美国斯坦福大学Lawrence Steinman团队比较了乌妥昔单抗与特立氟胺治疗复发性多发性硬化症的疗效与安全性。2022年8月24日出版的《新英格兰医学杂志》发表了这项成果。

单克隆抗体乌妥昔单抗增强抗体依赖性细胞裂解并产生B细胞耗竭。目前研究人员正在评估乌妥昔单抗治疗复发性多发性硬化症的疗效。

在两个相同、3期、双盲、双模拟试验（终极I和II）中，研究组招募复发性多发性硬化症患者，将其按1:1的比例随机分配，分别接受静脉注射乌妥昔单抗（第1天150 mg，第15天和第24、48和72周450 mg）和口服安慰剂，或口服特立氟胺（14 mg，每日一次）和静脉注射安慰剂。主要终点是年化复发率。次要终点包括96周时磁共振成像（MRI）上钆增强病变的数量和残疾恶化。

共有549名参与者参加了终极I试验，545名参加了终极II试验；中位随访时间为95周。在终极I试验中，乌妥昔单抗组和特立氟胺组的年化复发率分别为0.08和0.19（比率比为0.41），组间差异显著；在终极II试验中，两组的年化复发率分别为0.09和0.18（比率比为0.51），组间差异亦显著。

在终极I试验中，乌妥昔单抗组钆增强病变的平均数量为0.02，特立氟胺组为0.49（比率比为0.03），组间差异显著；在终极II试验中两组分别为0.01和0.25（比率比为0.04），组间差异亦显著。

在两项试验的汇总分析中，乌妥昔单抗组和特立氟胺组中5.2%和5.9%的受试者在12周时残疾恶化（危险比为0.84），组间差异不显著。乌妥昔单抗组47.7%的受试者发生输液相关反应。乌妥昔单抗组和特立氟胺组的严重感染发生率分别为5.0%和2.9%。

研究结果表明，在复发性多发性硬化症患者中，在96周的时间内，乌妥昔单抗的年化复发率和MRI脑损伤率均低于特立氟胺，但并未显著降低残疾恶化的风险。乌妥昔单抗与输注相关反应有关。

附：英文原文

Title: Ublituximab versus Teriflunomide in Relapsing Multiple Sclerosis

Author: Lawrence Steinman, M.D.,, Edward Fox, M.D., Ph.D.,, Hans-Peter Hartung, M.D.,, Enrique Alvarez, M.D., Ph.D.,, Peiqing Qian, M.D.,, Sibyl Wray, M.D.,, Derrick Robertson, M.D.,, DeRen Huang, M.D., Ph.D.,, Krzysztof Selmaj, M.D., Ph.D.,, Daniel Wynn, M.D.,, Gary Cutter, Ph.D.,, Koby Mok, Ph.D.,, Yanzhi Hsu, Ph.D.,, Yihuan Xu, Ph.D.,, Michael S. Weiss, J.D.,, Jenna A. Bosco, B.S.,, Sean A. Power, B.S.,, Lily Lee, Ph.D.,, Hari P. Miskin, M.Sc.,, and Bruce A.C. Cree, M.D., Ph.D.

Issue&Volume: 2022-08-24

Abstract:

Background

The monoclonal antibody ublituximab enhances antibody-dependent cellular cytolysis and produces B-cell depletion. Ublituximab is being evaluated for the treatment of relapsing multiple sclerosis.

Methods

In two identical, phase 3, double-blind, double-dummy trials (ULTIMATE I and II), participants with relapsing multiple sclerosis were randomly assigned in a 1:1 ratio to receive intravenous ublituximab (150 mg on day 1, followed by 450 mg on day 15 and at weeks 24, 48, and 72) and oral placebo or oral teriflunomide (14 mg once daily) and intravenous placebo. The primary end point was the annualized relapse rate. Secondary end points included the number of gadolinium-enhancing lesions on magnetic resonance imaging (MRI) by 96 weeks and worsening of disability.

Results

A total of 549 participants were enrolled in the ULTIMATE I trial, and 545 were enrolled in the ULTIMATE II trial; the median follow-up was 95 weeks. In the ULTIMATE I trial, the annualized relapse rate was 0.08 with ublituximab and 0.19 with teriflunomide (rate ratio, 0.41; 95% confidence interval [CI], 0.27 to 0.62; P<0.001); in the ULTIMATE II trial, the annualized relapse rate was 0.09 and 0.18, respectively (rate ratio, 0.51; 95% CI, 0.33 to 0.78; P=0.002). The mean number of gadolinium-enhancing lesions was 0.02 in the ublituximab group and 0.49 in the teriflunomide group (rate ratio, 0.03; 95% CI, 0.02 to 0.06; P<0.001) in the ULTIMATE I trial and 0.01 and 0.25, respectively (rate ratio, 0.04; 95% CI, 0.02 to 0.06; P<0.001), in the ULTIMATE II trial. In the pooled analysis of the two trials, 5.2% of the participants in the ublituximab group and 5.9% in the teriflunomide group had worsening of disability at 12 weeks (hazard ratio, 0.84; 95% CI, 0.50 to 1.41; P=0.51). Infusion-related reactions occurred in 47.7% of the participants in the ublituximab group. Serious infections occurred in 5.0% in the ublituximab group and in 2.9% in the teriflunomide group.

Conclusions

Among participants with relapsing multiple sclerosis, ublituximab resulted in lower annualized relapse rates and fewer brain lesions on MRI than teriflunomide over a period of 96 weeks but did not result in a significantly lower risk of worsening of disability. Ublituximab was associated with infusion-related reactions.

DOI: NJ202208253870807

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2201904