本文由小咖机器人翻译整理

期刊来源：N Engl J Med

原文链接：https://doi.org/10.1056/NEJMoa2309439

摘要内容如下：

背景

CD40-CD40L共刺激通路调节适应性和先天性免疫应答，并与多发性硬化的发病机制有关。Frexalimab是第二代抗CD40L单克隆抗体，用于评估多发性硬化症的治疗。

方法

在这项2期、双盲、随机试验中，我们按照4:4:1:1的比例，将复发性多发性硬化症患者分为三组：每4周静脉注射1200 mg frexalimab（负荷剂量为1800 mg），每2周皮下注射300 mg frexalimab（负荷剂量为600 mg），或与之匹配的安慰剂。主要终点是第12周相对于第8周磁共振成像所见的新的钆增强T1加权病变的数量。次要终点包括第12周相对于第8周的新的或扩大的T2加权病变的数量、第12周钆增强T1加权病变的总数以及安全性。12周后，所有参与者都可以接受开放标签的Frexalimab。

结果

在筛选的166名参与者中，129人被分配到试验组；125名参与者（97%）完成了为期12周的双盲期。参与者的平均年龄为36.6岁，66%为女性，30%在基线时有钆增强病变。在第12周，静脉注射1200 mg frexalimab组新的钆增强T1加权病变的校正平均数为0.2（95%可信区间[CI]，0.1至0.4），皮下注射300 mg frexalimab组为0.3（95%CI，0.1至0.6），而合并安慰剂组为1.4（95%CI，0.6至3.0）。与安慰剂相比，1200 mg组的比率为0.11（95%CI，0.03至0.38），300 mg组的比率为0.21（95%CI，0.08至0.56）。次要成像终点的结果通常与主要分析的结果方向相同。最常见的不良事件是2019年冠状病毒病和头痛。

结论

在一项涉及多发性硬化症患者的2期临床试验中，与安慰剂相比，用frexalimab抑制CD40L的效果通常有利于在第12周时更大程度地减少新的钆增强T1加权病变的数量。需要更大规模和更长时间的试验来确定Frexalimab对多发性硬化症患者的长期疗效和安全性。（由赛诺菲资助；ClinicalTrials.gov编号，NCT04879628。）

英文原文如下：

Abstracts

BACKGROUND  The CD40-CD40L costimulatory pathway regulates adaptive and innate immune responses and has been implicated in the pathogenesis of multiple sclerosis. Frexalimab is a second-generation anti-CD40L monoclonal antibody being evaluated for the treatment of multiple sclerosis.

METHODS  In this phase 2, double-blind, randomized trial, we assigned, in a 4:4:1:1 ratio, participants with relapsing multiple sclerosis to receive 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose), or the matching placebos for each active treatment. The primary end point was the number of new gadolinium-enhancing T1-weighted lesions seen on magnetic resonance imaging at week 12 relative to week 8. Secondary end points included the number of new or enlarging T2-weighted lesions at week 12 relative to week 8, the total number of gadolinium-enhancing T1-weighted lesions at week 12, and safety. After 12 weeks, all the participants could receive open-label frexalimab.

RESULTS  Of 166 participants screened, 129 were assigned to a trial group; 125 participants (97%) completed the 12-week double-blind period. The mean age of the participants was 36.6 years, 66% were women, and 30% had gadolinium-enhancing lesions at baseline. At week 12, the adjusted mean number of new gadolinium-enhancing T1-weighted lesions was 0.2 (95% confidence interval [CI], 0.1 to 0.4) in the group that received 1200 mg of frexalimab intravenously and 0.3 (95% CI, 0.1 to 0.6) in the group that received 300 mg of frexalimab subcutaneously, as compared with 1.4 (95% CI, 0.6 to 3.0) in the pooled placebo group. The rate ratios as compared with placebo were 0.11 (95% CI, 0.03 to 0.38) in the 1200-mg group and 0.21 (95% CI, 0.08 to 0.56) in the 300-mg group. Results for the secondary imaging end points were generally in the same direction as those for the primary analysis. The most common adverse events were coronavirus disease 2019 and headaches.

CONCLUSIONS  In a phase 2 trial involving participants with multiple sclerosis, inhibition of CD40L with frexalimab had an effect that generally favored a greater reduction in the number of new gadolinium-enhancing T1-weighted lesions at week 12 as compared with placebo. Larger and longer trials are needed to determine the long-term efficacy and safety of frexalimab in persons with multiple sclerosis. (Funded by Sanofi; ClinicalTrials.gov number, NCT04879628.).

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