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Table of Contents
REVIEW ARTICLE
Year : 2019  |  Volume : 16  |  Issue : 3  |  Page : 157-160

Edaravone: A new hope for patients with amyotrophic lateral sclerosis


1 Department of Neurology, Institute of Neurosciences, Indraprastha Apollo Hospitals, New Delhi, India
2 Department of Critical Care, Max Super Speciality Hospital, New Delhi, India

Date of Submission12-Aug-2019
Date of Acceptance02-Sep-2019
Date of Web Publication11-Sep-2019

Correspondence Address:
Pushpendra Nath Renjen
C-85, Anand Niketan, New Delhi - 110 021
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/am.am_48_19

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  Abstract 


Although the exact pathophysiology of amyotrophic lateral sclerosis (ALS) remains unclear, oxidative stress is known to play a pivotal role. There is no cure for ALS, but there are two drugs available to slow the progression of the disease. Till recently, riluzole, a glutamatergic neurotransmission inhibitor, was the only drug approved for ALS. However, in May 2017, edaravone, which is a potent-free radical scavenger, was also approved by the Food and Drug Administration for the treatment of ALS. In this article, the mechanism of action of edaravone and clinical trials establishing its efficacy are reviewed.

Keywords: Amyotrophic lateral sclerosis, edaravone, motor neuron disease, oxidative stress


How to cite this article:
Garg S, Chaudhari D, Renjen PN, Mishra A, Kumar A, Pradhan R. Edaravone: A new hope for patients with amyotrophic lateral sclerosis. Apollo Med 2019;16:157-60

How to cite this URL:
Garg S, Chaudhari D, Renjen PN, Mishra A, Kumar A, Pradhan R. Edaravone: A new hope for patients with amyotrophic lateral sclerosis. Apollo Med [serial online] 2019 [cited 2019 Sep 20];16:157-60. Available from: http://www.apollomedicine.org/text.asp?2019/16/3/157/266784




  Introduction Top


Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease, which causes extensive loss of upper and lower motor neurons in the brainstem and spinal cord.[1] In patients with ALS, the brain loses the ability to control muscle movement when the neurons' controlling mobility begins to die, resulting in complete paralysis in its latter stages. The average life expectancy of a person with ALS is 2–5 years from time of diagnosis, with death resulting from respiratory failure (e.g., aspiration pneumonia) and medical conditions related to immobility. About half of patients with ALS live at least 3 years or more after diagnosis; 20% live 5 years or more; and up to 10% survive for >10 years.[2],[3],[4] ALS became a cause célèbre in the USA when the famous baseball legend Lou Gehrig's died in 1941 by ALS.[5] More recently, British celebrity astrophysicist Stephen William Hawking, possibly one of the most famous patients with ALS to date, died on March 14, 2018.[6]

No curative drug for ALS has been discovered in its 160 years of recorded history despite there being more than 200 ALS clinical trials on the disease. In the early 1990s, riluzole was the only the Food and Drug Administration (FDA)-approved drug for clinical use.[7] Over the past decades, a multitude of experimental pharmaceutical therapies showed a delay in disease progression in transgenic ALS animal models but failed to show efficacy in clinical trials or are still in Phase I–III trials. After several decades, another drug, named edaravone, developed by Mitsubishi Tanabe Pharma, was approved by the FDA on May 5, 2017, after it was shown to be effective in halting ALS progression during early disease stages.[8]


  Amyotrophic Lateral Sclerosis, Oxidative Stress, and Edaravone Top


Oxidative stress, reactive oxygen species (ROS), and glutamate excitotoxicity are considered to be the main contributing factors in ALS.[9],[10],[11] Most patients present with sporadic ALS, but a few can have familial ALS as well. Mutations in superoxide dismutase type 1 (SOD1) constitute a type of familial ALS (ALS1). SOD1 converts toxic superoxide radicals to oxygen and hydrogen peroxide. SOD1 has antioxidant properties (removing superoxide radicals) but is also a pro-oxidant. The genetic mechanisms of SOD1 mutations in familial ALS are thought to represent a “toxic gain of function,” and mutated SOD1 can cause ALS via excessive oxidative stress.[12],[13],[14] SOD1 mutations are also found in sporadic ALS patients, suggesting a low penetrance with these mutations,[15] or probable de novo mutations of SOD1. These data suggest that oxidative stress can play a pivotal role in the development of ALS.[16]

