托勒布替尼与特立氟米特治疗复发性多发性硬化症，这一成果由德国弗莱堡大学Heinz Wiendl团队经过不懈努力而取得。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：Tolebrutinib是一种口服、脑渗透、生物活性的布鲁顿酪氨酸激酶抑制剂，可调节外周炎症和中枢神经系统内的持续免疫激活，包括疾病相关的小胶质细胞和B细胞。其治疗复发性多发性硬化症的有效性和安全性需要更多的数据。

方法：在两项3期、双盲、双虚拟、事件驱动的试验（GEMINI 1和GEMINI 2）中，复发性多发性硬化症患者以1:1的比例随机分配接受tolebrutinib （60mg每日一次）或teriflunomide （14mg每日一次）治疗，每一项均与安慰剂相匹配。主要终点为年复发率。关键的次要终点是确认残疾恶化，持续至少6个月，这是在一个事件时间分析中评估的，该分析汇集了所有试验。

结果：共有974名参与者参加了GEMINI 1899名参与者参加了GEMINI 2。中位随访时间为139周。在GEMINI 1中，托勒布替尼组和特立氟米特组的年复发率分别为0.13和0.12(比率比为1.06；95%置信区间为0.81 ~ 1.39；P=0.67)， GEMINI 2组分别为0.11和0.11(比率比1.00；95% CI, 0.75 ~ 1.32；P = 0.98)。确认残疾恶化持续至少6个月的参与者的总百分比为：托勒布替尼组为8.3%，特立氟米特组为11.3%(风险比，0.71；95% CI, 0.53 ~ 0.95；由于预先设定了分层检验计划，因此没有进行正式的假设检验，并且没有对多重检验调整置信区间的宽度)。两个治疗组中出现不良事件的参与者比例相似，尽管托勒布替尼组出现轻微出血的比例高于特立氟米特组（出现瘀点的比例为4.5%比0.3%，大量月经的比例为2.6%比1.0%）。

研究结果表明，托勒布替尼在降低复发性多发性硬化症患者的年化复发率方面并不优于特立氟米特。

附：英文原文

Title: Tolebrutinib versus Teriflunomide in Relapsing Multiple Sclerosis

Author: Jiwon Oh, Douglas L. Arnold, Bruce A.C. Cree, Carolina Ionete, Ho Jin Kim, Maria Pia Sormani, Sana Syed, Yixin Chen, Christina R. Maxwell, Patrick Benoit, Timothy J. Turner, Erik Wallstroem, Heinz Wiendl

Issue&Volume: 2025-04-08

Abstract: BACKGROUND

Tolebrutinib is an oral, brain-penetrant, and bioactive Bruton’s tyrosine kinase inhibitor that modulates peripheral inflammation and persistent immune activation within the central nervous system, including disease-associated microglia and B cells. More data are needed on its efficacy and safety in treating relapsing multiple sclerosis.

METHODS

In two phase 3, double-blind, double-dummy, event-driven trials (GEMINI 1 and GEMINI 2), participants with relapsing multiple sclerosis were randomly assigned in a 1:1 ratio to receive tolebrutinib (60 mg once daily) or teriflunomide (14 mg once daily), each with matching placebo. The primary end point was the annualized relapse rate. The key secondary end point was confirmed worsening of disability that was sustained for at least 6 months, which was assessed in a time-to-event analysis that was pooled across trials.

RESULTS

A total of 974 participants were enrolled in GEMINI 1, and 899 were enrolled in GEMINI 2. The median follow-up was 139 weeks. The annualized relapse rate in the tolebrutinib and teriflunomide groups was 0.13 and 0.12, respectively, in GEMINI 1 (rate ratio, 1.06; 95% confidence interval [CI], 0.81 to 1.39; P=0.67) and 0.11 and 0.11, respectively, in GEMINI 2 (rate ratio, 1.00; 95% CI, 0.75 to 1.32; P=0.98). The pooled percentage of participants with confirmed disability worsening sustained for at least 6 months was 8.3% with tolebrutinib and 11.3% with teriflunomide (hazard ratio, 0.71; 95% CI, 0.53 to 0.95; no formal hypothesis testing was conducted owing to the prespecified hierarchical testing plan, and the width of the confidence interval is not adjusted for multiple testing). The percentage of participants who had adverse events was similar in the two treatment groups, although the percentage with minor bleeding was higher in the tolebrutinib group than in the teriflunomide group (petechiae occurred in 4.5% vs. 0.3%, and heavy menses in 2.6% vs. 1.0%).

CONCLUSIONS

Tolebrutinib was not superior to teriflunomide in decreasing annualized relapse rates among participants with relapsing multiple sclerosis.

DOI: NJ202504080000008

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2415985