近日，德国夏洛特柏林医科大学Marcus Maurer团队完成fenebrutinib治疗慢性自发性荨麻疹的2期临床试验。该项研究成果于2021年11月8日在线发表在《自然—医学》杂志上。

研究人员表示，布鲁顿酪氨酸激酶（BTK）对FcεRI介导的肥大细胞激活至关重要，对慢性自发性荨麻疹（CSU）中B细胞产生自身抗体也至关重要。fenebrutinib是一种口服的、有效的、高选择性的、可逆的BTK抑制剂，可能对CSU有效。

一项双盲、安慰剂对照的2期试验（EudraCT ID 2016-004624-35）将93名患有抗组胺药难治性CSU的成人随机分为每天50毫克、每天150毫克和每天200毫克的fenebrutinib组或安慰剂组，为期8周。主要终点是第8周时7天以上荨麻疹活动评分（UAS7）从基线的变化。次要终点是第4周UAS7从基线的变化和第8周控制良好（UAS7≤6）的患者比例。fenebrutinib对IIb型自身免疫患者的疗效和对IgG-抗FcεRI的影响是探索性终点。安全性也得到了评估。

主要终点已经达到：每天两次200毫克和每天150毫克的fenebrutinib与安慰剂相比，在第8周出现了UAS7的剂量依赖性改善，但每天50毫克的fenebrutinib则没有。fenebrutinib每日150毫克和每日两次200毫克组（各2名患者）出现无症状、可逆的2级和3级肝转氨酶升高。fenebrutinib减少了抗组胺药难治性CSU患者的疾病活动，包括更多难治性IIb型自身免疫的患者。这些结果支持BTK抑制在抗组胺药难治性CSU中的潜在应用。

附：英文原文

Title: Fenebrutinib in H1 antihistamine-refractory chronic spontaneous urticaria: a randomized phase 2 trial

Author: Metz, Martin, Sussman, Gordon, Gagnon, Rmi, Staubach, Petra, Tanus, Tonny, Yang, William H., Lim, Jeremy J., Clarke, Holly J., Galanter, Joshua, Chinn, Leslie W., Chu, Tom, Teterina, Anastasia, Burgess, Tracy, Haddon, D. James, Lu, Timothy T., Maurer, Marcus

Issue&Volume: 2021-11-08

Abstract: Bruton’s tyrosine kinase (BTK) is crucial for FcεRI-mediated mast cell activation and essential for autoantibody production by B cells in chronic spontaneous urticaria (CSU). Fenebrutinib, an orally administered, potent, highly selective, reversible BTK inhibitor, may be effective in CSU. This double-blind, placebo-controlled, phase 2 trial (EudraCT ID 2016-004624-35) randomized 93 adults with antihistamine-refractory CSU to 50mg daily, 150mg daily and 200mg twice daily of fenebrutinib or placebo for 8 weeks. The primary end point was change from baseline in urticaria activity score over 7d (UAS7) at week 8. Secondary end points were the change from baseline in UAS7 at week 4 and the proportion of patients well-controlled (UAS7≤6) at week 8. Fenebrutinib efficacy in patients with type IIb autoimmunity and effects on IgG-anti-FcεRI were exploratory end points. Safety was also evaluated. The primary end point was met, with dose-dependent improvements in UAS7 at week 8 occurring at 200mg twice daily and 150mg daily, but not at 50mg daily of fenebrutinib versus placebo. Asymptomatic, reversible grade 2 and 3 liver transaminase elevations occurred in the fenebrutinib 150mg daily and 200mg twice daily groups (2 patients each). Fenebrutinib diminished disease activity in patients with antihistamine-refractory CSU, including more patients with refractory type IIb autoimmunity. These results support the potential use of BTK inhibition in antihistamine-refractory CSU.

DOI: 10.1038/s41591-021-01537-w

Source: https://www.nature.com/articles/s41591-021-01537-w