Electron leakage from the mitochondrial respiratory chain in cells produces ROS, which results in the formation of superoxide anion and hydrogen peroxide. Glutamate is a central nervous system neurotransmitter, and stimulation of N-methyl-D-aspartate-type glutamate receptor causes nitric oxide production. Superoxide anion reacts with nitric oxide to the form peroxynitrite anion (ONOO−), which in turn causes nitration of protein tyrosine residues. The cerebrospinal fluid (CSF) study in ALS patients has been found to have elevated levels of 3-nitrotyrosine by sevenfold when compared with controls.[17] Hydrogen peroxide decomposes into hydroxyl radicals (OH·). ONOO− and OH· are both highly reactive and react with lipids, proteins, and DNA.

Consequently, drugs that eliminate free radicals might protect motor neurons from oxidative stress and free radical damage in ALS patients. Two such drugs available are riluzole and edaravone. Riluzole belongs to the benzothiazole class, a glutamate antagonist, and it appears to block the excessive release of glutamate from motor neurons.[18],[19] Edaravone, developed by Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan, was initially approved for treating acute cerebral embolism.[20] It removes oxygen radicals, including nitric oxide. Edaravone has approximately 30-fold greater reaction with peroxynitrite than uric acid (a physiological scavenger for peroxynitrite) does.[21] Nagase et al. found lower plasma uric acid in ALS patients when compared to age-matched healthy controls and edaravone elevated this plasma uric acid, thus proving to be a possible scavenger for ONOO−.[22] The antioxidant mechanisms of edaravone include enhancement of prostacyclin production, OH· trapping, and quenching of active oxygen.


  Pivotal Clinical Trials Top


For edaravone, so far, only one Phase II open-label trial and two Phase III placebo-control randomized controlled trails have been conducted.[1] In all three trials, the primary outcome evaluated was motor function of patients.

Phase II clinical trial

Yoshino and Kimura conducted a clinical trial of edaravone in 20 ALS patients.[23] The design was an open-label, two-arm (30 and 60 mg/day edaravone), pre-edaravone, and post-edaravone comparison study. The primary outcome measure was change in scores on the revised ALS functional rating scale (ALSFRS-R), and the secondary outcome measure was 3-nitrotyrosine levels in the CSF. Changes in ALSFRS-R scores with 60 mg arm were 4.7 (2.1) points during the pretreatment period and 2.3 (3.6) points during the treatment period, which was a statistically significant difference (P = 0.036). The CSF levels of 3-nitrotyrosine decreased to undetectable levels after the treatment period. A safety analysis revealed no serious adverse events related to edaravone. This open-label trial with a historical control suggests that edaravone exerts an antioxidant effect and may have clinical efficacy in patients with ALS.

Phase III confirmatory trial (MCI 186-16 trial)

A Phase III confirmatory study was conducted at 29 sites in Japan.[24] The primary outcome measure was the change in ALSFRS-R scores compared with baseline. Secondary outcome measures included changes in forced vital capacity (FVC), grasping power, pinch strength, modified Norris scale, ALS assessment questionnaire-40 (ALSAQ-40), and time to activity of daily living (ADL)-independent status. A total of 206 patients were randomized: 102 patients were allocated to edaravone and 104 were to placebo. Changes in ALSFRS-R scores were −5.70 (0.85) and −6.35 (0.84) in the edaravone and placebo groups, respectively. There were no statistically significant differences between the groups (P = 0.411). The efficacy of edaravone against ALS was not demonstrated in this trial although a hypothesis-driven post hoc analysis suggested that edaravone was efficacious in a restricted subgroup (patients with milder symptoms and shorter duration of illness).

