Therapeutics

Edaravone

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Overview

Name: Edaravone
Synonyms: MCI-186, Radicava®, Radicut®, MT-1186
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Amyotrophic Lateral Sclerosis
U.S. FDA Status: Amyotrophic Lateral Sclerosis (Phase 4)
Company: Mitsubishi Tanabe Pharma
Approved for: Amyotrophic Lateral Sclerosis

Background

Edaravone is an antioxidant drug marketed to treat amyotrophic lateral sclerosis. A pyrazolone free-radical scavenger, it reduces oxidative damage, which is believed to contribute to neuron death in ALS.

Edaravone was approved in Japan in 2015, and in the U.S. in 2017, based primarily on results of a single clinical trial in early stage ALS patients conducted in Japan (May 2017 news; FDA review documentCruz, 2018). The European Medicines Agency declined to approve edaravone, citing a lack of confidence that the Japanese data would translate into a clinical benefit to the broader European patient population (EMA review document). The drug previously had been approved in 2001 in Japan for acute treatment of neurological symptoms and functional impairment due to ischemic stroke.

For ALS, the drug is given in cycles of intravenous infusions daily for two weeks, followed by a two-week break. It can cause hives, swelling, and shortness of breath in some people, due to anaphylactic reactions to sulfite-containing infusion components. Otherwise, it is well tolerated. Common side effects are bruising, problems walking, and headaches.

In May 2022, the FDA approved an oral formulation of this drug.

In ALS animal models, edaravone inhibits motor neuron death by reducing oxidative stress (Ito et al., 2008).

Oxidative stress plays a role in Alzheimer’s disease, as well, and edaravone has shown beneficial effects in multiple cellular and animal models of Aβ toxicity (e.g., Feng et al., 2019Feng et al., 2020Jiao et al., 2015).

Findings

For the first trial in ALS, Mitsubishi Tanabe conducted an open-label, Phase 2 study in 20 patients. Participants received six cycles of 30 or 60 mg edaravone by daily infusion for two weeks, alternating with a two-week pause, over six months. The primary endpoint was change in the ALS Functional Rating Scale (ALSFRS-R) score over six months of treatment, compared to the six months before treatment. According to published results, 60 mg edaravone significantly slowed the decline in ALSFRS scores, compared to the pretreatment interval (Yoshino and Kimura et al., 2006). Levels of oxidative stress marker 3-nitrotyrosine in CSF declined for most patients. 

In 2006, the company began a Phase 3 study in 206 ALS patients at 29 sites in Japan. Participants had to be able to feed themselves and show normal daily function, i.e., have no advanced disease yet. After a 12-week observation period, participants received six cycles of 60 mg edaravone or placebo over 24 weeks, followed by a 24-week open-label extension. The trial was negative on its primary endpoint, i.e., showed no significant group difference on the ALSFRS-R score, after 24 weeks of participants receiving edaravone or placebo (Abe et al., 2014). Subsequently, a post hoc analysis suggested a slowing of decline for a subset of patients with shorter disease duration and milder symptoms (Takahashi et al., 2017).

From 2006-2008, the company ran a similarly designed Phase 3 study, enrolling 25 patients with more advanced symptoms who needed help with eating and moving around. In this trial, edaravone did not affect the decline in ALSFRS-R (Writing Group, 2017).

In 2011-2014, a third Phase 3 trial ran, using strict inclusion criteria to select the subset of patients most likely to benefit, based on the prior post hoc analysis. This trial enrolled 137 patients in 29 sites in Japan. It used the same 24-week treatment schedule, with a 24-week open-label extension. The study reported less worsening on the ALSFRS-R in the edaravone group, who lost 5.01 points compared to a 7.50-point loss for placebo. There was no difference in adverse events or serious adverse events between edaravone and placebo, and no deaths. There were no positive effects on secondary findings of lung capacity, movement, survival, or other measures (Jan 2016 conference news; Writing Group et al., 2017). In a post hoc analysis of 123 patients who completed the open-label extension, slowing on the ALSFRS-R was observed by 24 weeks, and maintained at 48 weeks (Shefner et al., 2020). On the basis of this study, edaravone received marketing approval in Japan, and then in the U.S. Later, an analysis of the study design questioned whether the risks of repeated infusions outweighed the drug’s apparent benefits (Turnbull, 2020).

