Guidelines recommend effective on-demand therapy for all individuals with hereditary angioedema. We aimed to assess the novel oral plasma kallikrein inhibitor, sebetralstat, which is in development, for on-demand treatment of hereditary angioedema attacks. In this two-part phase 2 trial, individuals with type 1 or 2 hereditary angioedema aged 18 years or older were recruited from 25 sites, consisting of specialty outpatient centres, across nine countries in Europe and the USA. Individuals were eligible if they had experienced at least three hereditary angioedema attacks in the past 93 days, were not on prophylactic therapy, and had access to and the ability to self-administer conventional attack treatment. In part 1 of the trial, participants were given a single 600 mg open-label oral dose of sebetralstat to assess safety, pharmacokinetics, and pharmacodynamics of the dose. Part 2 was a randomised, double-blind, placebo-controlled, two-sequence, two-period (2 × 2) crossover trial; participants were randomly assigned (1:1) to either sequence 1, in which they were given a single dose of 600 mg of sebetralstat to treat the first eligible attack and a second dose of placebo to treat the second eligible attack, or sequence 2, in which they were given placebo to treat the first eligible attack and then 600 mg of sebetralstat to treat the second eligible attack. Participants and investigators were masked to treatment assignment. The primary endpoint was time to use of conventional attack treatment within 12 h of study drug administration, which was assessed in all participants who were randomly assigned to treatment and who received study drug for two attacks during part 2 of the study. Safety was assessed in all participants who received at least one dose of study drug, starting in part 1. This study is registered with , , and is completed. Between July 2, 2019, and Dec 8, 2020, 84 individuals were screened and 68 were enrolled in part 1 and received sebetralstat (mean age 38·3 years [SD 13·2], 37 [54%] were female, 31 [46%] were male, 68 [100%] were White). 42 (62%) of 68 participants completed pharmacokinetic assessments. Sebetralstat was rapidly absorbed, with a geometric mean plasma concentration of 501 ng/mL at 15 min. In a subset of participants (n=6), plasma samples obtained from 15 min to 4 h after study drug administration had near-complete protection from ex vivo stimulated generation of plasma kallikrein and cleavage of high-molecular-weight kininogen. In part 2, all 68 participants were randomly assigned to sequence 1 (n=34) or sequence 2 (n=34). 53 (78%) of 68 participants treated two attacks (25 [74%] in the sequence 1 group and 28 [82%] in the sequence 2 group). Time to use of conventional treatment within 12 h of study drug administration was significantly longer with sebetralstat versus placebo (at quartile 1: >12 h [95% CI 9·6 to >12] 8·0 h [3·8 to >12]; p=0·0010). There were no serious adverse events or adverse event-related discontinuations. Oral administration of sebetralstat was well tolerated and led to rapid suppression of plasma kallikrein activity, resulting in increased time to use of conventional attack treatment and faster symptom relief versus placebo. Based on these results, a phase 3 trial to evaluate the efficacy and safety of two dose levels of sebetralstat in adolescent and adult participants with hereditary angioedema has been initiated (). KalVista Pharmaceuticals.

中文翻译：

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一种研究性口服血浆激肽释放酶抑制剂，用于按需治疗遗传性血管性水肿：一项分为两部分、随机、双盲、安慰剂对照、交叉 2 期试验

指南建议对所有遗传性血管性水肿患者进行有效的按需治疗。我们的目的是评估正在开发的新型口服血浆激肽释放酶抑制剂 sebetralstat，用于按需治疗遗传性血管性水肿发作。在这项由两部分组成的 2 期试验中，从欧洲和美国 9 个国家的 25 个地点（包括专科门诊中心）招募了年龄在 18 岁或以上的患有 1 型或 2 型遗传性血管水肿的个体。如果个人在过去 93 天内经历过至少 3 次遗传性血管性水肿发作、未接受预防性治疗、并且能够获得并有能力自行进行常规发作治疗，则符合资格。在试验的第 1 部分中，参与者接受了单次 600 mg 开放标签口服剂量的 sebetralstat，以评估该剂量的安全性、药代动力学和药效学。第 2 部分是一项随机、双盲、安慰剂对照、双序列、两阶段 (2 × 2) 交叉试验；参与者被随机分配 (1:1) 至序列 1，其中他们接受单剂 600 mg sebetralstat 治疗第一次符合条件的发作，并服用第二剂安慰剂治疗第二次符合条件的发作，或序列 2，其中，他们服用安慰剂来治疗第一次符合条件的发作，然后服用 600 毫克 sebetralstat 来治疗第二次符合条件的发作。参与者和研究人员对治疗分配情况不知情。主要终点是在研究药物给药后 12 小时内使用常规发作治疗的时间，对所有随机分配接受治疗并在研究第 2 部分期间接受两次发作研究药物的参与者进行评估。从第 1 部分开始，对所有接受至少一剂研究药物的参与者进行安全性评估。本研究已注册， ， ，并已完成。2019 年 7 月 2 日至 2020 年 12 月 8 日期间，对 84 名受试者进行了筛查，其中 68 名受试者参加了第 1 部分并接受了 sebetralstat（平均年龄 38·3 岁 [SD 13·2]，37 名 [54%] 为女性，31 名[ 46%] 为男性，68 [100%] 为白人）。68 名参与者中有 42 名 (62%) 完成了药代动力学评估。Sebetralstat 被迅速吸收，15 分钟时几何平均血浆浓度为 501 ng/mL。在一部分参与者 (n=6) 中，研究药物给药后 15 分钟至 4 小时内获得的血浆样本几乎完全免受离体刺激的血浆激肽释放酶的产生和高分子量激肽原的裂解。在第 2 部分中，所有 68 名参与者被随机分配到序列 1 (n=34) 或序列 2 (n=34)。68 名参与者中有 53 名 (78%) 治疗了两次发作（序列 1 组中 25 名 [74%]，序列 2 组中 28 名 [82%]）。与安慰剂相比，sebetralstat 在研究药物给药后 12 小时内使用常规治疗的时间明显更长（在四分位数 1 时：>12 小时 [95% CI 9·6 至 >12] 8·0 小时 [3·8 至 >12] ]；p=0·0010)。没有严重的不良事件或不良事件相关的停药。口服sebetralstat具有良好的耐受性，并能快速抑制血浆激肽释放酶活性，从而与安慰剂相比，增加了使用常规发作治疗的时间，并更快地缓解症状。基于这些结果，一项 3 期试验已启动，旨在评估两种剂量水平的 sebetralstat 对患有遗传性血管水肿的青少年和成人参与者的有效性和安全性 ()。卡尔维斯塔制药公司。