Efficacy and Safety of Once Daily Dosing vs. Approved On/Off Dosing of Edaravone Oral Suspension Up to 48 Weeks in Patients With Amyotrophic Lateral Sclerosis (Study MT‐1186‐A02)

ABSTRACT

Introduction/Aims

An On/Off dosing regimen of intravenous (IV) edaravone and edaravone oral suspension is approved in the US for the treatment of amyotrophic lateral sclerosis (ALS). Placebo‐controlled clinical trials showed IV edaravone slows the rate of physical functional decline. This study evaluated whether investigational daily dosing displayed superior efficacy vs. approved on/off dosing of edaravone oral suspension, and assessed safety and tolerability, over 48 weeks in patients with ALS.

Methods

Study MT‐1186‐A02 (NCT04569084) was a multicenter, phase 3b, double‐blind, parallel group, superiority study that randomized patients to edaravone oral suspension (105‐mg dose) administered Once Daily or the same edaravone oral suspension dose administered according to the approved On/Off regimen including placebo to mimic daily drug dosing. Patients had definite or probable ALS, baseline forced vital capacity ≥ 70%, and baseline disease duration ≤ 2 years. The primary endpoint was a combined assessment of function and survival (CAFS) at week 48, which included change in ALS Functional Rating Scale‐Revised (ALSFRS‐R) and time to death.

Results

CAFS at week 48 indicated Once Daily dosing did not show a statistically significant difference vs. approved on/off dosing (p = 0.777). Both dosing regimens provided comparable change from baseline ALSFRS‐R total score to week 48 (least squares mean difference: 0.27 [95% CI −1.43 to 1.97]). Edaravone oral suspension was well tolerated, and no new safety concerns were identified in either group.

Discussion

Daily edaravone oral suspension did not show superiority and had equivalent safety and tolerability vs. the approved On/Off regimen, reinforcing the appropriateness of the approved dosing regimen.

Abbreviations

AE

adverse event

ALS

amyotrophic lateral sclerosis

ALSAQ‐40

ALS Assessment Questionnaire‐40

ALSFRS‐R

ALS Functional Rating Scale‐Revised

BL

baseline

BW

body weight

CAFS

combined assessment of function and survival

CI

confidence interval

C‐SSRS

Columbia‐Suicide Severity Rating Scale

COVID‐19

coronavirus disease 2019

DBT

double‐blind treatment

ECG

electrocardiogram

EOT

end of treatment

ET

early termination

FA

futility analysis

FAS

full analysis set

FDA

Food and Drug Administration

FVC

forced vital capacity

HR

hazard ratio

IDMC

Independent Data Monitoring Committee

IV

intravenous

K‐M

Kaplan–Meier

LS

least squares

PAMV

permanent assisted mechanical ventilation

PB‐TURSO

sodium phenylbutyrate and taurursodiol

PK

pharmacokinetic

SAF

safety analysis set

SD

standard deviation

SE

standard error

Study 19

Study MCI186‐19

Study A02

Study MT‐186‐A02

SVC

slow vital capacity

TEAE

treatment‐emergent adverse event

TESAE

serious TEAE

US

United States

1. Introduction

Although there are currently 3 United States (US) Food and Drug Administration (FDA)‐approved active pharmaceutical agents for amyotrophic lateral sclerosis (ALS) that have been shown to prolong survival and/or slow functional decline (riluzole, edaravone, and tofersen), there is no cure [1, 2, 3]. In December 1995, riluzole was the first therapy to be approved by the FDA [1]. Intravenous (IV) edaravone was FDA approved in May 2017 for patients with ALS [2] based on the results of the pivotal phase 3 trial MCI186‐19 (Study 19) [4]. IV edaravone has been approved in a number of additional countries. In Study 19, patients randomized to IV edaravone displayed a 33% slower rate of physical functional decline at 24 weeks (p = 0.0013), as measured by the ALS Functional Rating Scale‐Revised (ALSFRS‐R) [5], vs. patients randomized to placebo [4]. Notably, Study 19 enrolled an enriched patient population, which required participants to fit criteria including, but not limited to, patients with definite or probable ALS as per El Escorial revised criteria, disease duration of ≤ 2 years, and forced vital capacity (FVC) ≥ 80% of predicted. Edaravone oral suspension was approved by the FDA in May 2022 [2]. Pharmacokinetic (PK) and bioequivalence studies demonstrated similar pharmacokinetic profiles between a 105‐mg dose of edaravone oral suspension and the 60‐mg dose of IV edaravone [6, 7]. Safety and tolerability of edaravone oral suspension were assessed in a global, multicenter, open‐label, phase 3 study (MT‐1186‐A01) in adults with ALS who had a baseline predicted FVC ≥ 70% and a disease duration of ≤ 3 years [8]. The primary safety analysis for Study MT‐1186‐A01 was assessed at weeks 24 and 48. Patients received a 105‐mg edaravone oral suspension dose in treatment cycles that replicated the approved On/Off dosing schedule of IV edaravone. This study indicated that edaravone oral suspension was well tolerated during 48 weeks of treatment and no new safety concerns were identified as compared to the established IV edaravone safety profile.