In October 2019, two observational studies began to examine biomarkers of edaravone action. One is enrolling 160 ALS patients in the U.S. The investigators will categorize patients into four ALS phenotypes—lower-motor-neuron predominant, upper-motor-neuron predominant, bulbar predominant, generalized ALS—and compare markers of oxidative stress and antioxidant capacity in blood, urine, and CSF in those taking edaravone or not as part of their clinical care. The study will run through September 2023.

Mitsubishi Tanabe Pharma is sponsoring the second observational study. REFINE-ALS follows 300 patients prescribed edaravone, who will give blood and urine samples to be tested for markers of oxidative stress, inflammation, and neurodegeneration. This study will run through March 2023 at 39 locations in the U.S. (Berry et al., 2021).

In a meta-analysis of published post-marketing clinical data, edaravone appeared effective in Asian countries, where its reported benefits on ALSFRS-R scores and lung capacity were similar to those seen in the clinical trials. The drug appeared to have little clinical benefit in European countries. There was insufficient data in the U.S. to draw conclusions (Ortiz et al., 2020). In another study of U.S. military veterans with ALS, edaravone use was associated with a higher risk of hospitalization (Vu et al., 2020). A descriptive study of edaravone use in Argentina found adverse effects were rare, but access was limited, with fewer than half of patients covered through health insurance, and longer times to begin treatment compared to riluzole (Quarracino et al., 2020). Two studies in Japan reported improved long-term survival with edaravone (Okada et al., 2018; Houzen et al., 2021). In the latter study, median survival was 49 months in patients treated with edaravone for an average of two years, compared to 25 months for a clinically similar group who did not take edaravone. This small study enrolled 45 patients. At the April 2022 American Academy of Neurology conference, Mitsubishi Tanabe Pharma reported that, based on an analysis of U.S. insurance claim records, ALS patients who took edaravone for at least a year survived six months longer than patients who did not take the drug (press release).

In Italy, a small study attempting to monitor edaravone efficacy with MRI reported more cortical thinning and white-matter-tract fractional anisotrophy in the edaravone compared to control group, implying faster progression (Distaso et al., 2021). 

In January 2022, a post-marketing study of real-life use reported that edaravone had failed to slow disease progression compared to the standard treatment of riluzole (Witzel et al., 2022, editorial by Glass and Fournier, comment by Richard Bedlack). Conducted by German researchers between 2017 and 2020, the study compared outcomes for 141 ALS patients who received edaravone plus riluzole with those of 130 comparable controls who got riluzole only. After a median treatment time of 13.9 months, the groups showed no difference in decline on the ALSFRS-R, survival probability, time to ventilation, or rate of progression. This negative outcome held even for a subgroup of more mildly affected patients who met all inclusion/exclusion criteria of the positive Japanese Phase 3 trial. Adverse effects consisted mainly of infusion site infections and allergic reactions and were noted in 16 percent of participants. A small study of 30 patients in India also found no effect on ALSFRS after six months of treatment (Tomar et al., 2022).

Mitsubishi Tanabe Pharma is developing an oral edaravone formulation under the name MT-1186. In 2019-2020, MT-1186 completed safety and bioequivalence studies in Japan (Shimizu et al., 2021; Shimizu et al., 2021). In November 2019, the company began an open-label safety study in 150 ALS patients in North America, Europe, and Japan. Participants, who must be living and functioning independently, will take the drug in the same four-week on-off cycles as the infused drug, for up to 48 weeks. The primary outcome is adverse events, with secondary outcomes to be changes in ALSFRS-R and time to death. The trial ultimately enrolled 185 patients and was completed in October 2021. The company added a 96-week extension that will run through September 2023.

