番茄社区

SAVANNAH, Ga. -- Daily oral edaravone (Radicava ORS) was not superior to the FDA-approved on/off regimen in amyotrophic lateral sclerosis (ALS), a phase IIIb trial showed.

Both on/off dosing and daily oral edaravone led to similar scores (P=0.777) on the Combined Assessment of Function and Survival (CAFS) at week 48, reported Jeffrey Rothstein, MD, PhD, of Johns Hopkins University in Baltimore, and co-authors at the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) annual meeting.

The CAFS ranks patients' clinical outcomes based on changes in ALS Functional Rating Scale-Revised (ALSFRS-R) scores and time to death. Both dosing regimens provided comparable changes in ALSFRS-R scores from baseline to week 48, Rothstein and colleagues said.

"There was no superiority demonstrated when comparing the daily dosing regimen versus the approved on/off dosing regimen for any key or other secondary efficacy endpoints from baseline to week 48, including no significant difference between groups when measuring time to death, tracheostomy, or permanent assisted mechanical ventilation," they noted.

The trial was in 2023 based on a pre-planned futility analysis that indicated a low probability of daily treatment being superior.

"The study confirmed that daily dosing showed no significant difference in efficacy, reinforcing the suitability of the current FDA-approved regimen," said Gustavo Suarez Zambrano, MD, of edaravone maker Mitsubishi Tanabe Pharma America.

"Importantly, no new safety concerns were identified, further validating oral edaravone's safety profile," Zambrano told 番茄社区.

Oral edaravone was based on bioequivalence and long-term safety studies comparing it with the IV edaravone formulation, which was approved for ALS in 2017. The drug is designed to offset oxidative stress, which is implicated in ALS.

The phase IIIb trial evaluated whether daily dosing offered superior benefits in ALS compared with the FDA-approved on/off regimen over 48 weeks in 383 ALS patients. The study was a postmarketing commitment after IV edaravone was approved.

The of oral edaravone is 105 mg (5 mL) taken orally or by feeding tube after overnight fasting. In this study, half of participants received the approved on/off regimen which is administered in 28-day cycles: treatment for 14 days followed by placebo for 14 days in cycle 1, then treatment for 10 days followed by placebo for 18 days for the remaining cycles. The once-daily group received 105 mg each day throughout the study.

Trial participants had definite or probable ALS according to and a baseline forced vital capacity of at least 70%. Their first ALS symptom had occurred within the past 2 years.

Mean baseline age was about 59 and 64% were men. More than a third (37.3%) were from the Asia Pacific region, 33.9% were from North America, and 28.7% were from Europe. The mean disease duration from onset of symptoms to screening was 1.2 years.

In total, 246 patients completed the 48-week double-blind treatment period. The most common reason for stopping treatment was the study's early termination, followed by patients withdrawing consent.

Most participants -- 85.9% in the once-daily group and 93.2% in the on/off group -- reported one or more treatment-emergent adverse events (TEAEs). Falls, COVID-19, dysphagia, and constipation were reported in both groups.

Serious TEAEs emerged in 27.1% of the once-daily group and 28.8% of the on/off group, most commonly dysphagia. TEAEs related to the study drug were reported in 24.5% of the once-daily group and 16.8% of the on/off group, most frequently headache.

"Overall, no significant differences in the incidence of TEAEs between groups were observed," Rothstein and colleagues noted. "There were no significant safety findings observed; no new safety signal was identified."

The ALSFRS-R changes observed at week 48 in this trial were similar to ones seen in previous studies of IV edaravone, the researchers added.

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