Chakravarthy Usha, Bailey Clare, Brown David, Campochiaro Peter, Chittum Mark, Csaky Karl, Tufail Adnan, Yates Paul, Cech Patrick, Giraudon Mylene, Delmar Paul, Szczesny Piotr, Sahni Jayashree, Boulay Anne, Nagel Sandra, Fürst-Recktenwald Sabine, Schwab Dietmar
Eye and Ear Clinic, Royal Victoria Hospital, Belfast, United Kingdom.
Bristol Eye Hospital, Bristol, United Kingdom.
Ophthalmol Retina. 2017 Nov-Dec;1(6):474-485. doi: 10.1016/j.oret.2017.03.003. Epub 2017 May 23.
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).
Open-label, single and multiple ascending-dose study.
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.
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.
Safety and tolerability, changes in baseline BCVA, and central subfield thickness (CST).
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 μm (range, -101 to 10 μm; n = 11) and -117 μm (range, -252 to -7 μm; 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 μm; range, -188 to -1 μm; n = 6).
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.
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）和另一种关键血管生成因子血管生成素2。开展了一项玻璃体内注射RG7716的I期研究，以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。
开放标签、单剂量和多剂量递增研究。
24例被诊断为新生血管性AMD的患者，最佳矫正视力（BCVA）为20/40至20/400（Snellen等效视力），且尽管在过去6个月内接受了3次或更多次玻璃体内抗VEGF治疗，但荧光素血管造影显示渗漏或光谱域光学相干断层扫描显示有液性暗区，即难治性黄斑中心凹下脉络膜新生血管形成。
在逐步递增剂量组中分别给予0.5mg、1.5mg、3mg和6mg的玻璃体内单剂量RG7716，每组3例患者。在多剂量阶段，纳入6例患者，分别接受3mg和6mg的RG7716各3次治疗。
安全性和耐受性、基线BCVA变化以及中心子野厚度（CST）。
单剂量组和多剂量组均未出现剂量限制性毒性。治疗中出现的眼部不良事件均为轻度。有1例患者退出研究，发生1例严重不良事件，主要研究者均认为与研究药物无关。在联合单剂量组和6mg多剂量组中，末次给药后28天的BCVA较基线分别平均提高了7个字母（范围为0 - 18个字母；n = 11）和7.5个字母（范围为3 - 18个字母；n = 6）。相应的CST较基线的平均降低值分别为42μm（范围为 - 101至10μm；n = 11）和 - 117μm（范围为 - 252至 - 7μm；n = 6）。多次给予3mg的RG7716后，BCVA（平均 - 0.5个字母；范围为 - 9至8个字母；n = 6）和CST（平均 - 9μm；范围为 - 188至 - 1μm；n = 6）均未观察到变化。
RG7716耐受性良好，总体安全性良好，有证据表明BCVA和解剖学参数有所改善。这些数据支持在II期试验中对RG7716进行进一步评估。
