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 document; Cruz, 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, Radicava ORS; edavarone is not approved by the European Medicines Agency (Dorst and Genge, 2022).

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., 2019; Feng et al., 2020; Jiao 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). A separate post hoc analysis of individual ALSFRS items identified lower motor functions, such as walking and climbing stairs, as those preserved by edaravone (Brooks et al., 2022). 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).

A post hoc analyses of prior clinical trials, and an observational study, linked baseline urate levels and their rate of change to disease progression and treatment response (Takahashi et al., 2022, Han et al., 2022).

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 has developed 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, Shimiziu et al., 2022). 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, was completed in October 2021, and was reported to have shown good tolerability (Genge et al., 2022). 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. In January 2022, two similar, 300-patient efficacy studies of the oral formulation started up. One is enrolling at 20 sites in the United States, Canada, the United Kingdom, and Japan; the other is enrolling at 38 sites across Europe; both will run until June 2024.  

The Dutch company Treeway is also developing an oral formulation of edaravone for ALS, called TW001, for ALS and Alzheimer's disease.

Edaravone is also being trialed in ischemic stroke, intracerebral hemorrhage, alcohol-induced brain injury, and optic neuritis. 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.