Study MT‐1186‐A02, which investigated edaravone oral suspension, was a postmarketing commitment study conducted as part of the FDA approval process for IV edaravone. The primary objective of Study MT‐1186‐A02 was to evaluate and compare whether an investigational Once Daily dosing regimen of edaravone oral suspension displayed superior efficacy to the approved On/Off dosing regimen in patients with ALS based on combined assessment of function and survival (CAFS) at week 48. The secondary objectives were to evaluate the safety and tolerability of these 2 dosing regimens over 48 weeks.

2. Methods

2.1. Study Design

Study MT‐1186‐A02 (NCT04569084) was a phase 3b, multicenter, double‐blind, parallel group, randomized study evaluating 2 different dosing regimens of edaravone oral suspension (Radicava ORS, Mitsubishi Tanabe Pharma America, Jersey City, New Jersey). The study design included a screening period of 8 weeks, followed by a double‐blind treatment period of up to 48 weeks. End‐of‐treatment (EOT) assessments occurred at week 48 or at early termination (ET). A safety follow‐up period occurred 2 weeks after the last dose. Patients who completed the 48‐week double‐blind treatment period could enroll in extension Study MT‐1186‐A04, which was a phase 3b, multicenter, double‐blind, parallel group, randomized extension study that evaluated the efficacy and safety of the 2 treatment regimens of edaravone oral suspension for an additional period of up to 48 weeks. Concomitant use of riluzole was permitted provided doses and regimens remained unchanged from screening through EOT or ET before week 48, although de novo use of riluzole was prohibited. Concomitant use of sodium phenylbutyrate and taurursodiol (PB‐TURSO) was permitted once commercially available and had to be taken at least 1 h after edaravone oral suspension.

2.2. Study Drug Administration

Patients were randomized 1:1 to either the Once Daily regimen or the On/Off regimen. For the Once Daily regimen group, edaravone oral suspension 105 mg was administered Once Daily for 28 days in Cycles 1 through 12. For the On/Off regimen group, edaravone oral suspension 105 mg was administered for 14 days, followed by placebo for 14 days in Cycle 1. Subsequently, repeat edaravone oral suspension 105 mg was administered for 10 days, followed by placebo for 18 days in Cycles 2 through 12.

2.3. Study Population

The inclusion criteria were: males and females aged 18 to 75 years, ALS diagnosis of definite ALS or probable ALS according to El Escorial revised Airlie House diagnostic criteria [9], baseline score ≥ 2 points on each individual item of the ALSFRS‐R at screening and baseline visits, screening and baseline %FVC ≥ 70% of predicted, 1‐ to 4‐point decline for 8 weeks (±7 days) in total ALSFRS‐R score between screening and baseline visits, first symptom of ALS ≤ 2 years ago.

The main exclusion criteria were patients who were undergoing treatment for a malignancy; were pregnant or lactating at the screening visit; had a significant risk of suicidality; had alanine aminotransferase or aspartate aminotransferase elevations > 2 times the upper limit of normal at screening; had a glomerular filtration rate < 30 mL/min per 1.73 m² at screening; had a history of hypersensitivity to edaravone, any of the additives or inactive ingredients of edaravone, or sulfites; had hereditary problems of fructose intolerance; had received any previous treatment with edaravone; or who were unable to take their medications orally at baseline.

2.4. Standard Protocol Approvals, Registrations, and Patient Consents

Approvals were received from ethical standards committees on human experimentation (institutional or regional review boards) for this clinical study. Written informed consent was obtained from all patients participating in this study. This trial was registered with Clinicaltrials.gov, number NCT04569084.

