Allergy, Asthma and Immunology, Department of Medicine and Pediatrics, Penn State University, Hershey, PA, USA.
Allergy, Immunology & Angioedema Center, Barzilai University Hospital, Ashkelon, Israel.
Lancet. 2023 Apr 1;401(10382):1079-1090. doi: 10.1016/S0140-6736(23)00350-1. Epub 2023 Feb 28.
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 vs >17 years) and baseline attack rate (1 to <3 attacks per month vs ≥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 ClinicalTrials.gov, NCT04656418.
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.
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，与激肽释放酶-激肽系统失调有关。Garadacimab（CSL312）是一种新型的、完全人源化的单克隆抗体，可抑制激活的 XII 因子（FXIIa），目前正在研究用于预防遗传性血管性水肿发作。本研究旨在评估每月皮下注射 garadacimab 预防遗传性血管性水肿的疗效和安全性。
VANGUARD 是一项关键性、多中心、随机、双盲、安慰剂对照、III 期临床试验，在 7 个国家（加拿大、德国、匈牙利、以色列、日本、荷兰和美国）招募了 I 型或 II 型遗传性血管性水肿患者（年龄≥12 岁）。符合条件的患者按年龄（≤17 岁与>17 岁）和基线发作率（每月 1 至<3 次发作与每月≥3 次发作）分层，通过交互反应技术（IRT）系统随机分配接受 garadacimab 或安慰剂治疗 6 个月（182 天）。随机分配名单和代码由 IRT 供应商在研究期间保存，研究人员、资金代表均无法访问。所有患者和研究现场工作人员，以及与研究现场或患者有直接互动的资金代表（或其代表）均以双盲方式对治疗分配情况进行了掩蔽。随机分配的患者在治疗期的第 1 天（治疗开始）接受 400mg 的皮下 garadacimab 负荷剂量，分为两剂 200mg 注射剂或体积匹配的安慰剂，随后每月自行（或由照顾者）给予五次额外的 200mg 皮下 garadacimab 或体积匹配的安慰剂。主要终点是在 6 个月治疗期间（第 1 天至第 182 天）由研究者评估的遗传性血管性水肿发作时间标准化次数（每月遗传性血管性水肿发作次数）。至少接受一剂 garadacimab 或安慰剂的患者被评估安全性。该研究在欧盟临床试验注册中心注册，注册号为 2020-000570-25，在美国临床试验注册中心注册，注册号为 NCT04656418。
2021 年 1 月 27 日至 2022 年 6 月 7 日期间，我们筛选了 80 名患者，其中 76 名符合入组研究的入组期标准。在 65 名符合 I 型或 II 型遗传性血管性水肿标准的合格患者中，39 名被随机分配至 garadacimab 组，26 名被随机分配至安慰剂组。1 名患者被错误分配且未进入治疗期（未接受研究药物剂量），因此，实际纳入了 39 名接受 garadacimab 治疗和 25 名接受安慰剂治疗的患者。64 名参与者中，38 名（59%）为女性，26 名（41%）为男性。55 名（86%）为白人，6 名（9%）为亚洲人（日本人），1 名（2%）为黑人或非裔美国人，1 名（2%）为夏威夷原住民或其他太平洋岛民，1 名（2%）被列为其他种族。在 6 个月的治疗期间（第 1 天至第 182 天），garadacimab 组每月经研究者确认的遗传性血管性水肿发作次数明显低于安慰剂组（0.27，95%CI 0.05 至 0.49），差异有统计学意义（p<0.0001），意味着平均差异为-87%（95%CI -96 至 -58；p<0.0001）。每月遗传性血管性水肿发作次数的中位数为 garadacimab 组 0（IQR 0.00-0.31），安慰剂组 1.35（1.00-3.20）。最常见的治疗期不良事件为上呼吸道感染、鼻咽炎和头痛。FXIIa 抑制与出血或血栓栓塞事件的风险增加无关。
每月皮下注射 garadacimab 可显著减少 12 岁及以上患者遗传性血管性水肿发作，与安慰剂相比具有良好的安全性。我们的研究结果支持 garadacimab 作为一种潜在的预防治疗方法，用于治疗青少年和成年患者的遗传性血管性水肿。
CSL 贝林。
