Long‐term safety of oral edaravone in Japanese patients with amyotrophic lateral sclerosis: Sub‐analysis of a global, open‐label, phase 3 study

Patients with amyotrophic lateral sclerosis (ALS) experience a slower rate of physical function decline when treated with intravenous edaravone. The oral suspension formulation of edaravone (105 mg) has a similar pharmacokinetic profile to intravenous edaravone (60 mg/60 min). The long‐term safety of oral edaravone in Japanese patients with ALS has not been reported. Therefore, a sub‐analysis of Japanese patients in a global phase 3 study (NCT04165824) was conducted to evaluate the safety and tolerability of oral edaravone in Japanese patients with ALS.

in initial symptoms such as muscle atrophy, limb dysfunction, and gait disturbance, and leading to dysarthria, dysphagia, respiratory impairment, and death.
7][8] However, this edaravone treatment regimen requires repeated IV administrations.This mode of delivery creates a burden for patients, caregivers, and medical personnel.Therefore, an alternative formulation of IV edaravone is needed.
An oral suspension formulation of edaravone (Radicava ORS®, Mitsubishi Tanabe Pharma Corporation, Osaka, Japan) has recently been approved in the United States, Canada, Japan, and Switzerland for the treatment of ALS. 9 This formulation can be easily administered by patients at home, reducing the burden on patients and their caregivers.Previous pharmacokinetic and bioequivalence studies have shown that 105 mg edaravone, as an oral suspension, has a similar pharmacokinetic profile to 60 mg/60 min IV edaravone. 10,11The safety and tolerability of this oral formulation has been assessed in a global, open-label, phase 3 study in patients with ALS. 12 However, the safety of the oral suspension formulation of edaravone within the Japanese population in this global study has not been reported.Therefore, this sub-analysis study evaluated the safety of oral edaravone over 48 weeks in the Japanese subpopulation of patients with ALS who were enrolled in the global phase 3 study. 12

| Study design
This prospective, open-label, multicenter phase 3 study evaluated the long-term safety and tolerability of an oral suspension formulation of edaravone in patients with ALS.The full details of the study have been described previously. 12The study design is shown in Figure 1 and included a screening period of up to 3 weeks, and an open-label treatment period of up to 48 weeks.The study was conducted at 50 sites across Japan, the United States, Canada, Germany, France, and Italy, between 19 November 2019 (first screening date) and 7 October 2021; the results from sites in Japan are described in this report.
This study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines.
Ethical approval was obtained from the relevant institutional or regional committees, and written informed consent was obtained from all patients participating in this study.The study was registered on Clini calTr ials.gov under the identifier NCT04165824.

| Study population and intervention
The full inclusion and exclusion criteria have been previously published. 12Briefly, eligible patients had a baseline forced vital capacity ≥70%, a disease duration of ≤3 years, and a diagnosis of definite ALS, probable ALS, probable laboratory-supported ALS, or possible ALS, according to the El Escorial revised Airlie House diagnostic criteria. 13Patients with a presence or history of any clinically significant disease other than ALS; alanine aminotransferase or aspartate aminotransferase higher than 2× the upper limit of normal at screening; or glomerular filtration rate <30 mL/min/1.73m 2 at screening were excluded.This report includes data from Japanese patients only.

Patients received edaravone 105 mg orally once daily on waking
(following an overnight fast). 14Fasting continued for at least 1-2 h after dosing.The first course of treatment comprised a 14-day dosing period, followed by a 14-day rest period.The second and subsequent courses comprised a 14-day dosing period (with 10 days of drug administration and 4 days without drug administration), followed by a 14-day rest period.Each treatment cycle had a 4-week duration.

| Study outcomes
The primary outcomes were the safety and tolerability of the oral suspension formulation of edaravone in patients in Japan.
F I G U R E 1 Study design.Edaravone was orally administered following an overnight fasting period, with the next meal at least 1 h after edaravone administration.The first course of treatment comprised a 14-day dosing period, followed by a 14-day rest period.The second and subsequent courses comprised a 14-day dosing period (with 10 days of drug administration and 4 days without drug administration), followed by a 14-day rest period.The following safety assessments were reported: adverse events (AEs), adverse drug reactions (ADRs), and treatment-emergent AEs (TEAEs).AEs associated with the normal progression of ALS were not reported.AEs were classified according to the Medical Dictionary for Regulatory Activities, Japanese version 23.0.
End-of-treatment assessments and safety follow-up evaluations were performed at week 48, approximately 2 weeks after receiving the last dose of edaravone (Figure 1).Additional safety assessments and the safety outcomes for the complete patient population at weeks 24 and 48 have been previously reported. 12As a preliminary evaluation showed that there was no difference in safety or tolerability between the 24-week and 48-week assessments for the Japanese population, only the second analysis results (week 48) are shown in this report.

