Honda Daisuke, Hide Michihiro, Fukuda Tomoo, Koga Keisuke, Morita Eishin, Moriwaki Shinichi, Sasaki Yoshihiro, Suzuki Yusuke, Collis Phil, Johnston Douglas T, Tomita Dianne, Desai Bhavisha, Ohsawa Isao
Department of Nephrology, Chiba University Graduate School of Medicine, Chiba, Japan.
Department of Dermatology, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan.
World Allergy Organ J. 2024 Mar 2;17(3):100882. doi: 10.1016/j.waojou.2024.100882. eCollection 2024 Mar.
Berotralstat is a once-daily oral inhibitor of plasma kallikrein for the prophylaxis of hereditary angioedema (HAE) in patients ≥12 years. APeX-J aimed to evaluate the efficacy and safety of berotralstat in Japan.
APeX-J was a Phase III trial comprising 3 parts (NCT03873116). Part 1 was a randomized, placebo-controlled evaluation of berotralstat 150 or 110 mg over 24 weeks. Part 2 was a 28-week dose-blinded phase in which berotralstat-treated patients continued the same dose and placebo patients were re-randomized to berotralstat 150 or 110 mg. In Part 3, all patients remaining on study received berotralstat 150 mg in an open-label manner for up to an additional 52 weeks. The primary endpoint of Parts 2 and 3 was long-term safety and tolerability, and secondary endpoints examined effectiveness.
Seventeen patients entered Part 2, and 11 continued into Part 3. Treatment-emergent adverse events (TEAEs) were reported by 14/17 patients (82.4%) in Parts 2 or 3; the most common were nasopharyngitis, abdominal pain, cystitis, influenza, and vertigo. One patient (5.9%) experienced a drug-related TEAE (Grade 4 increased hepatic enzyme). No drug-related serious TEAEs were reported. For patients who completed 26 months of treatment with berotralstat 150 mg (n = 5), mean (standard error of the mean) monthly HAE attack rates and on-demand medication use decreased from baseline by 1.15 (0.09) attacks/month and 2.8 (0.64) doses/month, respectively. Sustained improvements were also observed in patient quality of life and treatment satisfaction.
Long-term prophylaxis with berotralstat raised no new safety signals and was effective at reducing attacks and improving patient-reported outcomes.
ClinicalTrials.gov NCT03873116. Registered March 13, 2019. Retrospectively registered.
贝罗他司他是一种每日一次的口服血浆激肽释放酶抑制剂，用于预防12岁及以上患者的遗传性血管性水肿（HAE）。APeX-J旨在评估贝罗他司他在日本的疗效和安全性。
APeX-J是一项III期试验，包括3个部分（NCT03873116）。第1部分是对150或110mg贝罗他司他进行24周的随机、安慰剂对照评估。第2部分是一个28周的剂量盲法阶段，在此阶段，接受贝罗他司他治疗的患者继续使用相同剂量，而安慰剂组患者重新随机分配至150或110mg贝罗他司他组。在第3部分中，所有继续参与研究的患者以开放标签方式接受150mg贝罗他司他治疗，最长可达52周。第2部分和第3部分的主要终点是长期安全性和耐受性，次要终点是疗效。
17名患者进入第2部分，11名患者继续进入第3部分。在第2部分或第3部分中，14/十七（约82.4%）的患者报告了治疗中出现的不良事件（TEAE）；最常见的是鼻咽炎、腹痛、膀胱炎、流感和眩晕。1名患者（5.9%）发生了与药物相关的TEAE（4级肝酶升高）。未报告与药物相关的严重TEAE。对于完成150mg贝罗他司他26个月治疗的患者（n=5），平均（平均标准误）每月HAE发作率和按需用药量分别较基线水平降低了1.15（0.09）次/月和2.8（0.64）剂/月。患者的生活质量和治疗满意度也有持续改善。
贝罗他司他长期预防未产生新的安全信号，在减少发作和改善患者报告结局方面有效。
ClinicalTrials.gov NCT03873116。2019年3月13日注册。回顾性注册。
