Edaravone and its clinical development for amyotrophic lateral sclerosis

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.

Keywords:

• Amyotrophic lateral sclerosis
• edaravone
• mechanism of action
• development history

Introduction

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Rapid progression of symptoms results directly from degeneration in motor neurons, causing the loss of motor function. Most patients will eventually need assistance with activities of daily living. Disease progression ultimately leads to respiratory compromise and eventual respiratory failure, which is a leading cause of death in ALS (1).

In the majority of ALS patients (90–95%), the disease occurs without family history. These patients are categorized as having sporadic ALS (SALS). Familial ALS (FALS) is usually identified if ALS has occurred in at least one other family member (1). SALS and FALS are clinically and pathologically indistinguishable, in that they show similar clinical deterioration and functional loss of motor neurons (2).

While the etiology of ALS is unknown, multiple lines of evidence suggest that oxidative stress may be one of the major mechanisms in the progression of motor neuron degeneration and glial dysfunction observed in ALS, whether by direct effects on these cells or by the exacerbation of other pathological mechanisms (2,3). The presence of free radicals or oxidative stress is impractical to measure directly in research studies and, therefore, oxidative stress biomarkers, such as products of DNA oxidation (8-hydroxy-2′-deoxyguanosine) (4–7), lipid oxidation (4-hydroxy-2,3-nonenal [HNE] (8), malondialdehyde [MDA] (7,9), or 15-F_2t-isoprostane [IsoP] (5)), and protein oxidation (3-nitrotyrosine [3NT] (10,11) or advanced oxidation protein products [AOPP] (12,13)) are utilized to obtain a “footprint” of free radical or high oxidative stress. Simpson et al. reported that lipid peroxide levels measured by HNE in serum were higher in ALS patients compared with normal control subjects at all the stages of ALS (8). Some biomarkers of oxidative stress, themselves, are known to have neurotoxic effects (3).

Edaravone is understood to be a free radical scavenger. It was approved in Japan in 2001 for the improvement of neurological symptoms, disruption of daily living, and functional impairment associated with acute ischemic stroke (14). This article will describe the properties of edaravone and how clinical studies in stroke were followed by phase II and III studies performed during its clinical development for ALS. Other articles, describing the individual studies and related analyses, are contained in this same supplementary issue of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration (ALSFTD).

Edaravone mechanism of action

The biochemical properties of edaravone and evidence from in vitro and in vivo studies suggest that edaravone may have protective effects against oxidative stress. As the acid-dissociation constant (pK_a) of edaravone is 7.0, a dissociated anionic and hydrophilic form and a non-dissociated neutral and lipophilic form are simultaneously present under physiological conditions. With these physicochemical properties, edaravone may distribute in both hydrophilic conditions, such as the cytoplasm, and in lipophilic conditions, such as the cell membrane. Edaravone has shown anti-oxidative effects against water-soluble peroxyl radicals like vitamin C and lipid-soluble peroxyl radicals like vitamin E (15) and has been shown to scavenge free radicals, including lipid peroxyl radical (LOO·), as well as peroxynitrite (ONOO⁻) another form of reactive oxygen species through its electron donating properties (16–18). Edaravone has shown protective effects on neurons (19), glia (microglia, astrocytes, and oligodendrocytes) (20–22), and vascular endothelial cells (23) against oxidative stress and has been shown to suppress the inflammatory response of activated microglial cells (24). Therefore, while the exact mechanism of action of edaravone for ALS is unknown, its potential mechanism may be a combination of these protective effects rather than a direct effect on motor neurons.

In ALS patients in an open-label phase II study with six cycles of edaravone (24-week study MCI186-12), levels of the oxidative stress marker 3NT in cerebrospinal fluid (CSF) were diminished after the first treatment cycle of 60 mg edaravone once a day (2-week administration) and were undetectably low in most patients after the sixth treatment cycle (25). Reduction of 3NT might be a result from reduction of peroxynitrite (ONOO⁻) by edaravone because the formation of nitrotyrosine represents a specific peroxynitrite-mediated protein modification (26).