In November 2020, the company started a 48-week Phase 3 efficacy study of oral edaravone at 84 locations worldwide. It aims to enroll 380 participants with a similar mild symptomatic profile as the IV Phase 3. The trial has two arms, where participants take drug daily or in on/off cycles. There is no placebo group. The primary outcome remains the ALSFRS-R. The trial is scheduled to end in July 2023; a two-year extension is planned to run until June 2024.

The Dutch company Treeway is also developing an oral formulation of edaravone for ALS. In 2018, this company reported Phase 1 results in 18 healthy volunteers indicating that TW001 was safe and that the bioavailability of a single oral dose of 140 mg exceeded that of a one-hour infusion of 60 mg Radicava. TW001 received Orphan Drug Designation by the European Medicines Agency in 2014 and by the Food and Drug Administration in 2015. In November 2021, Treeway, in collaboration with the Spanish company Ferrer, began a Phase 3 trial of TW001, now also called FNP122 or FAB122. Called ADORE, the trial will enroll 300 ALS patients across Europe, to compare safety and efficacy of a 100 mg daily dose to placebo. The study will run until mid-2024.

In April 2022, Treeway registered a Phase 2 trial of TW001 in Alzheimer patients. To begin in September 2022, it will enroll 60 people with early AD, defined as an MMSE score greater than 20, plus CSF or PET evidence of brain amyloid. Dosing will be 100 mg daily for up to four months, against primary outcomes of adverse events, and plasma and CSF biomarkers of oxidative stress. Other outcomes include pharmacokinetics, plasma biomarkers of AD pathology and neurodegeneration, urine oxidative stress markers, and cognition assessed with the CDR-SB.

Edaravone is also being trialed in ischemic stroke, intracerebral hemorrhage, and alcohol-induced brain injury. It appears to improve outcomes after ischemic stroke in trials in certain countries in Asia (Chen et al., 2021; Xu et al., 2021). A nanoparticle formulation reduced inflammation and improved neurological function after surgery for cerebral hemorrhage in Chinese patients (Dang et al., 2021).

For details on edaravone trials, see clinicaltrials.gov. For TW001/FNP122 trials, see clinicaltrials.gov.