2.5. Endpoints

The primary efficacy endpoint was CAFS score at week 48. The CAFS score is composed of change of ALSFRS‐R score and time to death, with a higher CAFS rank indicating a better outcome than a lower CAFS rank [10]. The protocol for this study prespecified that the primary endpoint was change from baseline to week 48 in ALSFRS‐R total score. However, since there were ≥ 19 deaths, recorded as more than a few death events during the trial, the primary endpoint was changed to the CAFS score at week 48 for the study, as this was above the prespecified number in the protocol and statistical analysis plan to revise the primary endpoint. Key secondary efficacy endpoints included the following assessments: change from baseline in % slow vital capacity (%SVC) at week 48; change from baseline in ALS Assessment Questionnaire‐40 (ALSAQ‐40) at week 48 [11]; time to death ± tracheostomy ± permanent assisted mechanical ventilation (PAMV; ≥ 23 h/day); time to death or PAMV (≥ 23 h/day); and time to death. Other secondary efficacy endpoints included: change from baseline in ALSFRS‐R score at weeks 4, 8, 12, 24, 36, and 48; change from screening and baseline in %FVC at weeks 24 and 48; change from baseline in %SVC at weeks 4, 8, 12, 24, and 36; change from baseline in ALSAQ‐40 at week 24; change from baseline in body weight at weeks 4, 8, 12, 24, 36, and 48; CAFS score at week 24; King's ALS Clinical Stage derived from ALSFRS‐R score and death [12, 13]. Safety endpoints included the following assessments: adverse events (AEs), adverse drug reactions, and treatment‐emergent adverse events (TEAEs; eg, grade, incidence, severity); physical examination; 12‐lead electrocardiogram (ECG) parameters; vital signs, orthostatic hypotension; laboratory safety assessments; unsteadiness and sensory evaluation (evaluated by interview and assessment of vibratory sensation with a tuning fork applied to the lateral side of the right and left ankles); and Columbia‐Suicide Severity Rating Scale (C‐SSRS) [14].

2.6. Statistical Analyses

2.6.1. Determination of Sample Size

Assuming the use of a t‐test, with a 2‐sided alpha level of 5% and a 30% dropout rate up to week 48, a sample size of 190 patients per group (380 patients in total) provided 85.5% power to detect a treatment effect size of 0.37 (i.e., an absolute treatment difference of 2.6 with an associated standard deviation of 7) in the change in ALSFRS‐R score from baseline to week 48 between the Once Daily 105 mg edaravone oral suspension group and the On/Off 105 mg edaravone oral suspension group. A sample size of 190 patients per group had 78% power to detect a statistically significant result if the true hazard ratio (HR) between the Once Daily 105 mg edaravone oral suspension group (test) and On/Off 105 mg edaravone oral suspension group (control) was HR = 0.3, namely, a 70% risk reduction in the hazard assuming a 90% survival rate at week 48 for the control group. This calculation assumed a 2‐sided alpha of 5% using the log‐rank test and a follow‐up time of 48 weeks.

2.6.2. Analysis Population

The efficacy full analysis set (FAS) was defined as all randomized patients who had received at least 1 dose of study medication and had any efficacy data collected after randomization.

2.6.3. Primary Analysis Method

The CAFS was used to jointly analyze the ALSFRS‐R score and time to death [10]. This analysis ranked clinical outcomes based on survival time and change in the ALSFRS‐R score at week 48. The CAFS score at week 48 was evaluated using multiple imputation assuming missing at random for missing data plus analysis of covariance with treatment group and randomization strata of ALSFRS‐R rate of decline score during the screening period (2 levels of strata: [−1, −2] or [−3, −4]) and geographical region (3 levels of strata: Europe, North America, or Asia Pacific) as a fixed effect, baseline ALSFRS‐R total score as a covariate.

2.6.4. Type I Error Control

The family‐wise type I error of 5% was maintained for the primary endpoint and key secondary endpoints. To control the overall type I error rate for multiple comparisons across the primary endpoint and the secondary endpoints, the fixed sequence procedure was applied.

2.6.5. Analysis Method for Key and Other Secondary Endpoints

The changes from baseline to all post‐baseline visits until week 48 in %SVC/ALSAQ‐40/ALSFRS‐R total score/%FVC were estimated using a mixed model for repeated measures. The endpoint of time to events (death, tracheostomy and PAMV) was summarized using the number of events and percentage and displayed by Kaplan–Meier (K‐M) estimates with 95% CI stratified by treatment group, and a Cox proportional hazards regression model was also performed.

