Edaravone for amyotrophic lateral sclerosis: More evidence for long‐term benefit

Amyotrophic lateral sclerosis (ALS) is a progressive and ultimately terminal neurodegenerative disease with incompletely defined pathophysiology, no cure, and few disease-modifying therapies. More than two decades have passed since the glutamate inhibitor riluzole was approved for the treatment of ALS after it demonstrated extended survival averaging 2 to 3 months when compared with placebo. In 2017, the potent antioxidant edaravone was approved by the United States Food and Drug Administration (FDA) for use in ALS patients. Compared with healthy controls, ALS patients have shown higher levels of a number of biomarkers of oxidative stress, including 3-nitrotyrosine, coenzymeQ10, 8-hydroxydeoxyguanosine, and 4-hydroxy-2,3-nonenal, thought to contribute to the disease. Edaravone is a free radical scavenger of peroxyl radicals and perioxynitrites, promoting cell survival against oxidative stress and potentially inhibiting apoptosis. Edaravone was first approved in Japan in 2001 as a treatment for acute ischemic stroke. Subsequently, when given before disease onset in G93Amutant superoxide dismutase 1 (SOD1) transgenic mice, the drug was shown to slow motor decline, reduce biomarkers of oxidative stress and SOD1 aggregation in spinal motor neurons, and improve motor neuron survival, suggesting it could potentially be a disease-modifying therapy in ALS. In Study 19 MCI186 (MCI186-19), a phase 3, randomized, controlled study of a select group of Japanese ALS patients followed over 6 months, investigators were able to show significant slowing of the rate of decline on the Amyotrophic Lateral Sclerosis Functional Rating Scale—revised (ALSFRS-R) in treated compared with untreated subjects, which led to approval by the FDA. However, subsequent to the publication of the study and FDA approval, concerns have been raised about the generalizability of the study results, especially given the selective nature of the inclusion criteria. Eligible subjects had to have a relatively short disease duration (≤24 months), high disease certainty (definite or probable ALS by revised El Escorial criteria), generally preserved respiratory function (forced vital capacity ≥80%) and motor function (a score of ≥2 on each subdomain of the ALSFRS-R), and evidence of fast disease progression (decrease of 1–4 points on the ALSFRS-R) over a 12-week screening period. In addition, the study provided no information regarding longer term efficacy or survival. An open-label, 24-week extension phase of the study subsequently confirmed the safety and tolerability of edaravone and suggested possible continued benefit but was limited by the lack of a control population. In this issue of Muscle and Nerve, in an attempt to address these concerns, Shefner and colleagues present the findings of a post-hoc analysis of 93 ALS subjects who participated in the randomized MCI186-19 Study, including 53 subjects on edaravone and 40 subjects on placebo, who then completed the open-label extension study. As all subjects were treated with edaravone in the open-label component of MCI186-19, direct comparison to placebo was not possible. Instead, multiple linear-regression analyses were used to project the outcome for placebo patients and to compare the outcome with those who were treated in the initial randomized study. In addition, the progression rate in the group originally randomized to edaravone in MCI186-19 was estimated for the 24 weeks of that study and then used to predict progression for the next 24 weeks in the open-label extension study. The projected placebo group showed significantly greater decline in the rate of the ALSFRS-R from baseline through week 48 than the group who were on treatment. The rate of decline in the ALSFRS-R scores for the placebo-edaravone group (subjects originally randomized to placebo and then open-label edaravone) was significantly slower than that of the projected placebo group, similar to the rate of decline of those subjects originally treated with edaravone and continued on the medication during open-label extension. This post-hoc analysis of data collected from both MCI186-19 randomized, controlled, open-label studies is notable as it provides evidence that edaravone may benefit patients with ALS for periods of treatment as long as 48 weeks. In addition, as few patients met the original inclusion criteria from the initial randomized, controlled study at the time of entry into the open-label extension trial, the latter study would suggest that individuals with more advanced disease, longer duration of disease, and slower disease progression could potentially also benefit from treatment with edaravone. This study is not without shortcomings. The open-label nature of the trial and post-hoc analysis are distinct limitations of the methodology as is the small sample size and lack of survival data. As the authors also acknowledge, the projected outcomes analysis is an estimate that could allow for significant statistical error, as disease progression in ALS is often not linear. Finally, the authors limited their observations to the change in ALSFRS-R and made no attempt to determine changes in a number of the secondary outcome measures that were evaluated in the randomized trial, such as forced vital capacity or quality of life, which may have provided additional information on the long-term impact of edaravone. Although Received: 17 November 2019 Revised: 23 November 2019 Accepted: 25 November 2019