Abstract：
BACKGROUND: Older age and longer disease duration (DD) may impact the effectiveness of disease-modifying therapies in patients with multiple sclerosis (MS). Siponimod is a sphingosine 1-phosphate receptor modulator approved for the treatment of active secondary progressive MS (SPMS) in many countries. The pivotal phase 3 EXPAND study examined siponimod versus placebo in a broad SPMS population with both active and non-active disease. In this population, siponimod demonstrated significant efficacy, including a reduction in the risk of 3-month confirmed disability progression (3mCDP) and 6-month confirmed disability progression (6mCDP). Benefits of siponimod were also observed across age and DD subgroups in the overall EXPAND population. Herein we sought to assess the clinical impact of siponimod across age and disease duration subgroups, specifically in participants with active SPMS.
METHODS: This study is a post hoc analysis of a subgroup of EXPAND participants with active SPMS (≥ 1 relapse in the 2 years before the study and/or ≥ 1 T1 gadolinium-enhancing magnetic resonance imaging lesion at baseline) receiving oral siponimod (2 mg/day) or placebo during EXPAND. Data were analyzed for participant subgroups stratified by age at baseline (primary cut-off: < 45 year ≥ 45 years; and secondary cut-off: < 50 years or ≥ 50 years) and by DD at baseline (< 16 years or ≥ 16 years). Efficacy endpoints were 3mCDP and 6mCDP. Safety assessments included adverse events (AEs), serious AEs, and AEs leading to treatment discontinuation.
RESULTS: Data from 779 participants with active SPMS were analyzed. All age and DD subgroups had 31-38% (3mCDP) and 27-43% (6mCDP) risk reductions with siponimod versus placebo. Compared with placebo, siponimod significantly reduced the risk of 3mCDP in participants aged ≥ 45 years (hazard ratio [HR]: 0.68; 95% confidence interval [CI]: 0.48-0.97), < 50 years (HR: 0.69; 95% CI: 0.49-0.98), ≥ 50 years (HR: 0.62; 95% CI: 0.40-0.96), and in participants with < 16 years DD (HR: 0.68; 95% CI: 0.47-0.98). The risk of 6mCDP was significantly reduced with siponimod versus placebo for participants aged < 45 years (HR: 0.60; 95% CI: 0.38-0.96), ≥ 45 years (HR: 0.67; 95% CI: 0.45-0.99), < 50 years (HR: 0.62; 95% CI: 0.43-0.90), and in participants with < 16 years DD (HR: 0.57; 95% CI: 0.38-0.87). Increasing age or longer MS duration did not appear to increase the risk of AEs, with an observed safety profile that remained consistent with the overall active SPMS and overall SPMS populations in EXPAND.
CONCLUSIONS: In participants with active SPMS, treatment with siponimod demonstrated a statistically significant reduction in the risk of 3mCDP and 6mCDP compared with placebo. Although not every outcome reached statistical significance in the subgroup analyses (possibly a consequence of small sample sizes), benefits of siponimod were seen across a spectrum of ages and DD. Siponimod was generally well tolerated by participants with active SPMS, regardless of baseline age and DD, and AE profiles were broadly similar to those observed in the overall EXPAND population.
METHODS: This study is a post hoc analysis of a subgroup of EXPAND participants with active SPMS (≥ 1 relapse in the 2 years before the study and/or ≥ 1 T1 gadolinium-enhancing magnetic resonance imaging lesion at baseline) receiving oral siponimod (2 mg/day) or placebo during EXPAND. Data were analyzed for participant subgroups stratified by age at baseline (primary cut-off: < 45 year ≥ 45 years; and secondary cut-off: < 50 years or ≥ 50 years) and by DD at baseline (< 16 years or ≥ 16 years). Efficacy endpoints were 3mCDP and 6mCDP. Safety assessments included adverse events (AEs), serious AEs, and AEs leading to treatment discontinuation.
RESULTS: Data from 779 participants with active SPMS were analyzed. All age and DD subgroups had 31-38% (3mCDP) and 27-43% (6mCDP) risk reductions with siponimod versus placebo. Compared with placebo, siponimod significantly reduced the risk of 3mCDP in participants aged ≥ 45 years (hazard ratio [HR]: 0.68; 95% confidence interval [CI]: 0.48-0.97), < 50 years (HR: 0.69; 95% CI: 0.49-0.98), ≥ 50 years (HR: 0.62; 95% CI: 0.40-0.96), and in participants with < 16 years DD (HR: 0.68; 95% CI: 0.47-0.98). The risk of 6mCDP was significantly reduced with siponimod versus placebo for participants aged < 45 years (HR: 0.60; 95% CI: 0.38-0.96), ≥ 45 years (HR: 0.67; 95% CI: 0.45-0.99), < 50 years (HR: 0.62; 95% CI: 0.43-0.90), and in participants with < 16 years DD (HR: 0.57; 95% CI: 0.38-0.87). Increasing age or longer MS duration did not appear to increase the risk of AEs, with an observed safety profile that remained consistent with the overall active SPMS and overall SPMS populations in EXPAND.
CONCLUSIONS: In participants with active SPMS, treatment with siponimod demonstrated a statistically significant reduction in the risk of 3mCDP and 6mCDP compared with placebo. Although not every outcome reached statistical significance in the subgroup analyses (possibly a consequence of small sample sizes), benefits of siponimod were seen across a spectrum of ages and DD. Siponimod was generally well tolerated by participants with active SPMS, regardless of baseline age and DD, and AE profiles were broadly similar to those observed in the overall EXPAND population.
