Department of Hospital Pharmaceutics, School of Pharmacy, Showa University, Tokyo, Japan.
Division of Infection Control Sciences, Department of Clinical Pharmacy, School of Pharmacy, Showa University, Tokyo, Japan.
Cochrane Database Syst Rev. 2024 Jun 3;6(6):CD015804. doi: 10.1002/14651858.CD015804.pub2.
Neovascular age-related macular degeneration (AMD) is a progressive eye disease characterized by choroidal neovascularization (CNV) and is a leading cause of vision loss and disability worldwide. Although intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is an effective treatment option that helps to prevent vision loss or to improve visual acuity in people with neovascular AMD, treatment imposes a significant financial burden on patients and healthcare systems. A biosimilar is a biological product that has been developed to be nearly identical to a previously approved biological product. The use of biosimilars may help reduce costs and so may increase patient access to effective biologic medicines with similar levels of safety to the drugs on which they are based.
To assess the benefits and harms of anti-VEGF biosimilar agents compared with their corresponding anti-VEGF agents (i.e. the reference products) that have obtained regulatory approval for intravitreal injections in people with neovascular AMD.
We searched CENTRAL, MEDLINE, Embase, two other databases, and two trials registries together with reference checking and contact with study authors to identify studies that are included in the review. The latest search date was 2 June 2023.
We included randomized controlled trials (RCTs) that compared approved anti-VEGF biosimilars with their reference products for treating the eyes of adult participants (≥ 50 years) who had an active primary or recurrent choroidal neovascularization lesion secondary to neovascular AMD.
Our outcomes were: best-corrected visual acuity (BCVA), central subfield thickness (CST), vision-related quality of life, serious ocular and non-ocular adverse events (AE), treatment-emergent adverse events (TEAEs), anti-drug antibodies (ADAs), and serum concentrations of biosimilars and reference drugs.
We assessed the risk of bias (RoB) for seven outcomes reported in a summary of findings table by using the Cochrane RoB 2 tool.
We synthesized results for each outcome using meta-analysis, where possible, by calculating risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI) for dichotomous outcomes and continuous outcomes, respectively. Where this was not possible due to the nature of the data, we summarized the results narratively. We used GRADE to assess the certainty of evidence for prespecified outcomes.
We included nine parallel-group multi-center RCTs that enrolled a total of 3814 participants (3814 participating eyes), with sample sizes that ranged from 160 to 705 participants per study. The mean age of the participants in these studies ranged from 67 to 76 years, and the proportion of women ranged from 26.5% to 58.7%. Ranibizumab (Lucentis) was the reference product in seven studies, and aflibercept (Eyelea) was the reference product in two others. All the included studies had been supported by industry. The follow-up periods ranged from 12 to 52 weeks (median 48 weeks). Five studies (56%) were conducted in multi-country settings across Europe, North America and Asia, two studies in India, and one each in Japan and the Republic of Korea. We judged all the included studies to have met high methodological standards.
