Background

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.

Objectives

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.

Methods

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.

Results

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.

Conclusions

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.gov Identifiers

NCT00530348; NCT00548405; NCT00930553; NCT02255656.

中文翻译：

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Alemtuzumab 对高度活动性疾病患者进行 9 年随访的有效性和安全性：TOPAZ 扩展研究中 CARE-MS I 和 II 患者的事后分析。

背景

在复发缓解型多发性硬化症患者中，阿仑单抗与皮下干扰素-β-1a（SC IFNB-1a）相比的疗效已在 2 年内得到证实，且疗效持续超过 7 年。Alemtuzumab 被美国神经病学学会实践指南列为高度活动性疾病 (HAD) 患者的推荐治疗方法，而欧洲的标签适应症最近仅限于治疗 HAD 患者。目前没有关于 HAD 的共识定义，之前也没有探讨过阿仑单抗在各种 HAD 定义中的疗效。

目标

在这项事后分析中，我们评估了阿仑单抗在比较 Alemtuzumab 和 Rebif ^®在多发性硬化症 (CARE-MS) 试验患者中的疗效和安全性，这些患者至少符合四种不同的 HAD 定义（一种原发性和三种备择方案）。2 年多来，阿仑单抗治疗的 HAD 患者与 SC IFNB-1a 治疗的 HAD 患者进行了比较，对阿仑单抗组的患者进行了额外的 7 年随访。

方法

CARE-MS 研究中的患者接受了阿仑单抗（基线：5 天；12 个月后：3 天）或 SC IFNB-1a（每周 3 次）。参加延长期的阿仑单抗治疗患者可以接受间隔≥12 个月的额外疗程。HAD 的四种定义被用于评估阿仑单抗的疗效：预先指定的主要定义（基线前一年内两次或多次复发，基线时至少有一处钆 [Gd] 增强病变）和三个专注于复发的替代定义、磁共振成像 (MRI) 或先前治疗反应标准。疗效结果是年复发率、扩展残疾状态量表评分的变化、6 个月确认的残疾恶化、6 个月确认的残疾改善、MRI 疾病活动和脑容量变化。

结果

在合并的 CARE-MS 人群中，208 名接受阿仑单抗治疗的患者符合主要的 HAD 定义。0-2 年的年化复发率为 0.27，3-9 年的年复发率为 0.16。9 年多来，62% 的患者没有 6 个月确诊的残疾恶化，50% 有 6 个月确诊的残疾改善，脑容量的中位累积变化为 - 2.15%。在第 9 年，62% 没有疾病活动的证据，69% 没有 MRI 疾病活动。使用替代的复发驱动的 HAD 定义观察到类似的疗效结果。对于满足替代 HAD 定义的患者，在先前的治疗中，重点是更高的 MRI 病灶计数或疾病活动，观察到某些终点的疗效降低。安全性与整个 CARE-MS 人群一致，直至第 9 年。

结论

9 年多来，根据四种 HAD 定义，阿仑单抗在 CARE-MS HAD 患者中的疗效保持不变。这些结果支持对具有早期 HAD 指标的患者使用阿仑单抗进行干预，包括频繁复发但没有高 MRI 活动。9 年来没有观察到 HAD 人群特有的安全信号。

ClinicalTrials.gov 标识符

NCT00530348；NCT00548405；NCT00930553; NCT02255656。