Background
Mitsubishi Tanabe Pharma Corporation (MTPC) began studying an intravenous (IV) formulation (Radicava) of edaravone for ALS/MND in 2001. Radicava was approved for the treatment of ALS/MND in Japan and South Korea in 2015, with subsequent approvals in Canada, Switzerland, China, Indonesia, Thailand and USA (2017).
Treatment with Radicava follows a regimen of initial treatment daily for 14 days, followed by a 14-day drug free period, and subsequent cycles of daily dosing for 10 of 14 days, followed by a 14-day drug free period.
During clinical development of IV Radicava, Mitsubishi Tanabe Pharma America (a wholly owned subsidiary of MTPC) began a series of steps to determine if an oral suspension of edaravone could add to or replace the IV formulation for treatment of people living with ALS. First, bioequivalence had to be established to demonstrate that the oral edaravone could provide identical exposure as the established IV formulation. Multiple studies were performed.
The process began with a phase 1, open-label, single-dose crossover study in 42 participants, comparing 105 mg oral edaravone with 60 mg/hr IV formulation. Through comparing the pharmacokinetics (how it moves through the body) of both, it was concluded that the two formulations, at their respective doses, demonstrated equivalent exposure. This study was published in 2021.
Further, two additional phase 1 studies were performed. The first study was a placebo-controlled, randomized, single-blind study of increasing oral edaravone doses from 30 to 300 mg in 56 participants. The second study, involving 84 participants, assessed whether oral edaravone interacted with other drugs and also examined potential pharmacokinetic differences between people of different racial backgrounds. In both cases, oral edaravone was considered safe and tolerable with no significant drug interaction effects or differences between racial backgrounds. See these studies.
Trial Design & Results
Following bioequivalence, the next step was to undertake a large safety and tolerability trial of oral edaravone at the intended clinical dose. On December 9, 2021, MTPA announced the results of the global phase 3 clinical trial assessing safety and tolerability of oral edaravone over 24 weeks. The study enrolled 185 participants with ALS across 50 sites in the United States, Canada, Europe and Japan and included a long-term safety extension study of up to 96 weeks. No severe treatment emergent adverse events (TEAEs) were reported.
On May 13, 2022, it was announced that the U.S. Food and Drug Administration (FDA) had approved RADICAVA ORS and it became available as of June 16. Marketing authorization for RADICAVA® Oral Suspension was granted in Canada (November 2022) and Switzerland (May 2023), and RADICUT® Oral Suspension 2.1% was granted regulatory approval in Japan in December 2022.
Simultaneously, MTPA launched a phase 3b, multi-national, randomized, doubleblind study to evaluate daily dosing of oral edaravone as compared to the current IV dosing regimen. Over 48 weeks, 380 participants either received oral edaravone once daily or for 10 days followed by an 18 day placebo suspension. This trial evaluated a comparison of change in ALSFRS-R as the primary outcome measure and additional outcomes including slow vital capacity, quality of life (ALSAQ-40).
It was set to read out late in 2023, however an interim analysis has shown that daily oral edaravone is not better than the current 2-weeks on/2-weeks off oral dosing regimen which matches the IV infusion regime. They have therefore discontinued the trial and also the associated expanded access program (EAP).
A Dutch company, Treeway, in partnership with Ferrer, conducted a Phase 3 trial (ADORE) of their own oral edaravone product, FNP122, which was taken daily. FNP122, formerly TW001, was previously announced to have bioavailability comparable to IV edaravone at doses used in treatment with Radicava. The ADORE trial was a 48-week trial that tested FNP122 against placebo in 300 patients across Europe. Patients who completed the ADORE trial had the opportunity to join an extension study where they received FNP122 for up to three years (more info on the clinical trial). In January 2024 Ferrer published a press release declaring that the Phase 3 ADORE trial did not meet primary or key secondary endpoints (press release). After 48 weeks daily dosing, the treated group did not show any significant difference in their ALSFRS-R score when compared to placebo. There was also no difference in the long-term survival rate between treated and placebo group after 48 or 72 weeks. This study, however, confirmed that FNP122 was safe and well tolerated.
Based on the lack of efficacy of oral edaravone FNP122, Ferrer announced that its open label extension study (more info on ADORETX) will be concluded. Full publication and results for the phase 3 trial and extension study of FNP122 are still pending.
To address community concerns, MTPA issued a statement discussing the differences between the results and products used in the trials by both companies.
Summary
Considering the available evidence, it is the opinion of the Scientific Advisory Council (SAC) that oral edaravone appears to be safe and tolerable, which underscores our commitment to prioritizing patient safety. However, the efficacy of oral edaravone has been brought into question following the results of the ADORE trial, prompting the need for a critical re-evaluation of its therapeutic benefits and potential impact on patient outcomes.
While the safety and tolerability profile of oral edaravone is encouraging, the findings from the ADORE trial highlight the need for a reassessment of its role in the treatment landscape. The SAC recognizes the importance of transparently addressing these uncertainties and engaging in constructive dialogue to better understand their implications for patient care. This is further complicated because oral edaravone is a currently marketed product in some countries, but not others, and full results for ADORE are currently pending.
We understand that this news may raise concerns and uncertainties within the community. It is essential for people living with ALS/MND to maintain open communication with healthcare providers and explore available treatment options.
International Alliance of ALS/MND Associations
March 2024
The original language of communication is English and any translation cannot be guaranteed for accuracy of messaging.