across different cases. Mean age, follow-up and BCVA score at baseline did not significantly influence the change of BCVA score or explain the heterogeneity detected across studies, but interestingly studies with a higher female percentage tend to have a lesser improvement in the BCVA score in the first 12 weeks (slope = -0.0853, P\u0026thinsp;=\u0026thinsp;0.002). Also, the subgrouping of studies into aflibercept biosimilars and ranibizumab biosimilars demonstrated that the effect of aflibercept biosimilars was significantly superior, as aflibercept biosimilars were not significantly different than their reference, while ranibizumab biosimilars were significantly inferior to their reference.\u003c/p\u003e\u003cp\u003eNoticeably, all trials reported that most BCVA gain occurred within the first 8\u0026ndash;12 weeks in all trials in all anti-VEGF biosimilars kinds, corresponding to the loading phase. Our findings support the concept that early response is a reliable surrogate for long-term efficacy and may guide clinicians in identifying poor responders who might benefit from treatment modification or switching strategies (\u003cspan additionalcitationids=\"CR14 CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eOur analysis demonstrated no clinically meaningful difference in the responders\u0026rsquo; rate between anti-VEGF biosimilars and their reference biologics (RR\u0026thinsp;=\u0026thinsp;1.06, P\u0026thinsp;=\u0026thinsp;0.36, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;30%). All included studies showed the same conclusion, suggesting that the findings are robust and consistent across different cases. Female percentage, follow-up subgrouping into aflibercept biosimilars and ranibizumab biosimilars and BCVA score at baseline did not significantly influence the responders\u0026rsquo; rate, while the mean age demonstrated a statistically significant association with the responders\u0026rsquo; rates (slope = -0.04, P\u0026thinsp;=\u0026thinsp;0.049).\u003c/p\u003e\u003cp\u003eOur analysis demonstrated no clinically meaningful difference in the incidence of Treatment-Emergent ADAs between anti-VEGF biosimilars and their reference biologics (RR\u0026thinsp;=\u0026thinsp;0.89, P\u0026thinsp;=\u0026thinsp;0.40, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.00%). All trials confirmed that the immunogenicity of ranibizumab and aflibercept biosimilars was minimal and clinically irrelevant, as the proportion of patients who developed treatment-emergent anti-drug antibodies was low (1\u0026ndash;6%). This finding should reassure clinicians that switching from the reference product to a biosimilar does not increase the risk of immune-mediated loss of efficacy or safety concerns.\u003c/p\u003e\u003cp\u003eOur analysis demonstrated no clinically meaningful difference in the incidence of ocular adverse events (RR\u0026thinsp;=\u0026thinsp;0.99, P\u0026thinsp;=\u0026thinsp;0.86, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.02%) and serious ocular adverse events (RR\u0026thinsp;=\u0026thinsp;1.06, P\u0026thinsp;=\u0026thinsp;0.67, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.02%) in the studied eye between anti-VEGF biosimilars and their reference biologics. The most commonly reported mild adverse events were conjunctival hemorrhage, eye pain or discomfort after injection and increased intraocular pressure shortly after injection, while endophthalmitis, retinal detachment and intraocular hemorrhage were the most common serious ocular adverse events, even though the incidence rates were very low. These findings confirmed that biosimilars did not pose additional ocular or systemic risks compared with their reference products. These findings were important for clinicians who may hesitate to switch stable patients to a biosimilar due to safety concerns. Long-term real-world data will still be valuable to monitor for very rare events.\u003c/p\u003e\u003cp\u003eOur findings were consistent with the most recent Cochrane review of anti-VEGF biosimilars in nAMD, which pooled data from nine randomized trials including more than 3,800 eyes. That review confirmed that biosimilars match their reference products in terms of visual acuity gain at 8\u0026ndash;12 weeks, prevention of vision loss at one year, and reduction in retinal thickness, with no clinically meaningful differences. Importantly, rates of ocular and systemic adverse events were similar between groups, and the incidence of treatment-emergent anti-drug antibodies was low and comparable. Taken together, these results reinforce that biosimilars deliver equivalent efficacy, safety, and immunogenicity to their originators, supporting their adoption as cost-saving alternatives in routine practice. Nonetheless, as the Cochrane authors highlighted, long-term data and real-world switching studies remain limited, and future research should address these evidence gaps to strengthen clinician confidence further (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eClinical Relevance:\u003c/p\u003e\u003cp\u003eThe equivalence in efficacy, safety, and immunogenicity between biosimilars and their reference drugs has major clinical and public health implications. Anti-VEGF therapy represents one of the highest ongoing costs in ophthalmology, with patients often requiring lifelong injections. The availability of lower cost biosimilars can significantly reduce the financial burden on healthcare systems, improve patient access to timely treatment, and reduce undertreatment driven by cost constraints. Wider use of biosimilars could therefore translate into better population-level visual outcomes while optimizing resource utilization.