瓦尔德希布伦大学医院Douglas L. Arnold研究组的一项最新研究提出了口服BTK抑制剂治疗多发性硬化症的安慰剂对照试验。2019年6月20日，国际知名学术期刊《新英格兰医学杂志》发表了这一成果。

Evobrutinib是一种选择性口服BTK抑制剂，在体内和体外均有抑制B细胞活化的作用。 在这个双盲、随机、二期试验中，研究人员将复发多发性硬化症患者分为五组:安慰剂组、Evobrutinib(剂量为每日25毫克、每日75毫克或每日两次，每次75毫克)，或富马酸二甲酯(DMF)作为参考。 主要终点是在第12周、第16周、第20周和第24周T1加权磁共振成像中发现的钆增强病变的总数(累计)。 主要第二终点包括扩大残疾状况量表(EDSS)评分的年复发率和与基线的变化。 将267例患者随机分为实验组。 12=24周内，安慰剂组平均增强病变数为3.85，evobrutinib 25mg组为4.06，evobrutinib 75mg 每日一次组为1.69，evobrutinib 75mg 每日两次组为1.15，DMF组为4.78。与安慰剂组相比，evobrutinib 25 mg组（p=0.32）、evobrutinib 75 mg每日一次（p=0.005）和evobrutinib 75 mg每日两次（p=0.06）组，经基线调整后，总病变数比率分别为1.45、0.30和0.44。安慰剂组24周未调整的年化复发率为0.37，Evobrutinib 25mg组为0.57，Evobrutinib 75mg每日一次组为0.13，Evobrutinib 75mg每日两次组为0.08，DMF组为0.20组间EDSS评分变化不显著。Evobrutinib组肝转氨酶值升高明显。复发性多发性硬化症患者，每天服用75毫克Evobrutinib一次，在12至24周内的强化病灶明显少于服用安慰剂的患者。 无论是25毫克每日一次的Evobrutinib还是75毫克每日两次的Evobrutinib，在任何剂量的年复发率或残疾进展方面，与安慰剂均无显著差异。 需要更长的时间和更大的试验来确定Evobrutinib对多发性硬化症患者的疗效和风险。

据介绍，Bruton酪氨酸激酶(BTK)调节B细胞和髓细胞的功能，涉及多发性硬化的发病机制。

附：英文原文

Title: Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis

Author: Xavier Montalban, M.D., Ph.D., Douglas L. Arnold, M.D., Martin S. Weber, M.D., Ivan Staikov, M.D., Ph.D., Karolina Piasecka-Stryczynska, M.D., Ph.D., Jonathan Willmer, M.D., Emily C. Martin, Ph.D., Fernando Dangond, M.D., Sana Syed, M.D., M.P.H

Issue&Volume: VOL.380 NO.25, 2019

Abstract:

BACKGROUND Bruton’s tyrosine kinase (BTK) regulates the functions of B cells and myeloid cells that are implicated in the pathogenesis of multiple sclerosis. Evobrutinib is a selective oral BTK inhibitor that has been shown to inhibit B-cell activation both in vitro and in vivo.

METHODS In this double-blind, randomized, phase 2 trial, we assigned patients with relapsing multiple sclerosis to one of five groups: placebo, evobrutinib (at a dose of 25 mg once daily, 75 mg once daily, or 75 mg twice daily), or open-label dimethyl fumarate (DMF) as a reference. The primary end point was the total (cumulative) number of gadolinium-enhancing lesions identified on T1-weighted magnetic resonance imaging at weeks 12, 16, 20, and 24. Key secondary end points included the annualized relapse rate and change from baseline in the score on the Expanded Disability Status Scale (EDSS).

RESULTS A total of 267 patients were randomly assigned to a trial group. The mean (±SD) total number of gadolinium-enhancing lesions during weeks 12 through 24 was 3.85±5.44 in the placebo group, 4.06±8.02 in the evobrutinib 25-mg group, 1.69±4.69 in the evobrutinib 75-mg once-daily group, 1.15±3.70 in the evobrutinib 75-mg twice-daily group, and 4.78±22.05 in the DMF group. The baseline adjusted rate ratios for the total number of lesions over time as compared with placebo were 1.45 in the evobrutinib 25-mg group (P=0.32), 0.30 in the evobrutinib 75-mg once-daily group (P=0.005), and 0.44 in the evobrutinib 75-mg twice-daily group (P=0.06). The unadjusted annualized relapse rate at week 24 was 0.37 in the placebo group, 0.57 in the evobrutinib 25-mg group, 0.13 in the evobrutinib 75-mg once-daily group, 0.08 in the evobrutinib 75-mg twice-daily group, and 0.20 in the DMF group. There was no significant effect of trial group on the change from baseline in the EDSS score. Elevations in liver aminotransferase values were observed with evobrutinib.

CONCLUSIONS Patients with relapsing multiple sclerosis who received 75 mg of evobrutinib once daily had significantly fewer enhancing lesions during weeks 12 through 24 than those who received placebo. There was no significant difference with placebo for either the 25-mg once-daily or 75-mg twice-daily dose of evobrutinib, nor in the annualized relapse rate or disability progression at any dose. Longer and larger trials are required to determine the effect and risks of evobrutinib in patients with multiple sclerosis.

DOI: 10.1056/NEJMoa1901981

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1901981