2.6.6. Pre‐Planned Interim Futility Analysis (FA)

An Independent Data Monitoring Committee (IDMC) conducted a pre‐planned review of the unblinded data for early stopping due to futility. The IDMC conducted the FA in an unblinded manner when 190 patients had completed the visit at week 48 or terminated early, which represents 50% of the anticipated total sample size of 380 patients in the study. The FA used the pre‐specified stopping rule using the conditional power to assess the study's original primary endpoint of ALSFRS‐R total score at week 48.

3. Results

3.1. Patients

In total, 594 patients were screened, and 384 patients were enrolled and randomized 1:1 into the Once Daily group or On/Off treatment group (Figure 1). A total of 246/384 (64.1%) patients completed the 48‐week double‐blind treatment (DBT) period, of whom 95/246 (38.6%) completed the 2‐week safety follow‐up period. Notably, patients who enrolled in the extension study, MT‐1186‐A04, were not required to complete the safety follow‐up, as they received safety assessments as part of Study MT‐1186‐A02. Of the 138/384 (35.9%) patients who discontinued study treatment, the most common reason for discontinuation was study terminated by Sponsor (49/138 [35.5%] patients) based on the IDMC recommendation and meeting the FA prespecified criteria for stopping Study MT‐1186‐A02. The second most common reason for discontinuation was patient withdrew consent (41/138 [29.7%] patients). Discontinuations were well balanced between the treatment groups.

FIGURE 1.

Patient disposition. DBT, double‐blind treatment; PK, pharmacokinetic. ^aOne patient randomized to the On/Off treatment group was excluded from the FAS and SAF because the patient did not receive any study treatment. ^bPatients who enrolled into the extension study, MT‐1186‐A04, were not required to complete the 2‐week safety follow‐up visit.

3.2. Demographic and Other Baseline Characteristics

Demographic and other baseline characteristics for the FAS were well balanced between groups (Table 1).

TABLE 1.

Demographic and other baseline characteristics (FAS).

	Edaravone oral suspension 105 mg Once Daily, n = 192	Edaravone oral suspension 105 mg On/Off, n = 191	Total N = 383
Sex, n (%)
Male	123 (64.1)	122 (63.9)	245 (64.0)
Female	69 (35.9)	69 (36.1)	138 (36.0)
Race, n (%)
White	115 (59.9)	108 (56.5)	223 (58.2)
Black/African American	3 (1.6)	2 (1.0)	5 (1.3)
Asian (Japanese)	63 (32.8)	64 (33.5)	127 (33.2)
Asian (not Japanese)	8 (42)	13 (6.8)	21 (5.5)
American Indian/Alaskan Native	0 (0)	1 (0.5)	1 (0.3)
Native Hawaiian/Pacific Islander	0 (0)	1 (0.5)	1 (0.3)
Not reported	0 (0)	1 (0.5)	1 (0.3)
Other	3 (1.6)	1 (0.5)	4 (1.0)
Age (years)
Mean (SD)	57.9 (10.6)	60.0 (9.5)	58.9 (10.1)
Median (min, max)	58.0 (29, 75)	62.0 (34, 75)	60.0 (29, 75)
Height (cm)
Mean (SD)	168.5 (9.7)	169.2 (9.8)	168.8 (9.7)
Median (min, max)	168.6 (141.2, 192.0)	168.7 (146.2, 195.6)	168.7 (141.2, 195.6)
Body weight (kg)
Mean (SD)	69.9 (14.6)	67.9 (15.3)	68.9 (15.0)
Median (min, max)	69.9 (37.1, 109.0)	65.6 (39.0, 124.2)	68.0 (37.1, 124.2)
BMI (kg/m2)
Mean (SD)	24.6 (4.3)	23.6 (3.8)	24.1 (4.1)
Median (min, max)	23.9 (16.1, 40.1)	23.1 (16.5, 36.6)	23.7 (16.1, 40.1)
Country, n (%)
United States	38 (19.8)	43 (22.5)	81 (21.1)
Canada	28 (14.6)	21 (11.0)	49 (12.8)
Germany	24 (12.5)	28 (14.7)	52 (13.6)
Italy	23 (12.0)	20 (10.5)	43 (11.2)
Switzerland	9 (4.7)	6 (3.1)	15 (3.9)
Japan	63 (32.8)	65 (34.0)	128 (33.4)
South Korea	7 (3.6)	8 (4.2)	15 (3.9)
Region, n (%)
North America	66 (34.4)	64 (33.5)	130 (33.9)
Europe	56 (29.2)	54 (28.3)	110 (28.7)
Asia Pacific	70 (36.5)	73 (38.2)	143 (37.3)

Abbreviations: BMI, body mass index; FAS, full analysis set.