\u003c/p\u003e\u003cp\u003eFuture Directions:\u003c/p\u003e\u003cp\u003eAlthough our meta-analysis confirmed that biosimilars were equivalent to reference drugs in efficacy, safety, and immunogenicity, important evidence gaps remained. Future studies should evaluate long-term outcomes beyond one year to confirm the durability of visual gains and continued safety, including the risk of rare adverse events. More real-world studies are also needed to assess treatment patterns under treat-and-extend regimens, adherence, and outcomes after switching from originator to biosimilar therapy. Additionally, health-economic analyses quantifying cost savings and the impact on access to care will be crucial to inform policy decisions and optimize the use of biosimilars in routine practice.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis meta-analysis of 17 randomized controlled trials including 6,694 patients with neovascular age-related macular degeneration demonstrates that ranibizumab and aflibercept biosimilars provide equivalent efficacy, safety, and immunogenicity compared with their reference biologics. Visual acuity gains were comparable across groups, with most improvement achieved during the first 8\u0026ndash;12 weeks of treatment. The incidence of anti-drug antibodies was low and not associated with loss of efficacy or increased adverse events, and the rates of ocular and systemic adverse events were similar between biosimilars and originators. These findings support the clinical adoption of anti-VEGF biosimilars as safe and effective, cost-saving alternatives that could improve access to therapy and reduce undertreatment. Future research should focus on long-term outcomes, real-world switching data, and health-economic analyses to guide sustainable implementation in routine practice.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAuthor Contributions.Y.M.A.-S. conceived and designed the study and supervised the project. Y.M.A.-S., A.K.A., B.B.A., M.A.A.-A., and R.M.A.-N. performed the literature search, study selection, data extraction, and risk-of-bias assessment. Y.M.A.-D. and R.M.A.-N. conducted the statistical analyses and prepared the figures and tables. Y.M.A.-S. drafted the manuscript. All authors interpreted the results, revised the manuscript critically for important intellectual content, and approved the final version. Y.M.A.-S. is the guarantor of the work.Initials key:Y.M.A.-S. = Yousef Mesaed Al-Shammari;Y.M.A.-D. = Yousef M. AlDhafiri;A.K.A. = Abdullah Kamal Ahmad;B.B.A. = Basel Bader Alkharraz;M.A.A.-A. = Mohammed Ahmad Al-Awadhi;R.M.A.-N. = Rahed Mesaed Alnabhan.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWong WL, Su X, Li X, Cheung CMG, Klein R, Cheng CY, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2(2):e106\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSchmidt-Erfurth U, Chong V, Loewenstein A, Larsen M, Souied E, Schlingemann R, et al. Guidelines for the management of neovascular age-related macular degeneration by the European Society of Retina Specialists (EURETINA). British Journal of Ophthalmology. 2014;98(9):1144\u0026ndash;67.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAmbati J, Fowler BJ. Mechanisms of Age-Related Macular Degeneration. Neuron. 2012;75(1):26\u0026ndash;39.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, et al. Vascular Endothelial Growth Factor in Ocular Fluid of Patients with Diabetic Retinopathy and Other Retinal Disorders. New England Journal of Medicine. 1994;331(22):1480\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFerris FL, Wilkinson CP, Bird A, Chakravarthy U, Chew E, Csaky K, et al. Clinical Classification of Age-related Macular Degeneration. Ophthalmology. 2013;120(4):844\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMarques AP, Ramke J, Cairns J, Butt T, Zhang JH, Muirhead D, et al. Global economic productivity losses from vision impairment and blindness. EClinicalMedicine. 2021;35:100852.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSolomon SD, Lindsley K, Vedula SS, Krzystolik MG, Hawkins BS. Anti-vascular endothelial growth factor for neovascular age-related macular degeneration. Cochrane Database of Systematic Reviews. 2019;2019(3).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSchmidt-Erfurth U, Garcia-Arumi J, Bandello F, Berg K, Chakravarthy U, Gerendas BS, et al. Guidelines for the Management of Diabetic Macular Edema by the European Society of Retina Specialists (EURETINA). Ophthalmologica. 2017;237(4):185\u0026ndash;222.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKhanna S, Komati R, Eichenbaum DA, Hariprasad I, Ciulla TA, Hariprasad SM. Current and upcoming anti-VEGF therapies and dosing strategies for the treatment of neovascular AMD: a comparative review. BMJ Open Ophthalmol. 2019;4(1):e000398.