美国国立卫生研究院Daniel S. Reich研究组取得一项新突破。他们的最新研究提出了托勒布替尼治疗非复发性继发性进行性多发性硬化症。相关论文于2025年4月8日发表在《新英格兰医学杂志》上。

背景：在多发性硬化症的整个过程中，可发生逐渐进行性的神经功能损害，这被称为残疾累积。目前多发性硬化症的疾病改善疗法对与复发无关的残疾累积效果有限，复发被认为部分是由中枢神经系统的慢性、非缓解性神经炎症引起的。Tolebrutinib是一种口服脑渗透布鲁顿酪氨酸激酶抑制剂，靶向外周和中枢神经系统的髓样细胞（包括小胶质细胞）和B细胞。对于非复发性继发性进行性多发性硬化症，尚无批准的治疗方法。

方法：在一项3期、双盲、安慰剂对照、事件驱动的试验中，研究组以2:1的比例随机分配患有非复发性继发性进行性多发性硬化症的参与者，接受托勒布替尼（60mg，每日一次）或匹配的安慰剂。主要终点是确认残疾进展持续至少6个月，在事件时间分析中进行评估。

结果：共有1131名受试者接受了随机分组：754名受试者接受托鲁替尼治疗，377名受试者接受安慰剂治疗。中位随访时间为133周。与安慰剂组相比，托勒布替尼组中确认残疾进展持续至少6个月的参与者比例较小(22.6% vs. 30.7%；风险比0.69；95%置信区间为0.55 ~ 0.88；P = 0.003)。托勒布替尼组15.0%的受试者发生严重不良事件，安慰剂组10.4%的受试者发生严重不良事件。托勒布替尼组中有4.0%的参与者和安慰剂组中有1.6%的参与者丙氨酸转氨酶水平升高到正常范围上限的3倍以上。

研究结果表明，在非复发性继发性进展性多发性硬化症患者中，接受托勒布替尼治疗的患者残疾进展的风险低于接受安慰剂治疗的患者。

附：英文原文

Title: Tolebrutinib in Nonrelapsing Secondary Progressive Multiple Sclerosis

Author: Robert J. Fox, Amit Bar-Or, Anthony Traboulsee, Celia Oreja-Guevara, Gavin Giovannoni, Patrick Vermersch, Sana Syed, Ye Li, Wendy S. Vargas, Timothy J. Turner, Erik Wallstroem, Daniel S. Reich

Issue&Volume: 2025-04-08

Abstract: BACKGROUND

Throughout the course of multiple sclerosis, gradually progressive neurologic impairment can occur, which has been called disability accrual. Current disease-modifying therapies for multiple sclerosis have limited effects on disability accrual unrelated to relapses, which is thought to be partially caused by chronic, nonresolving neuroinflammation within the central nervous system. Tolebrutinib is an oral, brain-penetrant Bruton’s tyrosine kinase inhibitor that targets myeloid cells (including microglia) and B cells in both the periphery and central nervous system. There are no approved treatments for nonrelapsing secondary progressive multiple sclerosis.

METHODS

In a phase 3, double-blind, placebo-controlled, event-driven trial, we randomly assigned participants with nonrelapsing secondary progressive multiple sclerosis, in a 2:1 ratio, to receive tolebrutinib (60 mg once daily) or matching placebo. The primary end point was confirmed disability progression that was sustained for at least 6 months, assessed in a time-to-event analysis.

RESULTS

A total of 1131 participants underwent randomization: 754 were assigned to receive tolebrutinib and 377 to receive placebo. The median follow-up was 133 weeks. A smaller percentage of participants in the tolebrutinib group than in the placebo group had confirmed disability progression sustained for at least 6 months (22.6% vs. 30.7%; hazard ratio, 0.69; 95% confidence interval, 0.55 to 0.88; P=0.003). Serious adverse events occurred in 15.0% of the participants in the tolebrutinib group and in 10.4% of those in the placebo group. A total of 4.0% of the participants in the tolebrutinib group and 1.6% of those in the placebo group had increases in alanine aminotransferase levels to more than 3 times the upper limit of the normal range.

CONCLUSIONS

In participants with nonrelapsing secondary progressive multiple sclerosis, the risk of disability progression was lower among those who received treatment with tolebrutinib than among those who received placebo.

DOI: NJ202504080000007

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2415988