3.3. Summary of Patient ALS History

Patient ALS history for the FAS is summarized in Table 2. Most patients were concomitantly using riluzole, while a minority were concomitantly using PB‐TURSO. The edaravone oral suspension regimen groups were well balanced except for concomitant use of PB‐TURSO due to its approval during the ongoing enrollment in this study.

TABLE 2.

Summary of patient ALS history (FAS).

	Edaravone oral suspension 105 mg Once Daily, n = 192	Edaravone oral suspension 105 mg On/Off, n = 191	Total N = 383
Disease duration from onset of symptoms to screening, years
Mean (SD)	1.2 (0.5)	1.2 (0.5)	1.2 (0.5)
Median (min, max)	1.1 (0.1, 2.2)	1.1 (0.2, 2.1)	1.1 (0.1, 2.2)
Disease duration from ALS diagnosis to screening, years
Mean (SD)	0.3 (0.3)	0.3 (0.3)	0.3 (0.3)
Median (min, max)	0.23 (0.0, 1.5)	0.3 (0.0, 1.6)	0.2 (0.0, 1.6)
ALSFRS‐R score at baseline
Mean (SD)	40.5 (3.1)	40.6 (3.0)	40.5 (3.0)
Median (min, max)	41.0 (30, 46)	41.0 (33, 47)	41.0 (30, 47)
ALSFRS‐R rate of decline score during the 8‐week screening period, n (%)
(−1, −2)	140 (72.9)	139 (72.8)	279 (72.8)
(−3, −4)	52 (27.1)	52 (27.2)	104 (27.2)
Region of Onset, n (%)
Bulbar	51 (26.6)	50 (26.2)	101 (26.4)
Limb	141 (73.4)	141 (73.8)	282 (73.6)
ALS diagnosis, n (%)
Sporadic	189 (98.4)	185 (96.9)	374 (97.7)
Familial	3 (1.6)	6 (3.1)	9 (2.3)
El Escorial revised Airlie House diagnostic criteria, n (%)
Definite ALS	74 (38.5)	70 (36.6)	144 (37.6)
Probable ALS	118 (61.5)	121 (63.4)	239 (62.4)
Concomitant use of riluzole, n (%)
Present	171 (89.1)	170 (89.0)	341 (89.0)
Absent	21 (10.9)	21 (11.0)	42 (11.0)
Concomitant use of PB‐TURSO, n (%)
Present	16 (8.3)	8 (4.2)	24 (6.3)
Absent	179 (91.7)	183 (95.8)	359 (93.7)

Abbreviations: ALS, amyotrophic lateral sclerosis; ALSFRS‐R, ALS Functional Rating Scale‐Revised; FAS, Full Analysis Set; PB‐TURSO, sodium phenylbutyrate and taurursodiol.

3.4. Pre‐Planned Interim Futility Analysis

The IDMC concluded that there was a low conditional probability for the investigational Once Daily regimen to show superiority to the approved, current On/Off regimen as measured by the ALSFRS‐R score at study completion, with consideration of the results from other efficacy endpoints, and thus the study was discontinued early.

3.5. Primary and Secondary Efficacy Endpoints

At the final analysis, the Once Daily regimen did not show superiority to the approved On/Off dosing regimen based on the primary efficacy endpoint of CAFS score at week 48, as there was no statistically significant difference between the 2 treatment groups (Table 3). Both dosing regimens provided comparable change in ALSFRS‐R total score from baseline to week 48, indicating similar efficacy (Table 3). This finding was consistent across all secondary efficacy endpoints evaluated (Table 3). There were no statistically significant (nominal p > 0.05) differences between the values for the Once Daily group vs. On/Off group from baseline to week 48 in the following secondary efficacy endpoints: slow vital capacity %, ALS Assessment Questionnaire‐40 (ALSAQ‐40) total score, %FVC, and body weight. Similar observations were made at all other timepoints evaluated (weeks 4 to 36) and for all individual domains analyzed (ALSAQ‐40; ALSFRS‐R).

TABLE 3.

Primary and secondary efficacy endpoints.

