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美国宾州州立大学Timothy Craig团队研究了预防性使用抗激活因子XII单克隆抗体garadacimab治疗C1酯酶抑制剂缺乏的遗传性血管水肿的效果。2022年2月24日，《柳叶刀》杂志发表了这一成果。

遗传性血管性水肿与激肽释放酶-激肽系统失调有关。因子XII（FXII）是激肽释放酶-激肽系统的关键启动子，是激肽释放酶-激肽系统产生血管水肿的中枢介质缓激肽。Garadacimab（CSL Behring）是一种针对激活FXII的一流、全人免疫球蛋白G4单克隆抗体，旨在预防C1酯酶抑制剂缺陷型遗传性血管水肿（HAE-C1-INH）患者的发作。该研究旨在评估每4周一次garadacimab治疗HAE-C1-INH患者的疗效。

在这项双盲、安慰剂对照的2期临床研究中，研究组在加拿大、德国、以色列和美国的12个研究中心招募HAE-C1-INH患者。符合条件的患者年龄在18-65岁之间，在筛查或开始遗传性血管水肿预防之前的3个月内，必须在连续2个月内至少发生过4次任何严重程度的发作。

经过4-8周的磨合期后，将患者随机分配（1:1:1:1），分别接受安慰剂或75 mg、200 mg或600 mg garadacimab治疗。患者接受初始静脉负荷剂量，然后在第6天和每4周接受分配治疗的皮下剂量，为期12周。主要终点是200 mg和600 mg garadacimab组与安慰剂组在12周皮下给药期间的意向治疗人群每月发作次数。对所有至少接受一剂或部分剂量研究治疗的患者进行安全性评估。

2018年10月29日至2019年8月28日，研究组共对54名患者进行了筛查，32名患者被随机分组，其中安慰剂组8名，garadacimab 75 mg组9名，garadacimab 200 mg组8名，garadacimab 600 mg组7名。患者的中位年龄为39.5岁，32例患者中18例（56%）为女性，14例（34%）为男性。

在12周的皮下注射治疗期间，安慰剂组每月中位发作4.6次，garadacimab 75 mg组每月发作0.0次，garadacimab 200 mg组每月发作0.0次，garadacimab 600 mg组每月发作0.3次。与安慰剂组相比，garadacimab 200 mg组和600mg组的发病率显著降低。未观察到严重不良事件、死亡或特别关注的不良事件（过敏反应、血栓栓塞事件和出血事件）。

研究结果表明，对于HAE-C1-INH患者，每4周接受200 mg和600 mg的garadacimab与安慰剂相比可显著减少每月发作次数，且在研究期间耐受性良好。Garadacimab是一种有效的皮下预防HAE-C1-INH患者的药物，值得进行临床3期评估。

附：英文原文

Title: Prophylactic use of an anti-activated factor XII monoclonal antibody, garadacimab, for patients with C1-esterase inhibitor-deficient hereditary angioedema: a randomised, double-blind, placebo-controlled, phase 2 trial

Author: Timothy Craig, Markus Magerl, Donald S Levy, Avner Reshef, William R Lumry, Inmaculada Martinez-Saguer, Joshua S Jacobs, William H Yang, Bruce Ritchie, Emel Aygren-Pürsün, Paul K Keith, Paula Busse, Henrike Feuersenger, Dipti Pawaskar, Iris Jacobs, Ingo Pragst, Mittie K Doyle

Issue&Volume: 2022-02-24

Abstract:

Background

Hereditary angioedema is associated with dysregulation of the kallikrein–kinin system. Factor XII (FXII) is a key initiator of the kallikrein–kinin system, which produces bradykinin, a central mediator of angioedema. Garadacimab (CSL Behring) is a first-in-class, fully human, immunoglobulin G4 monoclonal antibody targeting activated FXII, intended to prevent attacks in patients with C1-esterase inhibitor-deficient hereditary angioedema (HAE-C1-INH). We aimed to investigate garadacimab as a treatment every 4 weeks for patients with HAE-C1-INH.

Methods

In this double-blind, placebo-controlled, phase 2 study, patients with HAE-C1-INH were recruited from 12 research centres in Canada, Germany, Israel, and the USA. Eligible patients were aged 18–65 years and must have had at least four attacks of any severity over a consecutive 2-month period during the 3 months before screening or initiation of previous hereditary angioedema prophylaxis. After a run-in period of 4–8 weeks, patients were randomly assigned (1:1:1:1), using an interactive response technology via block randomisation (block sizes of 1–4), to either placebo or 75 mg, 200 mg, or 600 mg garadacimab. Patients were given an initial intravenous loading dose, and then, on day 6 and every 4 weeks for 12 weeks, they were given a subcutaneous dose of their allocated treatment. The primary endpoint was the number of monthly attacks in the intention-to-treat population (defined as all patients who underwent screening, provided consent, and were assigned to treatment) during the 12-week subcutaneous administration period assessed in the 200 mg and 600 mg garadacimab groups versus placebo. Safety was assessed in all patients who received at least one dose or partial dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03712228.

Findings

Between Oct 29, 2018, and Aug 28, 2019, 54 patients were screened, of whom 32 were randomly assigned to either placebo (n=8) or 75 mg (n=9), 200 mg (n=8), or 600 mg (n=7) garadacimab. The median age was 39·5 years (28·0–52·5) and 18 (56%) of 32 patients were female and 14 (34%) were male. The median number of monthly attacks during the 12-week subcutaneous treatment period was 4·6 (IQR 3·1–5·0) with placebo, 0·0 (0·0–0·4) with 75 mg garadacimab, 0·0 (0·0–0·0) with 200 mg garadacimab, and 0·3 (0·0–0·7) with 600 mg garadacimab. Compared with placebo, the rate of attacks was significantly reduced with garadacimab at 200 mg (reduced by 100% [95% CI 98–101]; p=0·0002) and 600 mg (reduced by 93% [54–110]; p=0·0003). No serious adverse events, deaths, or adverse events of special interest (anaphylaxis, thromboembolic events, and bleeding events) were observed.

Interpretation

Garadacimab 200 mg and 600 mg every 4 weeks significantly reduced the number of monthly attacks versus placebo and was well tolerated during the study. Garadacimab is an efficacious, subcutaneous prophylaxis in patients with HAE-C1-INH and warrants phase 3 evaluation.

DOI: 10.1016/S0140-6736(21)02225-X

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02225-X/fulltext

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