Lonvoguran Ziclumeran — 遗传性血管性水肿中的体内CRISPR基因编辑
完整摘要 · 中文译文
背景：遗传性血管性水肿是一种罕见且可能危及生命的遗传性疾病，其特征为反复发作且令人衰弱的肿胀发作。Lonvoguran ziclumeran（lonvo-z）——一种基于规律间隔成簇短回文重复序列（CRISPR）的研究性体内基因编辑治疗——正被开发为遗传性血管性水肿的单次给药治疗。 方法：在一项3期双盲试验中，我们以2:1的比例将16岁及以上且患有C1抑制剂缺乏型遗传性血管性水肿的患者随机分配，接受单次静脉输注lonvo-z（剂量为50 mg）或安慰剂。主要终点为输注后第5周至第28周期间，经研究者确认的遗传性血管性水肿发作次数（每月发作率）。 结果：共80名患者接受了随机分组；52名被分配接受lonvo-z治疗，28名接受安慰剂。截至2026年2月10日，中位随访时间为7.5个月（范围，4.9至12.8）。第5周至第28周期间，lonvo-z组的最小二乘平均月发作率为0.26（95%置信区间[CI]，0.15至0.45），安慰剂组为2.10（95% CI，1.55至2.86）（相对差异，-87%；95% CI，-93至-78；P<0.001）。从第1天至第28周，lonvo-z组和安慰剂组分别有92%和86%的患者报告了在输注lonvo-z或安慰剂期间或之后发生的不良事件。在输注期间或之后发生且lonvo-z组比安慰剂组更常见的不良事件中，最常见（发生在lonvo-z组>10%的患者中）的不良事件包括输注相关反应、头痛、疲劳、背痛和上呼吸道感染。lonvo-z组未报告严重或3级或更高级别的不良事件。结论：在遗传性血管性水肿患者中，单次静脉输注lonvo-z导致的遗传性血管性水肿发作率显著低于安慰剂。（由Intellia Therapeutics资助；HAELO ClinicalTrials.gov编号，NCT06634420。）
完整摘要 · 英文原文
BACKGROUND: Hereditary angioedema is a rare and potentially life-threatening genetic condition characterized by recurrent and debilitating swelling attacks. Lonvoguran ziclumeran (lonvo-z) - an investigational, in vivo gene-editing treatment based on clustered regularly interspaced short palindromic repeats (CRISPR) - is being developed as a single-dose treatment for hereditary angioedema. METHODS: In a phase 3, double-blind trial, we randomly assigned, in a 2:1 ratio, patients who were 16 years of age or older and had hereditary angioedema with C1 inhibitor deficiency to receive a single intravenous infusion of lonvo-z (at a dose of 50 mg) or placebo. The primary end point was the number of investigator-confirmed hereditary angioedema attacks per month (the monthly attack rate) from week 5 through week 28 after infusion. RESULTS: A total of 80 patients underwent randomization; 52 were assigned to receive lonvo-z and 28 to receive placebo. As of February 10, 2026, the median duration of follow-up was 7.5 months (range, 4.9 to 12.8). The least-squares mean monthly attack rate from weeks 5 through 28 was 0.26 (95% confidence interval [CI], 0.15 to 0.45) in the lonvo-z group and 2.10 (95% CI, 1.55 to 2.86) in the placebo group (relative difference, -87%; 95% CI, -93 to -78; P<0.001). Adverse events that occurred during or after infusion of lonvo-z or placebo were reported in 92% and 86% of the patients in the lonvo-z and placebo groups, respectively, from day 1 through week 28. Among the adverse events that occurred during or after infusion and more often in the lonvo-z group than in the placebo group, the most common (occurring in >10% of the patients in the lonvo-z group) included infusion-related reaction, headache, fatigue, back pain, and upper respiratory tract infection. No serious or grade 3 or higher adverse events were reported in the lonvo-z group. CONCLUSIONS: Among patients with hereditary angioedema, a single intravenous infusion of lonvo-z resulted in a significantly lower rate of hereditary angioedema attacks than placebo. (Funded by Intellia Therapeutics; HAELO ClinicalTrials.gov number, NCT06634420.).