Daily Oral Edaravone Fails to Display Superiority in Phase 3B Study MT-1186-A02 for ALS

Jeffrey Rothstein, MD, PhD

(Credit: Johns Hopkins Medicine)

New findings from the phase 3b study MT-1186-A02 (NCT04569084) assessing an investigational daily dosing of oral edaravone (Radicava ORS; Mitsubishi Tanabe Pharma America) showed that this form of the treatment was not superior in efficacy at 48 weeks compared with the on/off regimen of edaravone in patients with amyotrophic lateral sclerosis (ALS). Presented at the 2024 American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) meeting, held October 15-18, in Savannah, Georgia, these findings reinforce the appropriateness of the FDA-approved regimen.¹

In the analysis, results revealed that daily dosing did not show achieve a statistically significant difference versus on/off dosing with oral edaravone at week 48 on the combined assessment of function and survival (CAFS), which included change in ALS Functional Rating Scale-Revised (ALSFRS-R) and time to death. Conducted by lead author Jeffrey Rothstein, MD, PhD, the director of the Robert Packard Center for ALS Research at Johns Hopkins Medicine, and colleagues, the study reported that oral edaravone was well tolerated and displayed no new safety concerns in either treatment group.

“The global, multi-center, double-blind, phase 3b MT-1186-A02 study assessed the superiority of daily dosing of Radicava ORS (edaravone) compared to the standard FDA-approved on/off regimen in people with ALS. Final results confirmed that daily dosing of Radicava ORS showed no significant difference and did not demonstrate superiority, further supporting the suitability of the FDA-approved regimen," Gustavo A. Suarez Zambrano, MD, the vice president of medical affairs at Mitsubishi Tanabe Pharma America, told NeurologyLive^®. "With over 20 years dedicated to addressing unmet needs in ALS, this study exemplifies our ongoing commitment to the community, and we remain focused on advancing research and driving scientific innovation in this important area.”

The phase 3b study MT-1186-A02 was a multicenter, double-blind, parallel group superiority trial where investigators randomized participants to either 105-mg oral edaravone dose administered once daily or the same oral edaravone dose administered based on the FDA-approved on/off regimen. Authors noted that patients included in the study had definite or probable ALS, baseline forced vital capacity at least 70%, and baseline disease duration at most 2 years. In this analysis, investigators assessed if the daily dosing demonstrated superior efficacy, safety, and tolerability versus the approved on/off dosing regimen in ALS over a 48-week period.

Gustavo A. Suarez Zambrano, MD

(Credit: Mitsubishi Tanabe Pharma America)

Findings from a previous post-hoc analysis of the pivotal phase 3 study MCI186-19 showed a significant reduction in the cumulative occurrence of milestone events such as death, tracheostomy, permanent assisted ventilation (PAV) or hospitalization in patients with ALS treated with edaravone (Radicava; Mitsubishi Tanabe Pharma America). These findings were in line with previously conducted trials.^2,3

Published in Muscle & Nerve, the data compared those who continued with edaravone for an additional 24 weeks (edaravone-edaravone [EE] group: n = 65) after the 24-week double blind period and those who switched from placebo to active treatment at the 24-week mark (placebo-edaravone [PE] group; n = 58). All told, investigators observed a 53% relative risk reduction of milestone events in the EE group vs PE group at the 48-week point, with a hazard ratio (HR) of 0.47 (95% CI, 0.25-0.88; P = .02).

In May 2022, the FDA approved the oral formulation of edaravone for the treatment of ALS, which expanded the usage of a previously approved intravenous version. The approval was supported by data from the IV edaravone phase 3 pivotal trial, Study 19 (NCT01492686), which evaluated 137 patients with ALS. In the study, treatment with edaravone slowed loss of physical function by 33% compared with placebo at 24 weeks based on the ALS Functional Rating Scale-Revised.⁴

The original intravenous formulation was FDA-approved in May 2017, and is administered in 28-day cycles, with each patient receiving a 60 mg dose over the course of a 60-minute infusion. The oral formulation requires a 14-day induction period of daily administration followed by a 2-week drug-free period. This initial cycle is followed by a 10-day treatment cycle every 14 days, which is followed by a 14-day drug-free period. The most common adverse events associated with edaravone are bruising, gait disturbances, and headache, as well as fatigue.

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REFERENCES
1. Rothstein J, Genge A, De Silva S, et al. Phase 3B Study MT-1186-A02 to Investigate the Superiority of Daily Dosing vs the FDA-Approved On/Off Regimen of Oral Edaravone in Patients With Amyotrophic Lateral Sclerosis. Presented at: 2024 AANEM; October 15-18; Savannah, Georgia.
2. Mitisubishi Tanabe Pharma American announces post-hoc analysis examining effect of early intervention with Radicava (Edaravone) on survival and disease progression milestones in people with ALS. August 17, 2023. Accessed October 11, 2024. https://www.prnewswire.com/news-releases/mitsubishi-tanabe-pharma-america-announces-post-hoc-analysis-examining-effect-of-early-intervention-with-radicava-edaravone-on-survival-and-disease-progression-milestones-in-people-with-als
3. Brooks BR, Pioro EP, Sakata T, et al. The effects of intervention with intravenous edaravone in Study 19 on hospitalization, tracheostomy, ventilation, and death in patients with amyotrophic lateral sclerosis. Muscle & Nerve. Published online July 31, 2023. doi:10.1002/mus.27946
4. Mitsubishi Tanabe Pharma America Announces FDA Approval of RADICAVA ORS® (edaravone) for the Treatment of ALS. News release. Mitsubishi Tanabe Pharma America. May 13, 2022. Accessed October 11, 2024. https://www.prnewswire.com/news-releases/mitsubishi-tanabe-pharma-america-announces-fda-approval-of-radicava-ors-edaravone-for-the-treatment-of-als-301546937.html