With regard to efficacy, our meta-analyses demonstrated that anti-VEGF biosimilars for neovascular AMD resulted in little to no difference compared with the reference products for BCVA change at 8 to 12 weeks (MD -0.55 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, 95% CI -1.17 to 0.07; 8 studies, 3603 participants; high-certainty evidence) and the proportion of participants who lost fewer than 15 letters in BCVA at 24 to 48 weeks (RR 0.99, 95% CI 0.98 to 1.01; 7 studies, 2658 participants; moderate-certainty evidence). Almost all participants (96.6% in the biosimilar group and 97.0% in the reference product group) lost fewer than 15 letters in BCVA. The evidence from two studies suggested that there was no evidence of difference between biosimilars and reference products in vision-related quality of life measured by the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) summary scores at 24 to 48 weeks (MD 0.82, 95% CI -0.70 to 2.35; 2 studies, 894 participants; moderate-certainty evidence). With regard to the safety profile, meta-analyses also revealed little to no difference between anti-VEGF biosimilars and the reference products for the proportion of participants who experienced serious ocular AEs (RR 1.24, 95% CI 0.68 to 2.26; 7 studies, 3292 participants; moderate-certainty evidence), and for TEAEs leading to investigational product discontinuation or death (RR 0.96, 95% CI 0.63 to 1.46; 8 studies, 3497 participants; moderate-certainty evidence). Overall, 1.4% of participants in the biosimilar group and 1.2% in the reference product group experienced serious ocular adverse events. The most frequently documented serious ocular AEs were retinal hemorrhage and endophthalmitis. Although the evidence is of low certainty due to imprecision, meta-analysis suggested that anti-VEGF biosimilars led to no difference compared with the reference products for cumulative incidence of ADAs (RR 0.84, 95% CI 0.58 to 1.22; 8 studies, 3066 participants; low-certainty evidence) or mean maximum serum concentrations (MD 0.42 ng/mL, 95% CI -0.22 to 1.05; subgroup of 3 studies, 100 participants; low-certainty evidence). We judged the overall risk of bias to be low for all studies.
AUTHORS' CONCLUSIONS: In our review, low to high certainty evidence suggests that there is little to no difference, to date, between the anti-VEGF biosimilars approved for treating neovascular AMD and their reference products in terms of benefits and harms. While anti-VEGF biosimilars may be a viable alternative to reference products, current evidence for their use is based on a limited number of studies - particularly for comparison with aflibercept - with sparse long-term safety data, and infrequent assessment of quality of life outcomes. Our effect estimates and conclusions may be modified once findings have been reported from studies that are currently ongoing, and studies of biosimilar agents that are currently in development.