	Edaravone oral suspension 105 mg Once Daily, n = 192	Edaravone oral suspension 105 mg On/Off, n = 191	Difference [95% CI]; p value
Primary efficacy endpoint
CAFS score, LS mean rank	187.2	184.2	3.0 [−18.0, 24.1]; p = 0.777
Key secondary efficacy endpoints
Change from baseline in %SVC at week 48, LS mean [95% CI]	−26.94 [−31.79, −22.09]	−22.15 [−27.05, −17.26]	−4.78 [−11.62, 2.05]; p = 0.169
Change from baseline in ALSAQ‐40 at week 48, LS mean [95% CI]	34.09 [29.48, 38.69]	31.51 [26.84, 36.18]	2.57 [−3.73, 8.88]; p = 0.422
Time to death ± tracheostomy ± PAMV (≥ 23 h/day), number of events (%)	11 (5.7)	17 (8.9)	HR = 0.586 [0.273, 1.256]; Log‐rank nominal p = 0.224
Time to death or PAMV (≥ 23 h/day), number of events (%)	10 (5.2)	17 (8.9)	HR = 0.531 [0.242, 1.166]; Log‐rank nominal p = 0.151
Time to death, number of events (%)	9 (4.7)	16 (8.3)	HR = 0.512 [0.225, 1.164]; Log‐rank nominal p = 0.134
Other secondary efficacy endpoints
Change from baseline in ALSFRS‐R total score, LS mean [95% CI]
Week 48	−10.14 [−11.34, −8.94]	−10.41 [−11.62, −9.19]	0.27 [−1.43, 1.97]; nominal p = 0.756
Change from screening and baseline in %FVC, LS mean [95% CI]
Week 48	−26.65 [−30.53, −22.77]	−22.05 [−25.99, −18.11]	−4.60 [−9.95, 0.75]; nominal p = 0.092
Change from baseline in BW, LS mean [95% CI]
Week 48	−4.34 [−5.29, −3.39]	−3.25 [−4.21, −2.29]	−1.09 [−2.42, 0.25]; nominal p = 0.111
King's ALS clinical stage derived from ALSFRS‐R score and death
Number of events for any decline in stage from baseline, n (%)	103 (53.6)	103 (53.9)	Nominal p = 0.956
Number of events for any ≥ 2‐stage decline from baseline, n (%)	41 (21.4)	47 (24.6)	Nominal p = 0.449

Abbreviations: ALSAQ‐40; amyotrophic lateral sclerosis assessment questionnaire‐40; ALSFRS‐R, amyotrophic lateral sclerosis functional rating scale‐revised; BW, body weight; CAFS, combined assessment of function and survival; CI, confidence interval; FVC, forced vital capacity; HR, hazard ratio; LS, least squares; PAMV, permanent assisted mechanical ventilation; SVC, slow vital capacity.

In addition, a consistent effect of edaravone oral suspension was observed for ALSFRS‐R total score changes among Asian, European, and North American patients by a prespecified subgroup analysis (Figure 2). The number of events for time to death, tracheostomy, or PAMV in the Once Daily group (11 [5.7%] patients) was numerically lower than it was in the On/Off group (17 [8.9%] patients). Within the 3 events: death was the most frequent event in both groups (Once Daily: 8 [4.2%] patients; On/Off: 16 [8.3%] patients), 1 (0.5%) patient in the Once Daily group and none in the On/Off group received a tracheostomy, and 2 (1.0%) patients in the Once Daily group and 1 (0.5%) patient in the On/Off group received PAMV.

FIGURE 2.

Effect of edaravone oral suspension across regions in Study MT‐1186‐A02 based on change in ALSFRS‐R total score at Week 48. ALSFRS‐R, Amyotrophic Lateral Sclerosis Functional Rating Scale‐Revised; BL, baseline; LS, least squares; SD, standard deviation; SE, standard error.

