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Abstract
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.
Acknowledgements
The authors thank David E Hartree, PhD, CMPP, under contract with Mitsubishi Tanabe Pharma America, Inc., for medical writing support, which was funded by MTDA.
Declaration of interest
KT is an employee of Mitsubishi Tanabe Pharma Development America (MTDA). WK, SY, MA, and TS are employees of Mitsubishi Tanabe Pharma Corporation (MTPC). JP is an employee of MTDA and MTPC. The edaravone (MCI-186) clinical trials were funded by MTPC. The ALSFTD supplement, Edaravone (MCI-186) in ALS (Amyotrophic Lateral Sclerosis), was funded by Mitsubishi Tanabe Pharma America, Inc. The authors alone are responsible for the content of this article.