Takei Koji, Watanabe Kazutoshi, Yuki Satoshi, Akimoto Makoto, Sakata Takeshi, Palumbo Joseph
a Mitsubishi Tanabe Pharma Development America , Jersey City , NJ , USA and.
b Mitsubishi Tanabe Pharma Corporation , Tokyo , Japan.
Amyotroph Lateral Scler Frontotemporal Degener. 2017 Oct;18(sup1):5-10. doi: 10.1080/21678421.2017.1353101.
The etiology of amyotrophic lateral sclerosis (ALS) is unknown. Oxidative stress may be one of the major mechanisms involved. In vitro and in vivo data of edaravone suggest that it may possess broad free radical scavenging activity and protect neurons, glia, and vascular endothelial cells against oxidative stress. During the 1980s and 1990s, edaravone was developed for the treatment of acute ischemic stroke. In 2001, a clinical program in ALS was initiated and five clinical studies were conducted in Japan. Phase III studies were designed to rapidly evaluate (within a 24-week double-blind study window) functional changes using the Revised ALS Functional Rating Scale (ALSFRS-R) as a primary endpoint. The study populations were selected according to these considerations and were further refined as the studies proceeded. Although the first phase III study did not meet its primary endpoint, post-hoc analyses showed an apparent effect of edaravone, when additional patient inclusion criteria defined by ALSFRS-R score, pulmonary function, certainty of ALS diagnosis, and duration of disease were applied. This population was hypothesized not only to have retained broad functionality and normal respiratory function at study baseline but also to be likely to show measurable disease progression over 24 weeks. A second confirmatory phase III study applying these refinements in patient selection was prospectively designed and successfully documented a statistically significant difference between the edaravone and placebo groups in the ALSFRS-R primary endpoint. This paper describes and reviews data pertinent to the potential mechanism of action of edaravone, and reviews the development history of edaravone for the treatment of ALS.
肌萎缩侧索硬化症（ALS）的病因尚不清楚。氧化应激可能是其中的主要机制之一。依达拉奉的体外和体内数据表明，它可能具有广泛的自由基清除活性，并能保护神经元、神经胶质细胞和血管内皮细胞免受氧化应激的影响。在20世纪80年代和90年代，依达拉奉被开发用于治疗急性缺血性中风。2001年，启动了一项针对ALS的临床项目，并在日本进行了五项临床研究。III期研究旨在（在24周的双盲研究窗口内）快速评估功能变化，以修订的ALS功能评定量表（ALSFRS-R）作为主要终点。研究人群是根据这些考虑因素选择的，并在研究过程中进一步细化。尽管第一项III期研究未达到其主要终点，但事后分析显示，当应用由ALSFRS-R评分、肺功能、ALS诊断的确定性和疾病持续时间定义的额外患者纳入标准时，依达拉奉有明显效果。假设该人群不仅在研究基线时保留了广泛的功能和正常的呼吸功能，而且在24周内可能会出现可测量的疾病进展。第二项采用这些细化患者选择标准的验证性III期研究进行了前瞻性设计，并成功证明依达拉奉组和安慰剂组在ALSFRS-R主要终点上存在统计学显著差异。本文描述并回顾了与依达拉奉潜在作用机制相关的数据，并回顾了依达拉奉治疗ALS的研发历史。