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGIULIANI J, BONETTI A. The Economic Impact of Biosimilars in Oncology and Hematology: The Case of Trastuzumab and Rituximab. Anticancer Res. 2019;39(7):3971\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSharma A, Kumar N, Kuppermann BD, Bandello F, Loewenstein A. Understanding biosimilars and its regulatory aspects across the globe: an ophthalmology perspective. British Journal of Ophthalmology. 2020;104(1):2\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePage MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;n71.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWoo SJ, Veith M, Hamouz J, Ernest J, Zalewski D, Studnička J, et al. Efficacy and Safety of a Proposed Ranibizumab Biosimilar Product vs a Reference Ranibizumab Product for Patients with Neovascular Age-Related Macular Degeneration: A Randomized Clinical Trial. JAMA Ophthalmol. 2021;139(1):68\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLi B, Fan K, Zhang T, Wu Z, Zeng S, Zhao M, et al. Efficacy and Safety of Biosimilar QL1207 vs. the Reference Aflibercept for Patients with Neovascular Age-Related Macular Degeneration: A Randomized Phase 3 Trial. Ophthalmol Ther. 2024;13(1):353\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWoo SJ, Sadda SVR, Bradvica M, Vajas A, Sagong M, Ernest J, et al. Biosimilar SB15 versus reference aflibercept in neovascular age-related macular degeneration: 1-year and switching results of a phase 3 clinical trial. BMJ Open Ophthalmol. 2023;8(1).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLoewenstein A, Czumbel N, Ernest J, Dusov\u0026aacute; J, Pearlman J, Nowosielska A. Randomized Trial of Biosimilar XSB-001 versus Reference Ranibizumab in Patients with Neovascular Age-Related Macular Degeneration. In: Ophthalmology Retina. Elsevier Inc.; 2023. p. 753\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKang SW, Choi J, Sheth VS, Nowosielska A, Misiuk-Hojlo M, Papp A, et al. Comparison of the efficacy and safety of SCD411 and reference aflibercept in patients with neovascular age-related macular degeneration. Sci Rep. 2024;14(1).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYoon CK, Oh J, Bae K, Park UC, Yu KS, Yu HG. Efficacy and safety of a new ranibizumab biosimilar CKD-701 using a pro re nata treatment regimen in neovascular age-related macular degeneration: A phase 3 randomized clinical trial. PLoS One. 2022;17(11 November).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSingh R, Chauhan R, Saxena A, Shah A, Mondal L, Bakhle D, et al. A prospective, randomized, parallel group, double blind, multicenter study to compare the efficacy, safety and immunogenicity of Lupin\u0026rsquo;s Ranibizumab with Lucentis \u0026reg; in patients with neovascular age-related macular degeneration. Indian J Ophthalmol. 2022;70(8):3008\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBordon AF, Kaiser PK, Wolf A, Cen L, Heyn J, Dodeller F, et al. EFFICACY AND SAFETY OF THE PROPOSED BIOSIMILAR AFLIBERCEPT, SDZ-AFL, IN PATIENTS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION 52-Week Results From the Phase 3 Mylight Study [Internet]. Vol. 44, RETINA. 2024. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://links.lww.com/IAE/C274\u003c/span\u003e\u003cspan address=\"http://links.lww.com/IAE/C274\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKarkhaneh R, Faghihi H, Riazi-Esfahani H, Abrishami M, Bazvand F, Ebrahimiadib N, et al. Evaluating the Efficacy and Safety of Aflibercept Biosimilar (P041) Compared with Originator Product in Patients with Neovascular Age-Related Macular Degeneration. Ophthalmol Retina. 2024;8(8):744\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAgostini H, Baumane K, Balčiūnienė VJ, Ozols K, Soni R, Hamdi S, et al. A randomized, double-masked parallel-group, multicenter clinical study evaluating the efficacy and safety of the biosimilar candidate AVT06 compared to the reference product aflibercept in participants with neovascular age-related macular degeneration. Expert Opin Biol Ther. 2025;25(7):773\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGhosh AK, Nikumbh US, Shukla CK, Laul RS, Dixit A, Mahapatra SK, et al. Efficacy, Safety and Immunogenicity of Sun\u0026rsquo;s Ranibizumab Biosimilar in Neovascular Age-Related Macular Degeneration: A Phase 3, Double-Blind Comparative Study. Ophthalmol Ther. 2024;13(5):1369\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHamouz J, Nowosielska A, Święch-Zubilewicz A, Abengoechea S, Baumane K, Vajas A, et al. Efficacy and Safety of Ranibizumab Biosimilar QL1205 in Neovascular Age-Related Macular Degeneration: A Phase III Randomized Trial. Ophthalmol Retina. 2025;9(4):343\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHolz FG, Oleksy P, Ricci F, Kaiser PK, Kiefer J, Schmitz-Valckenberg S. Efficacy and Safety of Biosimilar FYB201 Compared with Ranibizumab in Neovascular Age-Related Macular Degeneration. Ophthalmology. 2022;129(1):54\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eApsangikar P, Ghadge P, Naik M, Nair S, Payghan R. Randomised, Double-blind, Comparative Clinical Study of New Ranibizumab Biosimilar in Neovascular (Wet) Age-Related Macular Degeneration. Clinical Ophthalmology. 2021;Volume 15:3087\u0026ndash;95.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eUMIN Clinical Trials Registry. A phase III study to evaluate the equivalence in efficacy and safety of SJP-0133 to Lucentis in patients with age-related macular degeneration. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034245\u003c/span\u003e\u003cspan address=\"https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034245\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. 2017;\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFriedman S, London N, Hamouz J, Ker\u0026eacute;nyi \u0026Aacute;, Papp A, Pregun T, et al. Randomized Trial of Biosimilar ABP 938 Compared with Reference Aflibercept in Adults with Neovascular Age-related Macular Degeneration. Ophthalmol Retina. 2025;\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRana P, Deshmukh H, Shah U, Kumar V, Kanungo S, Singhal D, et al. Efficacy and Safety of Biosimilar Ranibizumab (OPTIMAB\u0026reg;) versus Innovator Ranibizumab in Patients with Neovascular (Wet) Age-Related Macular Degeneration: A Double-Blind, Randomized, Multicenter, Phase III Study. Clinical Ophthalmology. 2024;Volume 18:3071\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSunaga T, Maeda M, Saulle R, Ng SM, Sato MT, Hasegawa T, et al. Anti-vascular endothelial growth factor biosimilars for neovascular age-related macular degeneration. Cochrane Database of Systematic Reviews. 2024;2024(7).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"inte","sideBox":"Learn more about [International Ophthalmology](https://www.springer.com/journal/10792)","snPcode":"10792","submissionUrl":"https://submission.nature.com/new-submission/10792/3","title":"International Ophthalmology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7909324/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7909324/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eNeovascular 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.\u003c/p\u003e\u003ch2\u003ePurpose\u003c/h2\u003e\u003cp\u003eTo 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).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe 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\u0026ndash;September 2025) was performed following PRISMA guidelines. Outcomes included change in best-corrected visual acuity (BCVA) at 12 weeks and study endpoint, \u0026ge;\u0026thinsp;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.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eSeventeen 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\u0026thinsp;=\u0026thinsp;0.17) or at study endpoint (MD =-0.32, p\u0026thinsp;=\u0026thinsp;0.23) between biosimilars and reference biologics. Responder rates (\u0026ge;\u0026thinsp;15-letter gain) were comparable (RR\u0026thinsp;=\u0026thinsp;1.06, p\u0026thinsp;=\u0026thinsp;0.36), as were rates of treatment-emergent ADAs (RR\u0026thinsp;=\u0026thinsp;0.89, p\u0026thinsp;=\u0026thinsp;0.40) and ocular adverse events (RR\u0026thinsp;=\u0026thinsp;0.99, p\u0026thinsp;=\u0026thinsp;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\u0026thinsp;=\u0026thinsp;0.53, p\u0026thinsp;=\u0026thinsp;0.02). Heterogeneity was generally low to moderate, and no significant publication bias was detected.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eOur 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.\u003c/p\u003e","manuscriptTitle":"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.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-03 11:41:16","doi":"10.21203/rs.3.rs-7909324/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-04T21:00:03+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-03T23:56:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"74367987145235443208855466965572322868","date":"2026-02-03T00:43:53+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-19T08:31:05+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"214791856380255380583276896572720567616","date":"2025-12-08T07:55:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"141397814305680401615928244447661428149","date":"2025-12-03T13:28:51+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-01T14:53:11+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-22T08:18:01+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-22T08:17:40+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Ophthalmology","date":"2025-10-21T01:01:01+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"inte","sideBox":"Learn more about [International Ophthalmology](https://www.springer.com/journal/10792)","snPcode":"10792","submissionUrl":"https://submission.nature.com/new-submission/10792/3","title":"International Ophthalmology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"0b1f0186-7c46-4bc3-a3ea-e62e718d1e04","owner":[],"postedDate":"December 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-23T16:01:16+00:00","versionOfRecord":{"articleIdentity":"rs-7909324","link":"https://doi.org/10.1007/s10792-026-04043-5","journal":{"identity":"international-ophthalmology","isVorOnly":false,"title":"International Ophthalmology"},"publishedOn":"2026-03-20 15:57:50","publishedOnDateReadable":"March 20th, 2026"},"versionCreatedAt":"2025-12-03 11:41:16","video":"","vorDoi":"10.1007/s10792-026-04043-5","vorDoiUrl":"https://doi.org/10.1007/s10792-026-04043-5","workflowStages":[]},"version":"v1","identity":"rs-7909324","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7909324","identity":"rs-7909324","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}