Department of Ophthalmology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
Department of Ophthalmology, Third Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
JAMA Ophthalmol. 2021 Jan 1;139(1):68-76. doi: 10.1001/jamaophthalmol.2020.5053.
Neovascular age-related macular degeneration is the leading cause of blindness in individuals 50 years or older. The availability of a ranibizumab biosimilar product (SB11) may facilitate access to an effective alternative to this treatment.
To demonstrate equivalence of efficacy, similar safety, and similar immunogenicity of SB11 compared with the reference ranibizumab.
DESIGN, SETTING, AND PARTICIPANTS: This randomized, double-masked, parallel-group phase 3 equivalence study was conducted in 75 centers in 9 countries from March 14, 2018, to December 9, 2019, among 705 participants 50 years or older with neovascular age-related macular degeneration with active subfoveal choroidal neovascularization lesions. Analysis was performed on an intent-to-treat basis.
Intravitreous injection of SB11 or ranibizumab, 0.5 mg, every 4 weeks through week 48.
Preplanned interim analysis after all participants completed the week 24 assessment of primary efficacy end points at week 8 for change from baseline in best-corrected visual acuity (BCVA) and week 4 for central subfield thickness (CST), with predefined equivalence margins for adjusted treatment differences of -3 letters to 3 letters for BCVA and -36 μm to 36 μm for CST.
Baseline and disease characteristics among 705 randomized participants (403 women [57.2%]; mean [SD] age, 74.1 [8.5] years) were comparable between treatment groups (SB11, 351; ranibizumab, 354). Least-squares mean (SE) changes in BCVA from baseline at week 8 were 6.2 (0.5) letters in the SB11 group vs 7.0 (0.5) letters in the ranibizumab group, with an adjusted treatment difference of -0.8 letter (90% CI, -1.8 to 0.2 letters). Least-squares mean (SE) changes in CST from baseline at week 4 were -108 (5) μm in the SB11 group vs -100 (5) μm in the ranibizumab group, with an adjusted treatment difference of -8 μm (95% CI, -19 to 3 μm). Incidences of treatment-emergent adverse events (231 of 350 [66.0%] vs 237 of 354 [66.9%]), including serious treatment-emergent adverse events (44 of 350 [12.6%] vs 44 of 354 [12.4%]) and treatment-emergent adverse events leading to study drug discontinuation (8 of 350 [2.3%] vs 5 of 354 [1.4%]), were similar in the SB11 and ranibizumab groups. Immunogenicity was low, with a cumulative incidence of antidrug antibodies up to week 24 of 3.0% (10 of 330) in the SB11 group and 3.1% (10 of 327) in the ranibizumab group.
These findings of equivalent efficacy and similar safety and immunogenicity profiles compared with ranibizumab support the use of SB11 for patients with neovascular age-related macular degeneration.
ClinicalTrials.gov Identifier: NCT03150589.
重要性：新生血管性年龄相关性黄斑变性是导致 50 岁及以上人群失明的主要原因。雷珠单抗生物类似药（SB11）的出现可能为这种治疗方法提供了一种更有效的替代方案。
目的：证明 SB11 与参照雷珠单抗在疗效、安全性和免疫原性方面具有等效性。
设计、地点和参与者：这是一项在 2018 年 3 月 14 日至 2019 年 12 月 9 日期间在 9 个国家的 75 个中心进行的随机、双盲、平行分组的 3 期等效性研究，共有 705 名年龄在 50 岁及以上、患有新生血管性年龄相关性黄斑变性且伴有活跃性脉络膜新生血管的患者参与，这些患者的病变位于黄斑下。分析基于意向治疗原则进行。
干预措施：玻璃体内注射 SB11 或雷珠单抗，剂量均为 0.5mg，每 4 周 1 次，共治疗 48 周。
主要观察指标和测量方法：在所有参与者完成第 24 周的主要疗效终点评估后（第 8 周评估最佳矫正视力 [BCVA]，第 4 周评估中心脉络膜厚度 [CST]）进行预定义的中期分析，在第 8 周，BCVA 的调整治疗差异的预设等效边界为 -3 个字母到 3 个字母，在第 4 周，CST 的调整治疗差异的预设等效边界为 -36μm 到 36μm。
结果：705 名随机参与者（403 名女性[57.2%]；平均[标准差]年龄，74.1[8.5]岁）的基线和疾病特征在治疗组之间（SB11 组 351 名，雷珠单抗组 354 名）具有可比性。SB11 组和雷珠单抗组的基线至第 8 周的 BCVA 最小二乘均值（SE）变化分别为 6.2（0.5）个字母和 7.0（0.5）个字母，调整后的治疗差异为 -0.8 个字母（90%置信区间，-1.8 至 0.2 个字母）。SB11 组和雷珠单抗组的基线至第 4 周的 CST 最小二乘均值（SE）变化分别为 -108（5）μm 和 -100（5）μm，调整后的治疗差异为 -8μm（95%置信区间，-19 至 3μm）。治疗中出现的不良事件（231 例[66.0%]）和严重治疗中出现的不良事件（44 例[12.6%]）与雷珠单抗组相似，SB11 组和雷珠单抗组的发生率分别为 231 例（66.0%）和 237 例（66.9%），SB11 组和雷珠单抗组的发生率分别为 44 例（12.4%）和 44 例（12.4%）。治疗中出现的不良事件导致研究药物停药（8 例[2.3%]）与雷珠单抗组（5 例[1.4%]）相似，SB11 组和雷珠单抗组的发生率分别为 8 例（2.3%）和 5 例（1.4%）。免疫原性较低，SB11 组至第 24 周的抗药物抗体累积发生率为 3.0%（330 例中有 10 例），雷珠单抗组为 3.1%（327 例中有 10 例）。
结论和相关性：这些结果表明，SB11 在疗效、安全性和免疫原性方面与雷珠单抗相当，支持将 SB11 用于治疗新生血管性年龄相关性黄斑变性的患者。
试验注册：ClinicalTrials.gov 标识符：NCT03150589。
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