德国柏林卡里特大学Marcus Maurer团队研究了一种按需治疗遗传性血管性水肿的实验性口服血浆激肽素抑制剂的疗效。相关论文发表在2023年2月11日出版的《柳叶刀》杂志上。

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。该研究旨在评估正在开发的新型口服血浆激肽素抑制剂sebetralstat，用于按需治疗遗传性血管性水肿发作的疗效。

在这项分为两部分的二期试验中，研究组从欧洲和美国9个国家的25个地点（包括专科门诊中心）招募年龄在18岁及以上的1或2型遗传性血管性水肿患者。如果患者在过去93天内经历了至少三次遗传性血管性水肿发作，没有预防性治疗，并且有机会、有能力自我管理常规发作治疗，则符合条件。在试验的第一部分，参与者被给予单次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。

第二部分为随机、双盲、安慰剂对照、双序列、两期（2 × 2）交叉试验，参与者被随机分配（1:1）到序列1，他们被给予单剂量600 mg sebetralstat治疗第一次符合条件的发作，之后安慰剂治疗第二次符合条件的发作；或者序列2，他们被给予安慰剂治疗第一次符合条件的发作，然后600 mg sebetralstat治疗第二次符合条件的发作。受试者和调查人员对治疗分配双盲。

主要终点是研究药物给药后12小时内进行常规发作治疗的时间，在所有随机分配到治疗组的参与者中进行评估，这些参与者在研究的第二部分中接受了两次发作的研究药物。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了安全性评估。

在2019年7月2日至2020年12月8日期间，研究组对84人进行了筛查，其中68人入组第一部分并接受sebetralstat治疗（平均年龄38.3岁， 37[54%]名为女性，31[46%]名为男性，68[100%]名为白人）。68名参与者中有42人（62%）完成了药代动力学评估。Sebetralstat吸收迅速，15 min时血药几何平均浓度为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对体外刺激产生的血浆激肽素和高分子量激肽原的裂解具有近乎完全的保护作用。

在第二部分中，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25人[74%]，序列2组28人[82%]）。在研究药物给药后12小时内使用常规治疗的时间，sebetralstat组明显长于安慰剂组。治疗组无严重不良事件或不良事件相关的停药。

研究结果表明，口服sebetralstat耐受性良好，可快速抑制血浆激肽素活性，导致使用常规发作治疗的时间增加，与安慰剂相比症状缓解更快。基于这些结果，一项评估两种剂量水平的sebetralstat在青少年和成人遗传性血管性水肿患者中有效性和安全性的3期试验已经启动（NCT05259917）。

附：英文原文

Title: An investigational oral plasma kallikrein inhibitor for on-demand treatment of hereditary angioedema: a two-part, randomised, double-blind, placebo-controlled, crossover phase 2 trial

Author: Emel Aygren-Pürsün, Andrea Zanichelli, Danny M Cohn, Mauro Cancian, Roman Hakl, Tamar Kinaciyan, Markus Magerl, Inmaculada Martinez-Saguer, Marcin Stobiecki, Henriette Farkas, Sorena Kiani-Alikhan, Vesna Grivcheva-Panovska, Jonathan A Bernstein, H Henry Li, Hilary J Longhurst, Paul K Audhya, Michael D Smith, Christopher M Yea, Andreas Maetzel, Daniel K Lee, Edward P Feener, Richard Gower, William R Lumry, Aleena Banerji, Marc A Riedl, Marcus Maurer

Issue&Volume: 2023/02/11

Abstract:

Background

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.

Methods

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 ClinicalTrials.gov, NCT04208412, and is completed.

Findings

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] vs 8·0 h [3·8 to >12]; p=0·0010). There were no serious adverse events or adverse event-related discontinuations.

Interpretation

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 (NCT05259917).

DOI: 10.1016/S0140-6736(22)02406-0

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)02406-0/fulltext