| Sample size and statistical analyses
The safety analysis population comprised all enrolled patients from Japanese sites who received at least one dose of the oral suspension formulation of edaravone.Continuous data were summarized using the number in the dataset, the number of observations, means, and standard deviation (SD).Categorical data were summarized by number and percentage.Missing data were neither included nor imputed, and unscheduled or repeat assessments were not included in summary tables.Descriptive statistics were used to evaluate the longterm safety and tolerability of oral edaravone.All statistical analyses were conducted using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA).

| Patients
A total of 185 patients with ALS were enrolled in this study globally; 65 patients were enrolled in Japan and were evaluated for safety for this report.The background characteristics of these patients are summarized in Table 1.Most patients were male (43/65, 66.2%), and age (mean ± SD) was 59.3 ± 9.3 years.The disease duration (mean ± SD) was 1.5 ± 0.6 years, and most patients were receiving concomitant treatment with riluzole (60/65, 92.3%).Only one patient had a diagnosis of familial ALS, and most patients had either definite (20/65, 30.8%) or probable (26/65, 40.0%)ALS, according to the El Escorial revised Airlie House diagnostic criteria.

| Safety assessments
The proportions of TEAEs and ADRs by week 48, excluding events associated with normal ALS progression, are summarized in Table 2.
No TEAEs or ADRs led to study drug discontinuations, and none were fatal.
TEAEs occurring with an incidence of at least 5% following edaravone treatment are shown in Table 3, excluding events associated with normal ALS progression.By week 48, the most common TEAEs were constipation (10/65, 15.4%), insomnia (8/65, 12.3%), and back pain (7/65, 10.8%).A full listing of all observed TEAEs, excluding events associated with normal progression of ALS, is provided in Table S1.This open-label study evaluated the long-term safety and tolerability of an oral suspension formulation of edaravone in Japanese patients with ALS.The most frequently observed TEAEs were constipation, insomnia, and back pain.The ADRs were diarrhea, abnormal hepatic function, and fatigue (all n = 1).The reported ADRs were similar to those reported in previous IV edaravone studies in patients with ALS, 7,8 and no serious ADRs, or ADRs leading to study drug discontinuation or death, were observed.These findings suggest that the oral suspension formulation of edaravone has an acceptable safety profile in Japanese patients, and no unexpected TEAEs were recorded.
It is important to note that the majority of patients in this study were receiving concomitant riluzole (92.3%), which is consistent with high rates of concomitant treatment with 60 mg intravenous edaravone and riluzole reported in previous trials. 7,8Therefore, the results should be interpreted in the context of combination riluzole treatment.Previous studies of IV edaravone have reported a high frequency of AEs in patients with ALS (approximately 85%). 7,8Common TEAEs with IV edaravone treatment include nasopharyngitis, gait disturbance, and constipation. 7Although this sub-analysis study did not report any cases of gait disturbance, this may reflect differences in recording measures.Overall, the frequency and type of ADRs were similar between this study and previous IV edaravone studies in Japan. 7,8Furthermore, the oral suspension formulation of edaravone offers greater convenience for patients, caregivers, and clinicians than IV administration because it is a less invasive procedure and requires a shorter administration time.These findings indicate that the oral suspension formulation of edaravone has a similar safety profile to IV edaravone and is an acceptable and convenient treatment option for patients with ALS in Japan.
6][17] In this study, only one case of renal and urinary disorders (pollakiuria) occurred.
However, as the pathophysiology of ALS differs from that of acute ischemic stroke, 16,17 the rates of renal impairment following edaravone treatment may also vary.
The incidence of ALS is thought to be lower in Japan than in other countries; furthermore, the causative mutations of familial ALS vary between populations. 18,19In Japan, patients with familial ALS often have mutations in the superoxide dismutase 1 gene and rarely have mutations in C9ORF72, whereas patients in Europe and the United States often have mutations in C9ORF72. 19Although the populations differed, this sub-analysis reported no notable differences in safety compared with the previously reported global population. 12portantly, this current study shows that the oral suspension formulation of edaravone is well tolerated in patients with ALS in Japan.
We acknowledge the limitations of this study given there was no control group, and no direct comparisons with other medications or formulations could be made.Moreover, the safety of oral edaravone beyond 1 year remains to be determined.
In conclusion, this study confirmed the safety and tolerability of the oral suspension formulation of edaravone in Japanese patients over 48 weeks, with no new safety concerns identified in this population.

ACK N OWLED G M ENTS
The authors thank Hannah Read, PhD, of Edanz (www.edanz.com) for providing medical writing support, which was funded by TA B L E 2 Adverse events following edaravone treatment (excluding events associated with normal ALS progression).

TA B L E 3
TEAEs with an incidence of at least 5% following edaravone treatment (excluding events associated with normal ALS progression).Abbreviations: ALS, amyotrophic lateral sclerosis; TEAE, treatmentemergent adverse event.
Data are shown as n (%).

TA B L E 1
Japanese patient baseline characteristics.
Note: Data are shown as n (%) or mean ± SD.