Hereditary angioedema is a rare and potentially life-threatening genetic disease that is associated with kallikrein–kinin system dysregulation. Garadacimab (CSL312), a novel, fully-human monoclonal antibody that inhibits activated factor XII (FXIIa), is being studied for the prevention of hereditary angioedema attacks. The aim of this study was to evaluate the efficacy and safety of once-monthly subcutaneous administrations of garadacimab as prophylaxis for hereditary angioedema. VANGUARD was a pivotal, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial that recruited patients (aged ≥12 years) with type I or type II hereditary angioedema across seven countries (Canada, Germany, Hungary, Israel, Japan, the Netherlands, and the USA). Eligible patients were randomly assigned (3:2) to receive garadacimab or placebo for 6 months (182 days) by an interactive response technology (IRT) system. Randomisation was stratified by age (≤17 years >17 years) and baseline attack rate (1 to <3 attacks per month ≥3 attacks per month) for the adult group. The randomisation list and code were kept by the IRT provider during the study, with no access by site staff and funding representatives. All patients and investigational site staff, and representatives from the funder (or their delegates) with direct interaction with the study sites or patients, were masked to treatment assignment in a double-blind fashion. Randomly assigned patients received a 400-mg loading dose of subcutaneous garadacimab as two 200-mg injections or volume-matched placebo on day 1 of the treatment period, followed by five additional self-administered (or caregiver-administered) monthly doses of 200-mg subcutaneous garadacimab or volume-matched placebo. The primary endpoint was the investigator-assessed time-normalised number of hereditary angioedema attacks (number of hereditary angioedema attacks per month) during the 6-month treatment period (day 1 to day 182). Safety was evaluated in patients who received at least one dose of garadacimab or placebo. The study is registered with the EU Clinical Trials Register, 2020-000570-25 and , . Between Jan 27, 2021, and June 7, 2022, we screened 80 patients, 76 of whom were eligible to enter the run-in period of the study. Of 65 eligible patients with type I or type II hereditary angioedema, 39 were randomly assigned to garadacimab and 26 to placebo. One patient was randomly assigned in error and did not enter the treatment period (no dose of study drug received), resulting in 39 patients assigned to garadacimab and 25 patients assigned to placebo being included. 38 (59%) of 64 participants were female and 26 (41%) were male. 55 (86%) of 64 participants were White, six (9%) were Asian (Japanese), one (2%) was Black or African American, one (2%) was Native Hawaiian or Other Pacific Islander, and one (2%) was listed as other. During the 6-month treatment period (day 1 to day 182), the mean number of investigator-confirmed hereditary angioedema attacks per month was significantly lower in the garadacimab group (0·27, 95% CI 0·05 to 0·49) than in the placebo group (2·01, 1·44 to 2·57; p<0·0001), corresponding to a percentage difference in means of –87% (95% CI –96 to –58; p<0·0001). The median number of hereditary angioedema attacks per month was 0 (IQR 0·00–0·31) for garadacimab and 1·35 (1·00–3·20) for placebo. The most common treatment-emergent adverse events were upper-respiratory tract infections, nasopharyngitis, and headaches. FXIIa inhibition was not associated with an increased risk of bleeding or thromboembolic events. Monthly garadacimab administration significantly reduced hereditary angioedema attacks in patients aged 12 years and older compared with placebo and had a favourable safety profile. Our results support the use of garadacimab as a potential prophylactic therapy for the treatment of hereditary angioedema in adolescents and adults. CSL Behring.

中文翻译：

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加拉达西玛（一种 XIIa 因子抑制剂）用于预防遗传性血管水肿 (VANGUARD) 的疗效和安全性：一项全球、多中心、随机、双盲、安慰剂对照 3 期试验

遗传性血管性水肿是一种罕见且可能危及生命的遗传病，与激肽释放酶-激肽系统失调有关。Garadacimab (CSL312) 是一种新型全人源单克隆抗体，可抑制活化因子 XII (FXIIa)，目前正在研究用于预防遗传性血管性水肿发作。本研究的目的是评估每月一次皮下注射加拉达西单抗预防遗传性血管性水肿的有效性和安全性。VANGUARD 是一项关键、多中心、随机、双盲、安慰剂对照的 3 期试验，招募了七个国家（加拿大、德国、匈牙利、以色列、日本）患有 I 型或 II 型遗传性血管水肿的患者（年龄≥12 岁） 、荷兰和美国）。通过交互式反应技术 (IRT) 系统，符合条件的患者被随机分配 (3:2) 接受加拉达西单抗或安慰剂治疗 6 个月（182 天）。成人组按年龄（≤17 岁>17 岁）和基线发作率（每月 1 至 <3 次发作，每月≥3 次发作）进行随机分层。研究期间，随机列表和代码由 IRT 提供者保存，现场工作人员和资助代表无法访问。所有患者和研究中心工作人员以及与研究中心或患者直接互动的资助者代表（或其代表）都以双盲方式隐藏治疗分配。随机分配的患者在治疗期的第一天接受 400 mg 负荷剂量的加拉达西单抗皮下注射，作为两次 200 mg 注射剂或容量匹配的安慰剂，然后另外接受 5 次自行给药（或护理人员给药）的每月剂量 200-mg mg 皮下注射加拉达西单抗或容量匹配的安慰剂。主要终点是研究者评估的 6 个月治疗期间（第 1 天至第 182 天）内遗传性血管水肿发作的时间归一化次数（每月遗传性血管水肿发作的次数）。在接受至少一剂加拉达西单抗或安慰剂的患者中评估了安全性。该研究已在欧盟临床试验注册处注册，2020-000570-25 和 , 。2021年1月27日至2022年6月7日期间，我们筛查了80名患者，其中76人符合进入研究磨合期的条件。在 65 名符合条件的 I 型或 II 型遗传性血管性水肿患者中，39 名被随机分配至加拉达西单抗组，26 名被随机分配至安慰剂组。一名患者被错误随机分配，没有进入治疗期（未接受研究药物剂量），导致 39 名患者被分配至加拉达西单抗组，25 名患者被分配至安慰剂组。64 名参与者中有 38 名（59%）为女性，26 名（41%）为男性。64 名参与者中有 55 名 (86%) 是白人，六名 (9%) 是亚洲人（日本人），一名 (2%) 是黑人或非裔美国人，一名 (2%) 是夏威夷原住民或其他太平洋岛民，一名 (2%) %)被列为其他。在 6 个月的治疗期间（第 1 天至第 182 天），加拉达西单抗组每月经研究者确认的遗传性血管性水肿发作的平均次数（0·27，95% CI 0·05 至 0·49）显着低于安慰剂组（2·01、1·44 至 2） ·57；p<0·0001)，对应于平均值的百分比差异为 –87% (95% CI –96 至 –58；p<0·0001)。加拉达昔单抗组每月遗传性血管性水肿发作的中位数为 0 次 (IQR 0·00–0·31)，安慰剂组为 1·35 (1·00–3·20)。最常见的治疗中出现的不良事件是上呼吸道感染、鼻咽炎和头痛。FXIIa 抑制与出血或血栓栓塞事件风险增加无关。与安慰剂相比，每月服用加拉达西单抗可显着减少 12 岁及以上患者的遗传性血管性水肿发作，并且具有良好的安全性。我们的结果支持使用加拉达西单抗作为治疗青少年和成人遗传性血管水肿的潜在预防疗法。CSL 贝林。