本文由小咖机器人翻译整理

期刊来源：Lancet

原文链接：https://doi.org/10.1016/S0140-6736(24)00310-6

摘要内容如下：

背景

频繁注射抗血管内皮生长因子A（VEGF-A）可降低新生血管性年龄相关性黄斑变性（NAMD）患者快速和严重视力丧失的风险。然而，由于治疗不足，许多患者随着时间的推移失去了视力。需要新的治疗方法来持续抑制VEGF-A。RGX-314（目前称为ABBV-RGX-314）是表达抗VEGF-A抗原结合片段的腺相关病毒血清型8载体，其在单次视网膜下注射后提供持续VEGF-A抑制的潜力。我们报道了视网膜下注射RGX-314治疗NAMD患者的安全性和有效性。

方法

在美国8个地点进行的开放标签、多队列、多中心、1/2a期、剂量递增研究中，我们将年龄为50-89岁、既往接受过抗VEGF注射治疗的NAMD患者纳入5个队列（使用5种不同剂量的RGX-314）。为了符合条件，参与者必须有继发于NAMD的黄斑新生血管，在中央子野有视网膜下或视网膜内液体，是人工晶状体（白内障摘除后），并且每个队列中第一个参与者的研究眼睛的最佳矫正视力（BCVA）在20/63和20/400之间，其他参与者在20/40和20/400之间。RGX-314的视网膜下注射是由经过实验室培训的玻璃体视网膜外科医生在没有前滤过泡的情况下进行的。队列1每只眼睛接受3×109个基因组拷贝，队列2接受1×1010个，队列3接受6×1010个两个额外剂量队列（队列4:1.6×1011；队列5:2.5×1011）。参与者在服用RGX-314后1天和1周进行观察，然后每月观察2年（直到第106周）。主要结果是RGX-314通过视网膜下注射给药至第26周的安全性。该分析包括参与研究的所有42名患者。该研究已在ClinicalTrials.gov（NCT03066258）注册。

调查结果

在2017年5月12日至2019年5月21日期间，我们筛选了110名患者，并招募了68名参与者。42名参与者对玻璃体内注射雷珠单抗表现出所需的解剖反应，然后接受了单次RGX-314注射（剂量范围为每只眼睛3×109至2.5×1011基因组拷贝），并随访了2年。在13名参与者中有20例严重不良事件，其中1例可能与RGX-314有关：在以每只眼睛2.5×1011基因组拷贝的剂量注射RGX-314 12个月后，黄斑区出现色素改变，视力严重下降。在视网膜下注射RGX-314几个月后，在下方视网膜周边观察到无症状的色素变化，最常见的剂量为每只眼睛6×1010基因组拷贝或更高。在常规玻璃体切除术后，没有临床确定的免疫反应或炎症超过预期。在大多数参与者中，6×1010基因组拷贝或更高的剂量导致房水中RGX-314蛋白的持续浓度和稳定或改善的最佳矫正视力和中央视网膜厚度，很少或没有补充抗VEGF-A注射。

解释

RGX-314的视网膜下给药通常耐受性良好，没有临床识别的免疫反应。RGX-314基因治疗为NAMD患者提供了一种持续抑制VEGF-A的新方法，该方法有可能在单次给药后控制渗出、维持视力并减轻治疗负担。这项研究的结果为评估NAMD患者RGX-314的关键计划提供了信息。

英文原文如下：

Abstracts

BACKGROUND  Frequent anti-vascular endothelial growth factor A (VEGF-A) injections reduce the risk of rapid and severe vision loss in patients with neovascular age-related macular degeneration (nAMD); however, due to undertreatment, many patients lose vision over time. New treatments that provide sustained suppression of VEGF-A are needed. RGX-314 (currently known as ABBV-RGX-314) is an adeno-associated virus serotype 8 vector that expresses an anti-VEGF-A antigen-binding fragment, which provides potential for continuous VEGF-A suppression after a single subretinal injection. We report results on the safety and efficacy of subretinal injection of RGX-314 in patients with nAMD.

METHODS  For this open-label, multiple-cohort, multicentre, phase 1/2a, dose-escalation study conducted at eight sites in the USA, we enrolled participants with nAMD aged 50-89 years who had previously been treated with anti-VEGF injections into five cohorts (with five different doses of RGX-314). To be eligible, participants had to have macular neovascularisation secondary to nAMD with subretinal or intraretinal fluid in the centre subfield, be pseudophakic (after cataract removal), and have a best-corrected visual acuity (BCVA) in the study eye between 20/63 and 20/400 for the first participant in each cohort and between 20/40 and 20/400 for others. Subretinal injection of RGX-314 was done without a pre-bleb by a wet-laboratory-trained vitreoretinal surgeon. Cohort 1 received 3 × 109 genome copies per eye, cohort 2 received 1 × 1010, and cohort 3 received 6 × 1010. Two additional dose cohorts (cohort 4: 1·6 × 1011; cohort 5: 2·5 × 1011) were added. Participants were seen 1 day and 1 week after administration of RGX-314, and then monthly for 2 years (up to week 106). The primary outcome was safety of RGX-314 delivered by subretinal injection up to week 26. This analysis includes all 42 patients enrolled in the study. This study is registered with ClinicalTrials.gov, NCT03066258.

FINDINGS  Between May 12, 2017, and May 21, 2019, we screened 110 patients for eligibility and enrolled 68. 42 participants demonstrated the required anatomic response to intravitreal ranibizumab and then received a single RGX-314 injection (dose range 3 × 109 to 2·5 × 1011 genome copies per eye) and were followed up for 2 years. There were 20 serious adverse events in 13 participants, of which one was possibly related to RGX-314: pigmentary changes in the macula with severe vision reduction 12 months after injection of RGX-314 at a dose of 2·5 × 1011 genome copies per eye. Asymptomatic pigmentary changes were seen in the inferior retinal periphery several months after subretinal injection of RGX-314 most commonly at doses of 6 × 1010 genome copies per eye or higher. There were no clinically determined immune responses or inflammation beyond that expected following routine vitrectomy. Doses of 6 × 1010 genome copies or higher resulted in sustained concentrations of RGX-314 protein in aqueous humour and stable or improved BCVA and central retinal thickness with few or no supplemental anti-VEGF-A injections in most participants.

INTERPRETATION  Subretinal delivery of RGX-314 was generally well tolerated with no clinically recognised immune responses. RGX-314 gene therapy provides a novel approach for sustained VEGF-A suppression in patients with nAMD that has potential to control exudation, maintain vision, and reduce treatment burden after a single administration. Results from this study informed the pivotal programme to evaluate RGX-314 in patients with nAMD.

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