3.6. Safety Endpoints

A total of 165 patients (85.9%) in the Once Daily group and 178 (93.2%) patients in the On/Off group reported ≥ 1 TEAE (Table 4). The overall most commonly reported TEAEs for both groups were fall, COVID‐19, dysphagia, and constipation. Except for COVID‐19, these TEAEs are consistent with the disease state. There were 52 (27.1%) patients in the Once Daily group and 55 (28.8%) patients in the On/Off group who experienced ≥ 1 serious TEAE (TESAE) when recording TESAEs reported by ≥ 1% of patients in either group. The most common TESAE was dysphagia in both the Once Daily group (16 [8.3%] patients) and the On/Off group (15 [7.9%] patients). One TESAE in each group (Once Daily: benign familial pemphigus; On/Off: pneumonia) was considered to be related to the study drug by the investigator. Overall, 21 patients died during the study; 8 (4.2%) patients in the Once Daily group and 13 (6.8%) patients in the On/Off group experienced a TEAE leading to death. The most common TEAE leading to death in both groups was respiratory failure (Once Daily: 3 [1.6%] patients; On/Off: 4 [2.1%] patients). None of the fatal TEAEs were related to the study drug. Overall, no significant differences in the incidence of TEAEs between groups were observed. The most common TEAEs, serious TEAEs, and TEAEs leading to death or treatment withdrawal were associated with ALS disease progression or were symptoms unspecific to ALS, though they did not represent unexpected events. No clear trends were observed in safety laboratory parameters, vital signs, physical examinations, or other safety‐related evaluations, and there were no notable differences between groups.

TABLE 4.

TEAEs reported by ≥ 5% of patients in the Once Daily and On/Off edaravone oral suspension regimen groups.

	Edaravone oral suspension 105 mg Once Daily, n = 192	Edaravone oral suspension 105 mg On/Off, n = 191
	Patients, n (%)	Patients, n (%)
Any TEAEs	165 (85.9)	178 (93.2)
Fall	37 (19.3)	35 (18.3)
COVID‐19	27 (14.1)	29 (15.2)
Dysphagia	27 (14.1)	26 (13.6)
Constipation	24 (12.5)	27 (14.1)
Diarrhea	20 (10.4)	14 (7.3)
Contusion	17 (8.9)	14 (7.3)
Muscular weakness	15 (7.8)	14 (7.3)
Back pain	9 (4.7)	20 (10.5)
Cough	15 (7.8)	11 (5.8)
Insomnia	11 (5.7)	14 (7.3)
Headache	15 (7.8)	9 (4.7)
Fatigue	12 (6.3)	10 (5.2)
Nasopharyngitis	11 (5.7)	8 (4.2)
Peripheral edema	10 (5.2)	9 (4.7)
Musculoskeletal pain	10 (5.2)	9 (4.7)
Depression	9 (4.7)	10 (5.2)
Dyspnea	9 (4.7)	10 (5.2)
Respiratory failure	9 (4.7)	10 (5.2)
Pruritus	11 (5.7)	8 (4.2)
Rash	13 (6.8)	4 (2.1)
Pain in extremity	4 (2.1)	10 (5.2)
Muscle spasms	3 (1.6)	10 (5.2)

Abbreviations: COVID‐19; coronavirus disease 2019; TEAE, treatment‐emergent adverse event.

3.7. Post Hoc Study MCI186‐19 and Study MT‐1186‐A02 ALSFRS‐R Comparisons

For both the previous phase 3 trial of IV edaravone, Study MCI186‐19 (Study 19), and the current phase 3b trial of edaravone oral suspension, Study MT‐1186‐A02, the change from baseline in ALSFRS‐R total score was consistent for patients from the edaravone‐only–treated groups across both clinical trials at week 48 (Figure 3).

FIGURE 3.

(Post hoc) Effect of edaravone across studies based on change in ALSFRS‐R total score at week 48 [4]. ALSFRS‐R, Amyotrophic Lateral Sclerosis Functional Rating Scale‐Revised; BL, baseline; LS, least squares; SD, standard deviation; SE, standard error; Study 19, Study MCI186‐19; Study A02, Study MT‐1186‐A02. Studies MCI186‐19 and MT‐1186‐A02 had different study designs. Some of these differences included different study populations and statistical analysis methods [4].

4. Discussion

In this study, the investigational Once Daily dosing regimen of edaravone oral suspension did not show superiority to the approved On/Off dosing regimen based on the primary endpoint of CAFS at 48 weeks. Both dosing regimens were well tolerated, with no new safety concerns identified. This study, and its extension Study MT‐1186‐A04, were prematurely discontinued due to meeting the futility criteria following a pre‐planned interim FA. Notably, while these studies were terminated early, this was not due to safety concerns, and the efficacy was comparable for the Once Daily and On/Off dosing schedules.

The primary efficacy endpoint of CAFS score at week 48 showed no superiority, as indicated by the lack of a statistically significant difference between the Once Daily and On/Off regimen treatment groups. This finding of no statistically significant difference between groups was also consistent across all secondary efficacy endpoints evaluated and supported the efficacy assessment from the interim FA.

