Phase I Trial of Anti-Vascular Endothelial Growth Factor/Anti-angiopoietin 2 Bispecific Antibody RG7716 for Neovascular Age-Related Macular Degeneration
Phase I Trial of Anti-Vascular Endothelial Growth Factor/Anti-angiopoietin 2 Bispecific Antibody RG7716 for Neovascular Age-Related Macular Degeneration
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DOI：
10.1016/j.oret.2017.03.003
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发表时间：
2017-11-01
影响因子：
4.5
通讯作者：
Schwab, Dietmar
中科院分区：
文献类型：
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作者：
Chakravarthy, Usha;Bailey, Clare;Schwab, Dietmar
目的：RG7716是一种新型双特异性抗体，可同时结合血管内皮生长因子（VEGF）和另一种关键的血管生成因子血管生成素2。玻璃体内注射RG7716的I期研究旨在评估新生血管性年龄相关性黄斑变性（AMD）患者的单剂量和多剂量安全性。设计：开放标签，单次 受试者：24 名被诊断为新生血管性 AMD 的患者，其最佳矫正视力 (BCVA) 为 20/40 至 20/400（Snellen 等效值），顽固性黄斑中心凹下脉络膜新生血管形成定义为荧光素血管造影渗漏或谱域光学相干断层扫描液体渗漏，尽管有 3 个或更多玻璃体内 前6个月内接受过抗VEGF治疗。方法：单次玻璃体内注射0.5 mg、1.5 mg、3 mg和6 mg RG7716，分逐步剂量递增组，每组3名患者。在多剂量阶段，6名患者入组并接受3 mg和6 mg RG7716各3次治疗。主要结果指标：安全性和耐受性、基线BCVA变化和中心亚视野厚度（CST）。结果：单剂量组或多剂量组均未出现剂量限制性毒性。治疗引起的眼部不良事件较轻微。有一次停药和 1 次严重不良事件，主要研究人员认为这两项事件与研究药物无关。在联合单剂量组和 6 mg 多剂量组中，BCVA 从基线到最后一次给药后 28 天分别增加了 7 个字母（范围，0-18 个字母；n = 11）和 7.5 个字母（范围，3-18 个字母；n = 6）。 CST 相对于基线的相应中值减少分别为 42 μm（范围，-101 至 10 μm；n = 11）和 -117（范围，-252 至 -7 μm；n = 6）。多次服用 3 mg RG7716 剂量后，BCVA（中位数，-0.5 个字母；范围，-9 至 8 个字母；n = 6）或 CST（中位数，-9 μ m；范围，-188 至 -1 μm；n = 6）均未观察到变化。 结论：RG7716 耐受性良好，总体上表现出良好的安全性，有证据表明 BCVA 和 解剖参数。这些数据支持对 RG7716 在 II 期试验中的进一步评估。 (C) 2017 年，美国眼科学会。
Purpose: RG7716 is a novel bispecific antibody that simultaneously binds vascular endothelial growth factor (VEGF) and another key angiogenic factor, angiopoietin 2. A phase I study of intravitreal RG7716 was conducted to evaluate single-dose and multiple-dose safety in patients with neovascular age-related macular degeneration (AMD).Design: Open-label, single and multiple ascending-dose study.Participants: Twenty-four patients diagnosed with neovascular AMD with best-corrected visual acuity (BCVA) of 20/40 to 20/400 (Snellen equivalent) and refractory subfoveal choroidal neovascularization defined as leakage on fluorescein angiography or fluid on spectral-domain optical coherence tomography despite 3 or more intravitreal anti-VEGF treatments in the preceding 6 months.Methods: Single intravitreal doses of 0.5 mg, 1.5 mg, 3 mg, and 6 mg RG7716 were administered in stepwise dose-escalation groups, each with 3 patients. In the multiple-dose phase, 6 patients were enrolled and received 3 treatments each of 3 mg and 6 mg RG7716.Main Outcome Measures: Safety and tolerability, changes in baseline BCVA, and central subfield thickness (CST).Results: There were no dose-limiting toxicities in either the single-dose or multiple-dose group. Treatment-emergent ocular adverse events were mild. There was a single withdrawal and 1 serious adverse event, both deemed to be unrelated to the study drug by principal investigators. In the combined single-dose groups and in the 6-mg multiple-dose group, BCVA increased from baseline to 28 days after the last dose administration by a median of 7 letters (range, 0-18 letters; n = 11) and 7.5 letters (range, 3-18 letters; n = 6), respectively. The corresponding median reduction from baseline in CST were 42 mu m (range, -101 to 10 mu m; n = 11) and -117 (range, -252 to -7 mu m; n = 6), respectively. After multiple 3-mg RG7716 doses, no changes were observed in either BCVA (median, -0.5 letters; range, -9 to 8 letters; n = 6) or CST (median, -9 mu m; range, -188 to -1 mu m; n = 6).Conclusions: RG7716 was well tolerated and exhibited an overall favorable safety profile, with evidence of improvements in BCVA and anatomic parameters. These data support further evaluation of RG7716 in phase II trials. (C) 2017 by the American Academy of Ophthalmology.