乌利昔单抗与特立氟胺治疗复发性多发性硬化症。

Ublituximab versus Teriflunomide in Relapsing Multiple Sclerosis.

机构信息

From the Beckman Center for Molecular Medicine, Stanford University, Stanford (L.S.), and the Weill Institute for Neurosciences, University of California, San Francisco, San Francisco (B.A.C.C.) - both in California; Central Texas Neurology Consultants, Round Rock (E.F.); Heinrich Heine University Medical School, Düsseldorf, Germany (H.-P.H.); the Brain and Mind Centre, University of Sydney, Sydney (H.-P.H.); Medical University of Vienna, Vienna (H.-P.H.); Palacký University Olomouc, Olomouc, Czech Republic (H.-P.H.); University of Colorado, Aurora (E.A.); Swedish Medical Center, Seattle (P.Q.); Hope Neurology, Knoxville, TN (S.W.); University of South Florida, Tampa (D.R.); Columbus Neuroscience, Westerville, OH (D.H.); the Department of Neurology, University of Warmia and Mazury, Olsztyn, and Center of Neurology, Lodz - both in Poland (K.S.); Consultants in Neurology, Northbrook, IL (D.W.); and TG Therapeutics, New York (G.C., K.M., Y.H., Y.X., M.S.W., J.A.B., S.A.P., L.L., H.P.M.).

出版信息

N Engl J Med. 2022 Aug 25;387(8):704-714. doi: 10.1056/NEJMoa2201904.

DOI:10.1056/NEJMoa2201904

PMID:36001711

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. (Funded by TG Therapeutics; ULTIMATE I and II ClinicalTrials.gov numbers, NCT03277261 and NCT03277248.).

摘要

背景

单克隆抗体 ublituximab 增强抗体依赖性细胞细胞毒性并导致 B 细胞耗竭。Ublituximab 正在评估用于治疗复发性多发性硬化症。

方法

在两项相同的、3 期、双盲、双模拟试验（ULTIMATE I 和 II）中，将复发性多发性硬化症患者随机分为 1:1 比例，分别接受静脉注射 ublituximab（第 1 天 150mg，第 15 天和第 24、48 和 72 周各 450mg）和口服安慰剂或口服特立氟胺（每天 14mg）和静脉注射安慰剂。主要终点是年复发率。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。

结果

共有 549 名参与者入组 ULTIMATE I 试验，545 名参与者入组 ULTIMATE II 试验；中位随访时间为 95 周。在 ULTIMATE I 试验中，ublituximab 的年复发率为 0.08，特立氟胺为 0.19（比率，0.41；95%置信区间[CI]，0.27 至 0.62；P<0.001）；在 ULTIMATE II 试验中，年复发率分别为 0.09 和 0.18（比率，0.51；95%CI，0.33 至 0.78；P = 0.002）。在 ULTIMATE I 试验中，ublituximab 组的平均钆增强病变数量为 0.02，特立氟胺组为 0.49（比率，0.03；95%CI，0.02 至 0.06；P<0.001），在 ULTIMATE II 试验中，ublituximab 组和特立氟胺组分别为 0.01 和 0.25（比率，0.04；95%CI，0.02 至 0.06；P<0.001）。在两项试验的汇总分析中，ublituximab 组和特立氟胺组分别有 5.2%和 5.9%的参与者在 12 周时残疾恶化（风险比，0.84；95%CI，0.50 至 1.41；P = 0.51）。在 ublituximab 组中，47.7%的参与者出现输注相关反应。在 ublituximab 组中，5.0%的参与者发生严重感染，特立氟胺组为 2.9%。

结论

在复发性多发性硬化症患者中，与特立氟胺相比，ublituximab 在 96 周内导致年复发率降低和 MRI 上脑病变减少，但残疾恶化的风险没有显著降低。Ublituximab 与输注相关反应有关。（由 TG Therapeutics 资助；ULTIMATE I 和 II ClinicalTrials.gov 编号，NCT03277261 和 NCT03277248）。