Last Updated: 16 May 2022

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References

News Citations

  1. Does Free Radical Scavenger Edaravone Slow ALS?
  2. FDA Approves Edaravone for Treatment of ALS

Paper Citations

  1. . Investigation of the therapeutic effects of edaravone, a free radical scavenger, on amyotrophic lateral sclerosis (Phase II study). Amyotroph Lateral Scler. 2006 Dec;7(4):241-5. PubMed.
  2. . 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 Dec;15(7-8):610-7. Epub 2014 Oct 6 PubMed.
  3. . Post-hoc analysis of MCI186-17, the extension study to MCI186-16, the confirmatory double-blind, parallel-group, placebo-controlled study of edaravone in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2017 Oct;18(sup1):32-39. PubMed.
  4. . Exploratory double-blind, parallel-group, placebo-controlled study of edaravone (MCI-186) in amyotrophic lateral sclerosis (Japan ALS severity classification: Grade 3, requiring assistance for eating, excretion or ambulation). Amyotroph Lateral Scler Frontotemporal Degener. 2017 Oct;18(sup1):40-48. PubMed.
  5. . Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017 Jul;16(7):505-512. Epub 2017 May 15 PubMed.
  6. . Long-term edaravone efficacy in amyotrophic lateral sclerosis: Post-hoc analyses of Study 19 (MCI186-19). Muscle Nerve. 2020 Feb;61(2):218-221. Epub 2019 Nov 11 PubMed.
  7. . Reappraisal of an ALS trial: unaccounted procedural risk. Lancet Neurol. 2020 Sep;19(9):717-718. PubMed.
  8. . Radicava/Edaravone Findings in Biomarkers From Amyotrophic Lateral Sclerosis (REFINE-ALS): Protocol and Study Design. Neurol Clin Pract. 2021 Aug;11(4):e472-e479. PubMed.
  9. . Post-Marketing Experience of Edaravone in Amyotrophic Lateral Sclerosis: A Clinical Perspective and Comparison With the Clinical Trials of the Drug. Cureus. 2020 Oct 6;12(10):e10818. PubMed.
  10. . Assessment of Use and Safety of Edaravone for Amyotrophic Lateral Sclerosis in the Veterans Affairs Health Care System. JAMA Netw Open. 2020 Oct 1;3(10):e2014645. PubMed.
  11. . Logistics and safety of edaravone treatment for amyotrophic lateral sclerosis: experience in Argentina. Acta Neurol Belg. 2020 May 20; PubMed.
  12. . Long-term effects of edaravone on survival of patients with amyotrophic lateral sclerosis. eNeurologicalSci. 2018 Jun;11:11-14. Epub 2018 May 17 PubMed.
  13. . Improved Long-Term Survival with Edaravone Therapy in Patients with Amyotrophic Lateral Sclerosis: A Retrospective Single-Center Study in Japan. Pharmaceuticals (Basel). 2021 Jul 21;14(8) PubMed.
  14. . Magnetic resonance metrics to evaluate the effect of therapy in amyotrophic lateral sclerosis: the experience with edaravone. J Neurol. 2021 Sep;268(9):3307-3315. Epub 2021 Mar 2 PubMed.
  15. . Safety and Effectiveness of Long-term Intravenous Administration of Edaravone for Treatment of Patients With Amyotrophic Lateral Sclerosis. JAMA Neurol. 2022 Feb 1;79(2):121-130. PubMed.
  16. . Unintended Consequences of Approving Unproven Treatments-Hope, Hype, or Harm?. JAMA Neurol. 2022 Jan 10; PubMed.
  17. . Efficacy and Safety of Edaravone in Amyotrophic Lateral Sclerosis Patients in Indian Population. J Assoc Physicians India. 2022 Apr;70(4):11-12. PubMed.
  18. . Evaluation of Pharmacokinetics, Safety, and Drug-Drug Interactions of an Oral Suspension of Edaravone in Healthy Adults. Clin Pharmacol Drug Dev. 2021 Mar 11; PubMed.
  19. . Bioequivalence Study of Oral Suspension and Intravenous Formulation of Edaravone in Healthy Adult Subjects. Clin Pharmacol Drug Dev. 2021 Oct;10(10):1188-1197. Epub 2021 May 6 PubMed.
  20. . Clinical effects and safety of edaravone in treatment of acute ischaemic stroke: A meta-analysis of randomized controlled trials. J Clin Pharm Ther. 2021 Feb 27; PubMed.
  21. . Edaravone Dexborneol Versus Edaravone Alone for the Treatment of Acute Ischemic Stroke: A Phase III, Randomized, Double-Blind, Comparative Trial. Stroke. 2021 Mar;52(3):772-780. Epub 2021 Feb 16 PubMed.
  22. . Influence of Nanoparticle-Loaded Edaravone on Postoperative Effects in Patients with Cerebral Hemorrhage. J Nanosci Nanotechnol. 2021 Feb 1;21(2):1202-1211. PubMed.
  23. . Edaravone (Radicava): A Novel Neuroprotective Agent for the Treatment of Amyotrophic Lateral Sclerosis. P T. 2018 Jan;43(1):25-28. PubMed.
  24. . Treatment with edaravone, initiated at symptom onset, slows motor decline and decreases SOD1 deposition in ALS mice. Exp Neurol. 2008 Oct;213(2):448-55. Epub 2008 Jul 31 PubMed.
  25. . Clinical and Pathological Benefits of Edaravone for Alzheimer's Disease with Chronic Cerebral Hypoperfusion in a Novel Mouse Model. J Alzheimers Dis. 2019;71(1):327-339. PubMed.
  26. . Protective effects of edaravone on white matter pathology in a novel mouse model of Alzheimer's disease with chronic cerebral hypoperfusion. J Cereb Blood Flow Metab. 2020 Oct 26;:271678X20968927. PubMed.
  27. . Edaravone alleviates Alzheimer's disease-type pathologies and cognitive deficits. Proc Natl Acad Sci U S A. 2015 Apr 21;112(16):5225-30. Epub 2015 Apr 6 PubMed.

