Neurology and Research Center for Clinical Neuroimmunology and Neuroscience Basel, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering University Hospital and University of Basel, Basel, Switzerland.
Cleveland Clinic, Cleveland, Ohio.
JAMA Neurol. 2021 May 1;78(5):558-567. doi: 10.1001/jamaneurol.2021.0405.
To our knowledge, the Oral Ponesimod Versus Teriflunomide In Relapsing Multiple Sclerosis (OPTIMUM) trial is the first phase 3 study comparing 2 oral disease-modifying therapies for relapsing multiple sclerosis (RMS).
To compare the efficacy of ponesimod, a selective sphingosine-1-phosphate receptor 1 (S1P1) modulator with teriflunomide, a pyrimidine synthesis inhibitor, approved for the treatment of patients with RMS.
DESIGN, SETTING, AND PARTICIPANTS: This multicenter, double-blind, active-comparator, superiority randomized clinical trial enrolled patients from April 27, 2015, to May 16, 2019, who were aged 18 to 55 years and had been diagnosed with multiple sclerosis per 2010 McDonald criteria, with a relapsing course from the onset, Expanded Disability Status Scale (EDSS) scores of 0 to 5.5, and recent clinical or magnetic resonance imaging disease activity.
Patients were randomized (1:1) to 20 mg of ponesimod or 14 mg of teriflunomide once daily and the placebo for 108 weeks, with a 14-day gradual up-titration of ponesimod starting at 2 mg to mitigate first-dose cardiac effects of S1P1 modulators and a follow-up period of 30 days.
The primary end point was the annualized relapse rate. The secondary end points were the changes in symptom domain of Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) at week 108, the number of combined unique active lesions per year on magnetic resonance imaging, and time to 12-week and 24-week confirmed disability accumulation. Safety and tolerability were assessed. Exploratory end points included the percentage change in brain volume and no evidence of disease activity (NEDA-3 and NEDA-4) status.
For 1133 patients (567 receiving ponesimod and 566 receiving teriflunomide; median [range], 37.0 [18-55] years; 735 women [64.9%]), the relative rate reduction for ponesimod vs teriflunomide in the annualized relapse rate was 30.5% (0.202 vs 0.290; P < .001); the mean difference in FSIQ-RMS, -3.57 (-0.01 vs 3.56; P < .001); the relative risk reduction in combined unique active lesions per year, 56% (1.405 vs 3.164; P < .001); and the reduction in time to 12-week and 24-week confirmed disability accumulation risk estimates, 17% (10.1% vs 12.4%; P = .29) and 16% (8.1% vs 9.9; P = .37), respectively. Brain volume loss at week 108 was lower by 0.34% (-0.91% vs -1.25%; P < .001); the odds ratio for NEDA-3 achievement was 1.70 (25.0% vs 16.4%; P < .001). Incidence of treatment-emergent adverse events (502 of 565 [88.8%] vs 499 of 566 [88.2%]) and serious treatment-emergent adverse events (49 [8.7%] vs 46 [8.1%]) was similar for both groups. Treatment discontinuations because of adverse events was more common in the ponesimod group (49 of 565 [8.7%] vs 34 of 566 [6.0%]).
In this study, ponesimod was superior to teriflunomide on annualized relapse rate reduction, fatigue, magnetic resonance imaging activity, brain volume loss, and no evidence of disease activity status, but not confirmed disability accumulation. The safety profile was in line with the previous safety observations with ponesimod and the known profile of other S1P receptor modulators.
ClinicalTrials.gov Identifier: NCT02425644.
重要性：据我们所知，口服 ponesimod 与特立氟胺治疗复发性多发性硬化症（OPTIMUM）试验是首次比较两种用于治疗复发性多发性硬化症（RMS）的口服疾病修正疗法的 3 期研究。
目的：比较选择性 sphingosine-1-phosphate receptor 1（S1P1）调节剂 ponesimod 与嘧啶合成抑制剂特立氟胺的疗效，这两种药物均被批准用于治疗 RMS 患者。
设计、地点和参与者：这项多中心、双盲、阳性对照、随机临床试验于 2015 年 4 月 27 日至 2019 年 5 月 16 日招募了年龄在 18 至 55 岁之间的患者，他们符合 2010 年 McDonald 标准诊断为多发性硬化症，发病呈复发病程，扩展残疾状态量表（EDSS）评分为 0 至 5.5，且近期有临床或磁共振成像疾病活动。
干预措施：患者随机（1:1）接受 20 mg ponesimod 或 14 mg 特立氟胺，每日一次，以及安慰剂，持续 108 周，在开始时使用 ponesimod 进行为期 14 天的逐渐递增滴定，以减轻 S1P1 调节剂的首剂心脏效应，随后进行为期 30 天的随访期。
主要结局和测量指标：主要终点是年化复发率。次要终点是第 108 周疲劳症状和影响问卷-复发性多发性硬化症（FSIQ-RMS）症状域的变化，每年联合独特活动病变的数量，以及 12 周和 24 周确认残疾累积的时间。评估安全性和耐受性。探索性终点包括脑容量的百分比变化和无疾病活动证据（NEDA-3 和 NEDA-4）状态。
结果：对于 1133 名患者（ponesimod 组 567 名，teriflunomide 组 566 名；中位数[范围]，37.0[18-55]岁；735 名女性[64.9%]），ponesimod 与 teriflunomide 相比，年化复发率的相对降低率为 30.5%（0.202 比 0.290；P<.001）；FSIQ-RMS 的平均差异为-3.57（-0.01 比 3.56；P<.001）；每年联合独特活动病变的数量相对减少 56%（1.405 比 3.164；P<.001）；12 周和 24 周确认残疾累积风险估计的减少分别为 17%（10.1%比 12.4%；P=.29）和 16%（8.1%比 9.9%；P=.37）。第 108 周时脑容量损失降低 0.34%（-0.91%比-1.25%；P<.001）；实现 NEDA-3 的优势比为 1.70（25.0%比 16.4%；P<.001）。治疗期间不良事件（ponesimod 组 565 例中的 502 例[88.8%]与 teriflunomide 组 566 例中的 499 例[88.2%]）和严重治疗期间不良事件（ponesimod 组 49 例[8.7%]与 teriflunomide 组 46 例[8.1%]）的发生率相似。由于不良事件而停药的情况在 ponesimod 组更为常见（ponesimod 组 565 例中的 49 例[8.7%]与 teriflunomide 组 566 例中的 34 例[6.0%]）。
结论和相关性：在这项研究中，ponesimod 在降低年化复发率、疲劳、磁共振成像活动、脑容量损失和无疾病活动证据方面优于 teriflunomide，但在确认残疾累积方面没有优势。安全性与 ponesimod 先前的安全性观察结果以及其他 S1P 受体调节剂的已知情况一致。
试验注册：ClinicalTrials.gov 标识符：NCT02425644。