Pharmacokinetics of edaravone

After IV infusion in human subjects, edaravone is metabolized into sulfate and glucuronide conjugates mainly in the liver, and is rapidly eliminated primarily by renal excretion. There is no accumulation in plasma concentration after repeated doses. Neither the sulfate nor the glucuronide has free radical scavenging activities. Edaravone and its metabolites are not expected to inhibit or induce CYP450 isozymes at the clinical dose level (27).

Clinical experience with edaravone before ALS

Five phase I studies of edaravone were conducted in healthy volunteers (47 Japanese and 50 Caucasian). A phase III study was conducted in acute ischemic stroke in Japanese patients with treatment initiated within 72 h of the onset of symptoms. The study drug edaravone 30 mg (or placebo) was administered intravenously over 30 min twice daily for 14 consecutive days. The study demonstrated a significant improvement in functional outcome in the edaravone group compared with the placebo group as evaluated by the modified Rankin Scale at 3 months. When a subset analysis was performed for the patients in whom edaravone was initiated within 24 h of stroke onset (according to an instruction by the Japanese health authority during their data review), the difference between the two groups was greater (14). The study result led to the approval of edaravone in Japan in 2001 for the improvement of neurological symptoms, disruption of daily activities, and functional impairment associated with acute ischemic stroke. The approved dosing regimen for acute ischemic stroke in Japan is the same as investigated in the study (30 mg intravenously over 30 min, twice daily, up to 14 d) with the recommendation that it should be initiated within 24 h of the onset of symptoms. Since 2001, approximately 1.7 million acute ischemic stroke patients have received edaravone in Japan.

Clinical studies of edaravone in ALS

The phase III studies of edaravone in ALS are shown in Table 1. The dosage regimen in all phase III studies was 60 mg by infusion over 60 min once a day for 14 d, followed by a 2-week break without infusions in the initial cycle. Repeating treatment cycles were comprised as 10 d of treatment out of 14 d, followed by a 2-week break without infusions. The 14-day treatment duration in each cycle was based on the regimen established in stroke patients in Japan. The 60-mg dose was selected based on the findings of a 24-week phase II study in ALS. This phase II study (Study MCI186-12) compared the disease course of enrolled patients “on drug” relative to their pre-treatment rates of decline. The 60 mg/d dose showed a statistically significant reduction in decline in ALSFRS-R, in addition to the reduction of 3NT in CSF after the 60 mg/d treatment as described in the previous section (25).

Table 1. Comparison of the populations evaluated for efficacy (inclusion criteria).

^aEESP: patients with 2 points or better, on each of the individual items of the ALSFRS-R and %FVC ≥ 80% in the full analysis set (FAS). EESP was set in a post-hoc exploratory analysis of Study MCI186-16, and was prespecified before the code break of MCI186-17.

^b dpEESP2y: patients with definite or probable diagnosis based on the El Escorial revised Airlie House diagnostic criteria for ALS and within two years after the onset of ALS in the EESP.

^cD: definite ALS; P: probable ALS; PLS: probable ALS-laboratory-supported.

^d The Japan ALS severity classification score ranges from 1 to 5 as follows: (1) able to work or perform housework; (2) independent living but unable to work; (3) requiring assistance for eating, excretion or ambulation; (4) presence of respiratory insufficiency, difficulty in coughing out sputum or dysphagia; and (5) using a tracheostomy tube, tube feeding or tracheostomy positive pressure ventilation.

In general, ALS clinical trials have faced challenges. One is the large variability in the rate of disease progression among patients (28). Phase III studies of edaravone were designed to rapidly evaluate (within a 24-week double-blind study window) functional changes using the ALSFRS-R as a primary endpoint. The study populations were selected according to these considerations and were further refined as the studies proceeded.