Cochrane Eyes and Vision US Project is supported by grant UG1EY020522, National Eye Institute, National Institutes of Health. Takeshi Hasegawa and Hisashi Noma were supported by Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (Grant numbers: 22H03554, 19K03092, 24K06239).
Protocol available via doi.org/10.1002/14651858.CD015804.
新生血管性年龄相关性黄斑变性（AMD）是一种进行性眼病，其特征为脉络膜新生血管（CNV），是全球视力丧失和残疾的主要原因。尽管玻璃体内抗血管内皮生长因子（anti-VEGF）治疗是一种有效的治疗选择，可以帮助预防新生血管性 AMD 患者的视力丧失或提高视力，但该治疗方法会给患者和医疗系统带来巨大的经济负担。生物类似药是一种已开发出来的与先前批准的生物产品几乎相同的生物产品。使用生物类似药可能有助于降低成本，从而可能增加患者获得具有与基础药物相似安全性水平的有效生物药物的机会。
评估抗 VEGF 生物类似药与已获得新生血管性 AMD 玻璃体内注射监管批准的相应抗 VEGF 药物（即参考产品）相比的获益和危害。
我们检索了 CENTRAL、MEDLINE、Embase、另外两个数据库和两个试验注册处，并通过参考文献检索和与研究作者联系来确定纳入本综述的研究。最新检索日期为 2023 年 6 月 2 日。
我们纳入了比较已批准的抗 VEGF 生物类似药与参考产品治疗年龄≥50 岁的成年参与者（≥50 岁）活跃原发性或复发性脉络膜新生血管性病变的随机对照试验（RCT）。这些参与者患有新生血管性 AMD。
我们的结局是最佳矫正视力（BCVA）、中心视网膜下厚度（CST）、与视力相关的生活质量、严重眼部和非眼部不良事件（AE）、治疗出现的不良事件（TEAEs）、抗药物抗体（ADA）以及生物类似药和参考药物的血清浓度。
我们使用 Cochrane 偏倚风险 2 工具评估了七个汇总结局表中报告的结果的偏倚风险，这些结果包括使用摘要表呈现的风险比（RR）和均值差值（MD）。对于连续结局，分别用于二分类结局和连续结局。如果由于数据的性质而不可能进行汇总分析，则我们将结果进行了叙述性总结。我们使用 GRADE 评估了预先指定结局的证据确定性。
我们纳入了九项平行组多中心 RCT，共纳入了 3814 名参与者（3814 只眼），每个研究的样本量范围为 160 至 705 名参与者。这些研究中参与者的平均年龄在 67 至 76 岁之间，女性比例在 26.5%至 58.7%之间。在七个研究中，雷珠单抗（Lucentis）是参考产品，而在另外两个研究中，阿柏西普（Eylea）是参考产品。所有纳入的研究均得到了行业的支持。随访期为 12 至 52 周（中位数 48 周）。五项研究（56%）在欧洲、北美和亚洲的多国家环境中进行，两项研究在印度进行，一项在日本进行，一项在大韩民国进行。我们判断所有纳入的研究都达到了高标准的方法学标准。
在疗效方面，我们的荟萃分析表明，新生血管性 AMD 的抗 VEGF 生物类似药与参考产品相比，在 8 至 12 周时的 BCVA 变化（MD -0.55 早期治疗糖尿病视网膜病变研究（ETDRS）字母，95%置信区间（CI）-1.17 至 0.07；8 项研究，3603 名参与者；高确定性证据）和 24 至 48 周时 BCVA 丢失少于 15 个字母的参与者比例（RR 0.99，95% CI 0.98 至 1.01；7 项研究，2658 名参与者；中度确定性证据）方面，几乎没有差异。生物类似药组和参考产品组中，超过 96.6%的参与者丢失的 BCVA 少于 15 个字母。两项研究的证据表明，生物类似药和参考产品在 24 至 48 周时使用 25 项国家眼科研究所视觉功能问卷（NEI-VFQ-25）综合评分测量的与视力相关的生活质量方面没有证据表明存在差异（MD 0.82，95% CI -0.70 至 2.35；2 项研究，894 名参与者；中度确定性证据）。在安全性方面，荟萃分析还表明，抗 VEGF 生物类似药与参考产品在严重眼部不良事件（RR 1.24，95% CI 0.68 至 2.26；7 项研究，3292 名参与者；中度确定性证据）和导致研究产品停药或死亡的治疗出现的不良事件（RR 0.96，95% CI 0.63 至 1.46；8 项研究，3497 名参与者；中度确定性证据）方面，几乎没有差异。生物类似药组和参考产品组中，分别有 1.4%和 1.2%的参与者发生严重眼部不良事件。最常见的严重眼部不良事件是视网膜出血和眼内炎。尽管由于不精确性，证据确定性为低，但荟萃分析表明，抗 VEGF 生物类似药与参考产品相比，累积 ADA 发生率（RR 0.84，95% CI 0.58 至 1.22；8 项研究，3066 名参与者；低确定性证据）或平均最大血清浓度（MD 0.42ng/mL，95% CI -0.22 至 1.05；3 项研究，100 名参与者；低确定性证据）方面无差异。我们判断所有研究的整体偏倚风险都较低。
在我们的综述中，低至高确定性证据表明，目前，与已批准用于治疗新生血管性 AMD 的抗 VEGF 生物类似药相比，其在获益和危害方面与参考产品几乎没有差异。虽然抗 VEGF 生物类似药可能是参考产品的一种可行替代品，但目前针对其使用的证据基于少数研究——特别是与阿柏西普的比较——且安全性数据有限，且很少评估生活质量结局。我们的效应估计值和结论可能会随着正在进行的研究和目前正在开发的生物类似药的研究的结果而有所修改。
Cochrane 眼部与视觉美国项目由美国国立卫生研究院国家眼科研究所（项目编号：UG1EY020522）提供资助。Takeshi Hasegawa 和 Hisashi Noma 得到了日本学术振兴会（资助编号：22H03554、19K03092、24K06239）的资助。
协议可通过 doi.org/10.1002/14651858.CD015804 获得。