Phase III trial for subgroup patients of ALS (MCI 186-19 trial)

The MCI 186-19 trial was a double-blind, parallel two-arm, placebo-control trial over the course of 24 weeks.[8] Patient eligibility was restricted to patients with milder disease and preserved FVC. The patients met the following four criteria: (a) functionality retained most ADLs (scores of ≥2 points or better on revised ALSFRS-R), (b) normal respiratory function (%FVC ≥80%), (c) definite or probable ALS based on El Escorial revised criteria, and (d) disease duration ≤2 years. The trial enrolled 69 and 68 patients for edaravone (60 mg, intravenous [IV] infusion) and placebo, respectively. The changes in ALSFRS-R were −5.01 (0.64) and −7.50 (0.66) in the edaravone and placebo groups, respectively, and the difference between the two groups was 2.49 (0.76), which was statistically significant (P = 0.001) [Figure 1].
Figure 1: Mean ALSFRS-R scores during treatment.[8] ALS: Amyotrophic lateral sclerosis, ALSFRS-R: Revised ALS functional rating scale, LOCF: Last observation carried forward

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Among the secondary outcome measures, improvements in ALSAQ-40 compared with baseline were greater in the edaravone than the placebo group, and the between-group difference was statistically significant (P = 0.0309). However, there was no difference in FVC, modified Norris scale (limb or bulbar), grip strength, pinch strength, or ALS severity classification at the end of cycle 6 in patients given edaravone compared with placebo. In this trial, the patients were allowed concomitant use of riluzole, but changes in use were not permitted in either trial; 62 of 68 edaravone treatment patients and 61 of 66 placebo treatment patients were prescribed riluzole [Figure 2].
Figure 2: Primary and secondary endpoints.[8] ALS: Amyotrophic lateral sclerosis, ALSAQ-40: ALS assessment questionnaire-40, ALSFRS-R: Revised ALS functional rating scale, FVC: Forced vital capacity (%), LOCF: Last observation carried forward. *Compared between treatment groups using an ANOVA with treatment group and three dynamic allocation factors

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  Dosage and Administration Top


The recommended dose of edaravone is 60 mg (IV over 60 min) administered from two consecutive single-dose polypropylene bags, each containing 30 mg of edaravone in 100 mL of clear, colorless aqueous solution. The infusion rate is approximately 1 mg or 3.33 mL per minute. Initial treatment cycle is once daily 60 mg dose for 14 days followed by a 14-day drug-free period. Further, treatment cycles consist of once daily dosing for 10 of 14 days, each followed by a 14-day drug-free period. The manufacturer recommends that no other medications should be injected or mixed with edaravone in the infusion bag.[25]


  Conclusion Top


The first drug approved by the FDA for the treatment of ALS was riluzole, and it should be offered to all patients to slow the disease progression. More recently, a new drug edaravone which works by acting as a free radical scavenger has shown promising results in a subset of ALS patients with milder disease and a shorter duration of illness. Based on evidence, concomitant use of riluzole and edaravone should be considered early in the disease process. Since no treatment exists to halt the underlying pathological process of ALS, various rehabilitative measures should be provided to the patient to improve the quality of life. Few examples of these are foot drop splints for better mobilization, finger extension splints to improve the grip, respiratory support in the form of noninvasive ventilation as well as long-term ventilation by tracheostomy, enteral feeding in cases of bulbar involvement, and so on. Further studies are warranted to study the efficacy of edaravone in advanced ALS disease and its safety in patients with renal and hepatic impairment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Jaiswal MK. Riluzole and edaravone: A tale of two amyotrophic lateral sclerosis drugs. Med Res Rev 2019;39:733-48.  Back to cited text no. 1
    
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21.
Fujisawa A, Yamamoto Y. Edaravone, a potent free radical scavenger, reacts with peroxynitrite to produce predominantly 4-NO-edaravone. Redox Rep 2016;21:98-103.  Back to cited text no. 21
    
22.
Nagase M, Yamamoto Y, Miyazaki Y, Yoshino H. Increased oxidative stress in patients with amyotrophic lateral sclerosis and the effect of edaravone administration. Redox Rep 2016;21:104-12.  Back to cited text no. 22
    
23.
Yoshino H, Kimura A. Investigation of the therapeutic effects of edaravone, a free radical scavenger, on amyotrophic lateral sclerosis (Phase II study). Amyotroph Lateral Scler 2006;7:241-5.  Back to cited text no. 23
    
24.
Abe K, Itoyama Y, Sobue G, Tsuji S, Aoki M, Doyu M, et al. Confirmatory double-blind, parallel-group, placebo-controlled study of efficacy and safety of edaravone (MCI-186) in amyotrophic lateral sclerosis patients. Amyotroph Lateral Scler Frontotemporal Degener 2014;15:610-7.  Back to cited text no. 24
    
25.
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