Study MCI186-16 [NCT00330681] (29), the first phase III study, was a randomized placebo-controlled study with six cycles of edaravone (24 weeks). A population of patients, selected at baseline for certainty of diagnosis, confirmation of the rate of progression of symptoms, good respiratory status, and functional independence were selected for study inclusion (Table 1). A beneficial trend favoring edaravone based on ALSFRS-R score was observed, although the difference was not statistically significant. Then, exploratory analyses of study MCI186-16 were conducted (30,31). It was considered that the effect of edaravone in slowing the decline in ALSFRS-R scores might be detectable in some patients depending on the baseline clinical characteristics. Accordingly, one category, designated as efficacy expected subpopulation (EESP), included only patients in whom all individual items of the ALSFRS-R were 2 or greater (i.e. broad retained functionality), with a percent predicted forced vital capacity (%FVC) of 80% or greater (almost normal respiratory function) at baseline. It was hypothesized that the requirement of two points or greater in each ALSFRS-R item would enhance scale sensitivity to detect functional deterioration in each ALSFRS-R item by avoiding a “floor effect”. It was also hypothesized that the criterion of normal or near normal %FVC would reduce variability in disease progression during the study period as respiratory insufficiency at baseline sometimes results in very rapid progress of ALS. The second subpopulation was designated as definite/probable EESP 2 years (dpEESP2y) and consisted of patients meeting the EESP criteria and who, in addition, had a definite or probable ALS diagnosis based on the El Escorial revised Airlie House diagnostic criteria (32), and were within 2 years from disease onset. This further refined population with certain diagnosis of disease was hypothesized to have a high likelihood of disease progression within the 24-week study window. By performing analyses that examined the difference from baseline, at the end of six cycles of treatment, in the endpoint of ALSFRS-R score, specifically comparing the effect of edaravone versus placebo, it was found that the observed difference in ALSFRS-R score, favoring edaravone over placebo, was of descriptively greater magnitude in the analysis of the EESP (2.20) than it had been seen to be in the equivalent analysis first performed in the full MCI186-16 population (0.65). The apparent advantage of edaravone treatment, versus placebo, was observed to be of still greater magnitude in the analysis of the dpEESP2y (3.01), than it had been seen to be in either the EESP, or in the full MCI186-16 population. The full concept and results of the post-hoc analyses of MCI186-16, and the efficacy and safety results applied to the subpopulations are included in a separate publication in this ALSFTD supplement.

Study MCI186-17 [NCT00424463] (33) was a randomized placebo-controlled extension study of six cycles (24 weeks) in patients continuing from MCI186-16. Patients who received edaravone in MCI186-16 were reassigned to either edaravone or placebo. Patients who received placebo in MCI186-16 were switched to edaravone. All the patients were offered open-label edaravone for the following 12 weeks (cycles 13–15). While a beneficial trend favoring edaravone based on ALSFRS-R score was observed, this was not statistically significant. However, post-hoc analyses in both the EESP and the dpEESP2y showed beneficial trends similar to those observed in MCI186-16 favoring edaravone.

Study MCI186-18 [NCT00415519] (34) was a randomized, placebo-controlled, exploratory study of 25 patients with more advanced ALS (Japan ALS severity grade 3) who were administered study drug for six cycles (24 weeks). While study MCI186-16 was conducted in patients with less advanced ALS, corresponding to grade 1 or 2, this study was designed to explore the efficacy and the safety of edaravone in consideration of the possibility that patients with more advanced ALS may also use edaravone. This exploratory study was not statistically powered and showed no difference between edaravone and placebo in the ALSFRS-R score. The incidences of adverse events were similar in the two groups. Full results of MCI186-17, MCI186-17 post-hoc, and MCI186-18 are published in three separate articles in the Supplement.