External Citations

  1. press release
  2. clinicaltrials.gov
  3. clinicaltrials.gov
  4. ; FDA review document
  5. EMA review document

Further Reading

Papers

  1. . Role of Edaravone as a Treatment Option for Patients with Amyotrophic Lateral Sclerosis. Pharmaceuticals (Basel). 2020 Dec 31;14(1) PubMed.
  2. . Edaravone: a new treatment for ALS on the horizon?. Lancet Neurol. 2017 Jul;16(7):490-491. Epub 2017 May 15 PubMed.
  3. . Design, synthesis and biological evaluation of edaravone derivatives bearing the N-benzyl pyridinium moiety as multifunctional anti-Alzheimer's agents. J Enzyme Inhib Med Chem. 2020 Dec;35(1):1596-1605. PubMed.
  4. . Improvement of a decreased anti-oxidative activity by edaravone in amyotrophic lateral sclerosis patients. J Neurol Sci. 2020 Aug 15;415:116906. Epub 2020 May 15 PubMed.
  5. . Therapeutic news in ALS. Rev Neurol (Paris). 2021 May;177(5):544-549. Epub 2021 Mar 26 PubMed.
  6. . Clinical efficacy of edaravone for the treatment of amyotrophic lateral sclerosis. Expert Opin Pharmacother. 2017 May;18(7):735-738. PubMed.
  7. . Evidence for generalizability of edaravone efficacy using a novel machine learning risk-based subgroup analysis tool. Amyotroph Lateral Scler Frontotemporal Degener. 2021 Jul 10;:1-9. PubMed.
  8. . Addressing the role of edaravone in the management of amyotrophic lateral sclerosis and gaps in care and access: expert panel recommendations. Am J Manag Care. 2021 Aug;27(12 Suppl):S231-S237. PubMed.
  9. . Effects of the Edaravone, a Drug Approved for the Treatment of Amyotrophic Lateral Sclerosis, on Mitochondrial Function and Neuroprotection. Antioxidants (Basel). 2022 Jan 20;11(2) PubMed.
  10. . Edaravone ameliorates depressive and anxiety-like behaviors via Sirt1/Nrf2/HO-1/Gpx4 pathway. J Neuroinflammation. 2022 Feb 7;19(1):41. PubMed.
  11. . Edaravone activates the GDNF/RET neurotrophic signaling pathway and protects mRNA-induced motor neurons from iPS cells. Mol Neurodegener. 2022 Jan 10;17(1):8. PubMed.
  12. . Exploring the Mechanism of Edaravone for Oxidative Stress in Rats with Cerebral Infarction Based on Quantitative Proteomics Technology. Evid Based Complement Alternat Med. 2022;2022:8653697. Epub 2022 Jan 4 PubMed.
  13. . Edaravone Dexborneol Treatment Attenuates Neuronal Apoptosis and Improves Neurological Function by Suppressing 4-HNE-Associated Oxidative Stress After Subarachnoid Hemorrhage. Front Pharmacol. 2022;13:848529. Epub 2022 Apr 21 PubMed.
  14. . Targeted delivery of edaravone by liposomes for the treatment of ischemic stroke. Nanomedicine (Lond). 2022 May 4; PubMed.