Center of Clinical Neuroscience, University Clinic Carl Gustav Carus, Fetscherstr. 74, 01307, Dresden, Germany.
Neurology Center of San Antonio, San Antonio, TX, USA.
CNS Drugs. 2020 Sep;34(9):973-988. doi: 10.1007/s40263-020-00749-x.
Alemtuzumab efficacy versus subcutaneous interferon-β-1a (SC IFNB-1a) was demonstrated over 2 years in patients with relapsing-remitting multiple sclerosis, with continued efficacy over 7 additional years. Alemtuzumab is included as a recommended treatment for patients with highly active disease (HAD) by the American Academy of Neurology Practice Guidelines, and the label indication in Europe was recently restricted to the treatment of HAD patients. There is currently no consensus definition for HAD, and alemtuzumab efficacy across various HAD definitions has not been explored previously.
In this post hoc analysis, we assess the efficacy and safety of alemtuzumab in Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) trial patients who met criteria for at least one of four separate definitions of HAD (one primary and three alternatives). Over 2 years, alemtuzumab-treated HAD patients were compared with SC IFNB-1a-treated HAD patients, with additional 7-year follow-up in patients from the alemtuzumab arm.
Patients in the CARE-MS studies received either alemtuzumab (baseline: 5 days; 12 months later: 3 days) or SC IFNB-1a (3 times weekly). Alemtuzumab-treated patients who enrolled in the extensions could receive additional courses ≥ 12 months apart. Four definitions of HAD were applied to assess alemtuzumab efficacy: the pre-specified primary definition (two or more relapses in the year prior to baseline and at least one gadolinium [Gd]-enhancing lesion at baseline) and three alternative definitions that focused on relapse, magnetic resonance imaging (MRI), or prior treatment response criteria. Efficacy outcomes were annualized relapse rate, change in Expanded Disability Status Scale score, 6-month confirmed disability worsening, 6-month confirmed disability improvement, MRI disease activity, and brain volume change. Adverse events were summarized for HAD patients meeting the primary definition.
In the pooled CARE-MS population, 208 alemtuzumab-treated patients met the primary HAD definition. Annualized relapse rate was 0.27 in years 0-2 and 0.16 in years 3-9. Over 9 years, 62% of patients were free of 6-month confirmed disability worsening, 50% had 6-month confirmed disability improvement, and median cumulative change in brain volume was - 2.15%. During year 9, 62% had no evidence of disease activity, and 69% were free of MRI disease activity. Similar efficacy outcomes were observed using an alternative relapse-driven HAD definition. For patients meeting alternative HAD definitions focused on either higher MRI lesion counts or disease activity while on prior therapy, reduced efficacy for some endpoints was seen. Safety was consistent with the overall CARE-MS population through year 9.
Over 9 years, alemtuzumab efficacy was maintained in CARE-MS HAD patients based on four HAD definitions. These results support intervention with alemtuzumab in patients with early indicators of HAD, including frequent relapse without high MRI activity. No safety signals were observed over 9 years that were unique to the HAD populations. CLINICALTRIALS.
NCT00530348; NCT00548405; NCT00930553; NCT02255656.
在复发缓解型多发性硬化症患者中，与皮下注射干扰素-β-1a（SC IFNB-1a）相比，阿仑单抗的疗效在 2 年内得到了证实，并且在 7 年以上的时间里持续有效。美国神经病学学会实践指南将阿仑单抗列为治疗高度活跃疾病（HAD）患者的推荐治疗方法，欧洲的标签适应证最近也被限制为治疗 HAD 患者。目前，对于 HAD 尚无共识定义，之前也没有对阿仑单抗在各种 HAD 定义中的疗效进行过探讨。
在这项事后分析中，我们评估了阿仑单抗在多发性硬化症比较阿仑单抗和重组干扰素β-1a疗效试验（CARE-MS）中 HAD 患者中的疗效和安全性，这些患者符合至少四种 HAD 定义（一个主要定义和三个替代定义）之一的标准。在 2 年内，接受阿仑单抗治疗的 HAD 患者与接受 SC IFNB-1a 治疗的 HAD 患者进行了比较，阿仑单抗组的患者在第 2 年额外随访了 7 年。
CARE-MS 研究中的患者接受阿仑单抗（基线：5 天；12 个月后：3 天）或 SC IFNB-1a（每周 3 次）治疗。参加扩展研究的阿仑单抗治疗患者可以间隔至少 12 个月接受额外的疗程。应用了四个 HAD 定义来评估阿仑单抗的疗效：预先规定的主要定义（基线前一年有两次或两次以上的复发，且基线时有至少一个钆增强病变）和三个替代定义，这些定义侧重于复发、磁共振成像（MRI）或既往治疗反应标准。疗效结局包括年复发率、扩展残疾状况量表评分变化、6 个月确认的残疾恶化、6 个月确认的残疾改善、MRI 疾病活动度和脑容量变化。对符合主要定义的 HAD 患者，总结了不良事件。
在合并的 CARE-MS 人群中，有 208 名接受阿仑单抗治疗的患者符合主要 HAD 定义。第 0-2 年的年复发率为 0.27，第 3-9 年的年复发率为 0.16。在 9 年期间，62%的患者无 6 个月确认的残疾恶化，50%有 6 个月确认的残疾改善，脑容量的中位数累计变化为-2.15%。在第 9 年，62%的患者没有疾病活动的证据，69%的患者没有 MRI 疾病活动。使用替代的以复发为主的 HAD 定义也观察到了类似的疗效结局。对于符合以更高的 MRI 病变计数或既往治疗期间疾病活动为特征的替代 HAD 定义的患者，一些终点的疗效有所降低。安全性在第 9 年时与整个 CARE-MS 人群一致。
在 CARE-MS HAD 患者中，阿仑单抗的疗效在 9 年期间保持稳定，这些结果支持在 HAD 早期患者中使用阿仑单抗进行干预，包括频繁复发而无高 MRI 活动。在 9 年期间，未观察到与 HAD 人群相关的独特安全性信号。临床试验注册：NCT00530348；NCT00548405；NCT00930553；NCT02255656。