ALSFRS‐R total score changes from baseline to week 48 were compared in a post hoc analysis of patients with ALS from the current Study MT‐1186‐A02 of edaravone oral suspension vs. the previous phase 3 Study MCI186‐19 of IV edaravone and showed that the change from baseline in ALSFRS‐R total score at week 48 was consistent for edaravone‐treated groups across both clinical trials. In a prespecified subgroup analysis, a consistent effect of edaravone oral suspension was observed for ALSFRS‐R total score changes among regions of Asian, European, and North American patients within Study MT‐1186‐A02.

There were no significant differences observed overall in the incidence of TEAEs between the 2 groups. Most common TEAEs, serious TEAEs, and TEAEs leading to death or treatment withdrawal were associated with ALS disease progression or were symptoms unspecific to ALS, although they did not represent unexpected events. There were no clear trends observed in safety laboratory parameters, vital signs, physical examinations, or other safety‐related evaluations, and there were no notable differences between groups. There were no significant safety findings observed and no new safety signals were identified. This study had the limitation of no placebo control group.

5. Conclusions

This trial provides data to support the appropriateness of the approved edaravone oral suspension dosing regimen, which expands on existing evidence supporting the use of FDA‐approved IV edaravone and edaravone oral suspension.

Author Contributions

Jeffrey Rothstein: investigation, writing – review and editing, writing – original draft. Angela Genge: conceptualization, investigation, writing – review and editing, writing – original draft. Shari De Silva: investigation, writing – review and editing, writing – original draft. Lorne Zinman: investigation, writing – original draft, writing – review and editing. Marvin Chum: investigation, writing – original draft, writing – review and editing. Adriano Chio: writing – original draft, writing – review and editing, investigation. Gen Sobue: conceptualization, investigation, writing – review and editing, writing – original draft. Masashi Aoki: conceptualization, investigation, writing – original draft, writing – review and editing. Hiide Yoshino: conceptualization, investigation, writing – original draft, writing – review and editing. Manabu Doyu: conceptualization, investigation, writing – review and editing, writing – original draft. Daniel Selness: conceptualization, funding acquisition, methodology, project administration, supervision, writing – review and editing, writing – original draft. Vesna Todorovic: writing – review and editing, writing – original draft. Nissim Sasson: conceptualization, data curation, formal analysis, methodology, validation. Manabu Hirai: conceptualization, writing – original draft, writing – review and editing. Fumihiro Takahashi: conceptualization, writing – review and editing, data curation, formal analysis, methodology, validation. Alejandro Salah: project administration, supervision, writing – original draft, writing – review and editing. Art Wamil: conceptualization, methodology, project administration, supervision, writing – original draft, writing – review and editing. Stephen Apple: supervision, project administration, writing – review and editing, writing – original draft.

Ethics Statement

We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Conflicts of Interest

J.R. is a consultant for Expansion Therapeutics, National Institutes of Health, Department of Defense, F Prime, The ALS Association; A.G. has served as a consultant for Mitsubishi Tanabe Pharma Inc.; S.D. and M.C. have nothing to disclose; L.Z. has received honoraria for consulting with MTP, Biogen, Amylyx, and Cytokinetics; A.C. serves on scientific advisory boards for Mitsubishi Tanabe, Roche, Biogen, Denali Pharma, A.C. Immune, Biogen, Lilly, and Cytokinetics and has received a research grant from Biogen; G.S., H.Y., and M.A. have served as medical advisors for Mitsubishi Tanabe Pharma Corporation; M.D. is a medical advisor for the MT‐1186‐A02 study; V.T. is an employee of Mitsubishi Tanabe Pharma Europe Ltd.; N.S. has served as a statistical consultant for NeuroDerm and Mitsubishi Tanabe Pharma Inc.; D.S., F.T., A.S., A.W., M.H., and S.A. are employees of Mitsubishi Tanabe Pharma America Inc.

Supporting information

Data S1. Supporting Information.

Rothstein J., Genge A., De Silva S., et al., “Efficacy and Safety of Once Daily Dosing vs. Approved On/Off Dosing of Edaravone Oral Suspension Up to 48 Weeks in Patients With Amyotrophic Lateral Sclerosis (Study MT‐1186‐A02),” Muscle & Nerve 72, no. 3 (2025): 433–442, 10.1002/mus.28448.

Data Availability Statement

All relevant data is contained within the manuscript.