摘要：
背景：年龄较大和疾病持续时间（DD）较长可能会影响多发性硬化症（MS）患者疾病修饰疗法的有效性。Siponimod是一种鞘氨醇1-磷酸受体调节剂，在许多国家被批准用于治疗活动性继发性进行性MS（SPMS）。关键的3期EXPAND研究在患有活动性和非活动性疾病的广泛SPMS人群中检查了siponimod与安慰剂的比较。在这个人群中,西波莫德表现出显著的疗效，包括降低3个月确认的残疾进展（3mCDP）和6个月确认的残疾进展（6mCDP）的风险。在整个EXPAND人群中，在年龄和DD亚组中也观察到了西波莫德的益处。在这里，我们试图评估siponimod跨年龄和疾病持续时间亚组的临床影响，特别是在具有活跃SPMS的参与者中。
方法：本研究是对EXPAND期间接受口服西波莫德（2mg/天）或安慰剂的活动SPMS（研究前2年内≥1次复发和/或基线时≥1次T1钆增强磁共振成像病变）的EXPAND参与者亚组的事后分析。根据基线时的年龄（主要截止：<45岁≥45岁；次要截止：<50岁或≥50岁）和基线时的DD（<16岁或≥16岁）对参与者亚组的数据进行分析。疗效终点为3mCDP和6mCDP。安全性评估包括不良事件（AE），严重的AE，和AE导致治疗中断。
结果：分析了779名具有活性SPMS的参与者的数据。与安慰剂相比，所有年龄和DD亚组的西波莫德风险降低31-38％（3mCDP）和27-43％（6mCDP）。与安慰剂相比，Siponimod显着降低年龄≥45岁参与者的3mCDP风险（风险比[HR]：0.68;95％置信区间[CI]：0.48-0.97），<50岁（HR：0.69；95%CI：0.49-0.98），≥50年（HR：0.62；95%CI：0.40-0.96），和<16岁DD的参与者（HR：0.68；95％CI：0.47-0.98）。对于年龄<45岁的参与者，使用西波莫德与安慰剂相比，6mCDP的风险显着降低（HR：0.60;95％CI：0.38-0.96），≥45岁（HR：0.67；95%CI：0.45-0.99），<50年（HR：0.62；95%CI：0.43-0.90），和<16岁DD的参与者（HR：0.57；95％CI：0.38-0.87）。年龄增加或MS持续时间延长似乎不会增加AE的风险，观察到的安全性与EXPAND中的总体活性SPMS和总体SPMS人群保持一致。
结论：在SPMS活跃的参与者中，与安慰剂相比,西波莫德治疗显示3mCDP和6mCDP的风险显著降低.尽管在亚组分析中并非每个结果都达到统计学意义（可能是小样本量的结果），西波莫德的益处可见于不同年龄和DD的范围。具有活动性SPMS的参与者通常对西波尼莫德的耐受性良好，无论基线年龄和DD，和AE概况与在整个EXPAND人群中观察到的大致相似。
方法：本研究是对EXPAND期间接受口服西波莫德（2mg/天）或安慰剂的活动SPMS（研究前2年内≥1次复发和/或基线时≥1次T1钆增强磁共振成像病变）的EXPAND参与者亚组的事后分析。根据基线时的年龄（主要截止：<45岁≥45岁；次要截止：<50岁或≥50岁）和基线时的DD（<16岁或≥16岁）对参与者亚组的数据进行分析。疗效终点为3mCDP和6mCDP。安全性评估包括不良事件（AE），严重的AE，和AE导致治疗中断。
结果：分析了779名具有活性SPMS的参与者的数据。与安慰剂相比，所有年龄和DD亚组的西波莫德风险降低31-38％（3mCDP）和27-43％（6mCDP）。与安慰剂相比，Siponimod显着降低年龄≥45岁参与者的3mCDP风险（风险比[HR]：0.68;95％置信区间[CI]：0.48-0.97），<50岁（HR：0.69；95%CI：0.49-0.98），≥50年（HR：0.62；95%CI：0.40-0.96），和<16岁DD的参与者（HR：0.68；95％CI：0.47-0.98）。对于年龄<45岁的参与者，使用西波莫德与安慰剂相比，6mCDP的风险显着降低（HR：0.60;95％CI：0.38-0.96），≥45岁（HR：0.67；95%CI：0.45-0.99），<50年（HR：0.62；95%CI：0.43-0.90），和<16岁DD的参与者（HR：0.57；95％CI：0.38-0.87）。年龄增加或MS持续时间延长似乎不会增加AE的风险，观察到的安全性与EXPAND中的总体活性SPMS和总体SPMS人群保持一致。
结论：在SPMS活跃的参与者中，与安慰剂相比,西波莫德治疗显示3mCDP和6mCDP的风险显著降低.尽管在亚组分析中并非每个结果都达到统计学意义（可能是小样本量的结果），西波莫德的益处可见于不同年龄和DD的范围。具有活动性SPMS的参与者通常对西波尼莫德的耐受性良好，无论基线年龄和DD，和AE概况与在整个EXPAND人群中观察到的大致相似。