Study MCI186-19 [NCT01492686] was a phase III, randomized, placebo-controlled study designed as a pivotal trial. This specific population (dpEESP2y) was prospectively defined in the protocol and enrolled into the trial. Study results were published as a full paper (31). Briefly, the primary endpoint of change in ALSFRS-R score at 24 weeks for edaravone versus placebo was statistically significant and the magnitude of difference was large enough to be clinically relevant (the least square mean difference 2.49 ± 0.76 standard error, p = 0.0013). Statistically significant and clinically relevant differences favoring edaravone were also observed for quality of life using the ALS Assessment Questionnaire (ALSAQ-40).

Study MCI186-19 continued in an open-label extension phase for an additional 24 weeks, during which all patients received edaravone. This extension phase, which is described in full in an article in the Supplement (35), demonstrated that the differences in ALSFRS-R, %FVC, and ALSAQ40 between edaravone and placebo at the end of cycle 6 were maintained beyond the 6-cycle primary endpoint, remaining robust through cycle 12 (48 weeks). Furthermore, time to event analysis (including death, disability of independent ambulation, loss of upper limb function, tracheotomy, use of respirator [except bi-level positive airway pressure], use of tube feeding, or loss of useful speech), for the patients originally randomized to edaravone at baseline and continued for 48 weeks, showed evidence to support the efficacy of edaravone in delaying definite disease progression events. The study also appeared to show that the benefits of edaravone therapy may be maximized when it is initiated early in the course of ALS.

This supplement also includes an article reporting an integrated safety analysis of all the placebo-controlled edaravone clinical trials in ALS. The overall incidences of adverse events were similar between the edaravone group and the placebo group. Treatment-emergent adverse events that were reported at a higher incidence (≥≥2%) in the edaravone group compared with the placebo were contusion, gait disturbance, headache, eczema, dermatitis contact, respiratory disorder, and glucose urine present.

Another article reports a population pharmacokinetic analysis based on the data from phase I studies to show a similar pharmacokinetic profile of edaravone between Japanese and Caucasian subjects. There is also an article reviewing similarities and differences in treatment patterns and disease course among Japan, Europe, and the US with relevance to the generalizability of the results of edaravone safety and efficacy trials, which were all conducted in Japan.

Conclusion

ALS clinical trials have faced challenges in handling large variability in disease progression among patients. In the series of clinical trials of edaravone in ALS, the ALSFRS-R, as a well-validated scale, was used as the primary endpoint to measure the rate of disease progression during a 24-week double-blind period, minimizing duration of placebo exposure in a serious and progressive disease. Although the first phase III study did not meet its primary endpoint, post-hoc analyses from that initial 24-week study (MCI186-16 double-blind) and its 24-week extension (MCI186-17 double-blind) produced encouraging results. The enrolment criteria of study MCI186-19 were prospectively defined, based on the findings of study MCI186-16. With this refinement of the study population, a statistical sample size calculation required fewer patients in study MCI186-19 compared with study MCI186-16. Study MCI186-19 achieved its pre-specified primary endpoint of change on the ALSFRS-R. In addition, less deterioration in secondary endpoint of quality of life was observed with edaravone compared with the placebo. Based on the experience gained in this clinical development program in ALS, it may be important to consider whether or not future studies in ALS can become increasingly efficient.

Edaravone has been approved for ALS in Japan and South Korea in 2015, and in the United States in 2017. Post-approval long-term registry studies are ongoing in Japan and South Korea. As a condition of edaravone approval by the US Food and Drug Administration, further formal explorations of dose response are planned. Supportive biomarkers are being considered.

To conclude, it is our hope that the positive findings of the clinical studies of edaravone are translated into reduced human suffering. We also hope that the trial design employed encourages future researchers to focus their efforts on the development of new therapies in ALS and the preservation of function and quality of life. We are indebted to the altruism of the patients and families who have taken part in these studies to create hope for the future.

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.

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.

Additional information

Funding

Mitsubishi Tanabe Pharmaceutical Corporation

Mitsubishi Tanabe Pharmaceutical Corporation