Oral deucrictibant for prophylaxis of hereditary angioedema attacks (CHAPTER-1): primary analysis of a randomised, double-blind, placebo-controlled, phase 2 trial.

Bradykinin B2 receptor antagonism is a proven mechanism for on-demand treatment of attacks, but no evidence exists on its effects when used prophylactically.

缓激肽B2受体拮抗已被证实是应对发作的按需治疗机制，但目前尚无证据表明其预防性使用的疗效。

Deucrictibant is an investigational orally bioavailable bradykinin B2 receptor antagonist.

Deucrictibant 是一种正在研究中的口服生物可利用的缓激肽 B2 受体拮抗剂。

We aimed to evaluate the efficacy, safety, and tolerability of two dose regimens of oral deucrictibant administered as prophylaxis against hereditary angioedema attacks.

我们的目标是评估两种剂量方案的口服 deucrictibant 作为预防遗传性血管性水肿发作的疗效、安全性和耐受性。

Methods

CHAPTER-1 was a multicentre, double-blind, placebo-controlled, randomised, phase 2 trial conducted in two parts, a double-blindplacebo controlled first part and an open-label second part, with only part 1 reported here.

CHAPTER-1 是一项多中心、双盲、安慰剂对照、随机、二期试验，分为两个部分进行，第一部分为双盲安慰剂对照，第二部分为开放标签，本报告仅涉及第一部分。

Part 1 recruited adults (aged 18-75 years) with hereditary angioedema type 1 or 2 from 37 sites (university hospitals and accredited angioedema centres) across North America, Europe, and Israel.

第一部分招募了来自北美、欧洲和以色列37个地点（大学医院和认证的血管性水肿中心）的18-75岁成年遗传性血管性水肿1型或2型患者。

Patients required a documented history of three or more attacks within the last 3 consecutive months before screening or two or more during the screening period (up to 8 weeks) to be eligible.

患者需要在筛查前的连续3个月内有三次或以上的发作记录，或者在最多8周的筛查期间有两次或以上的发作记录，才有资格参与研究。

An interactive response technology system randomised eligible patients 1:1:1 to receive oral deucrictibant 20 mg daily, 40 mg daily, or matching placebo for 12 weeks.

互动式响应技术系统将符合条件的患者按照1:1:1的比例随机分配，接受口服deucrictibant 20 mg每日一次、40 mg每日一次，或相应的安慰剂治疗，持续12周。

Randomisation to treatment groups was stratified by the baseline attack rate.

治疗组的随机分配是根据基线发作率进行分层的。

Patients, investigators, site personnel, and the sponsor were blinded to treatment assignment.

患者、研究人员、现场人员和赞助商对治疗分配情况是不知情的。

Masking was achieved with identically appearing deucrictibant and placebo capsules.

通过外观相同的安慰剂和活性药物胶囊实现了盲法设计。

The primary endpoint was the time-normalised number of investigator-confirmed attacks per 4 weeks (monthly attack rate) from weeks 1 to 12 and was assessed using the intention-to-treatset.

主要终点是从第1周到第12周，每4周（每月）由研究者确认的发作次数的标准化时间（月发作率），并使用意向治疗集进行评估。

The endpoint was analysed by comparing each deucrictibant group with the placebo group using a Poisson generalised linear model with a log link function and Pearson's χ2 scaling of SEs to account for potential dispersion.

终点通过使用具有对数链接函数的泊松广义线性模型和皮尔逊χ2缩放标准误来比较每个deucrictibant组与安慰剂组，以考虑潜在的分散。

The safety analysis set included all patients who were randomly assigned and who received one or more doses of study drug (deucrictibant or placebo).

安全性分析集包括所有被随机分配并且接受了一次或多次研究药物（deucrictibant或安慰剂）剂量的患者。

CHAPTER-1 is registered with ClinicalTrials.gov (NCT05047185) and is now complete.

CHAPTER-1 已在 ClinicalTrials.gov 注册（NCT05047185），目前研究已完成。

Results

Between March 9, 2022, and June 19, 2023, 44 patients were screened.

2022年3月9日至2023年6月19日期间，共筛选了44名患者。

Of 34 patients who were randomly assigned, 11 patients received deucrictibant 20 mg, 12 patients received deucrictibant 40 mg, and 11 patients received the placebo, with a median follow-up of 85·0 days (IQR 84·0-86·0). 21 (62%) patients were female, 13 (38%) were male, and 34 (100%) patients were White.

在随机分配的34名患者中，11名患者接受了20毫克的deucrictibant，12名患者接受了40毫克的deucrictibant，另外11名患者接受了安慰剂，中位随访时间为85.0天（四分位数间距84.0-86.0）。21名（62%）患者为女性，13名（38%）为男性，所有34名（100%）患者均为白人。

The least squares mean monthly attack rate (primary analysis) was 0·40 (95% CI 0·18-0·92) for deucrictibant 20 mg, 0·30 (0·11-0·81) for deucrictibant 40 mg, and 1·93 (1·30-2·88) for placebo; percent reduction in attack rate compared with placebo was 79·2% (95% CI 47·2-91·8) for deucrictibant 20 mg (p=0·0010) and 84·5% (95% CI 53·8-94·8) for deucrictibant 40 mg (p=0·0008).

最小二乘法计算的每月发作率（主要分析）为：deucrictibant 20毫克组为0.40（95%置信区间0.18-0.92），deucrictibant 40毫克组为0.30（95%置信区间0.11-0.81），安慰剂组为1.93（95%置信区间1.30-2.88）；与安慰剂相比，deucrictibant 20毫克组的发作率降低了79.2%（95%置信区间47.2-91.8，p=0.0010），deucrictibant 40毫克组的发作率降低了84.5%（95%置信区间53.8-94.8，p=0.0008）。

Treatment-related treatment-emergent adverse events were experienced by two (18%) patients receiving deucrictibant 20 mg, one (8%) patient receiving deucrictibant 40 mg, and one (9%) patient receiving the placebo; all were mild in severity (grade 1) and did not require dosing modification of the study drug.

接受20 mg deucrictibant治疗的两名患者（18%）和接受40 mg deucrictibant治疗的一名患者（8%）以及接受安慰剂的一名患者（9%）经历了与治疗相关的治疗后不良事件；所有这些不良事件的严重程度均为轻度（1级），无需对研究药物进行剂量调整。

There were no serious adverse events or deaths in any treatment group.

在任何治疗组中都没有严重不良事件或死亡。

interpretation

To the best of our knowledge, this trial provides the first clinical evidence and proof-of-concept for bradykinin B2 receptor antagonism as a therapeutic approach for the prevention of hereditary angioedema attacks and supports further investigation of oral deucrictibant for bradykinin-mediated angioedema.

据我们所知，本试验提供了首个临床证据和概念验证，证明缓激肽B2受体拮抗剂作为预防遗传性血管性水肿发作的治疗手段，并支持对口服deucrictibant用于缓激肽介导的血管性水肿进行进一步研究。

funding

Pharvaris.

Pharvaris 公司。