Edaravone Reduces Risk of Milestone Events, Increases Survival in ALS

Rix Brooks, MD

Findings from a 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 amyotrophic lateral sclerosis (ALS) treated with edaravone (Radicava; MT Pharma). These findings were in line with previously conducted trials.^1,2

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).

"While the ALSFRS-R is considered the gold standard used to assess ALS progression and treatment efficacy, there is value in exploring other outcome measures, including survival-related events," Gustavo A. Suarez Zambrano, MD, vice president of Medical Affairs, MT Pharma, said in a statement.¹ "This post-hoc analysis of our Phase 3 MCI186-19 study allows us to grow our understanding of the benefit of starting early and continued treatment with RADICAVA, and is a reflection of our commitment to ensure people with ALS are at the center of everything we do."

As the analysis was post-hoc, the investigators noted that results should be interpreted with caution. No deaths occurred during the double-blind period, while 2 occurred in the EE group and 4 in the PE group during the 24-week OLE. Adverse events (AEs) resulting in hospitalization in both the edaravone-first and placebo-first groups were because of problems with swallowing or respiratory function, which were incorporated into the Kaplan-Meier analysis for the cumulative occurrence of milestone events.

Overall, the study was further supported by the Cox PH model survival curve, where a significant separation in clinical curves for time to the cumulative end point of death, tracheostomy, PAV, or hospitalization was observed between the groups. Reanalyzing the Study 19 trial data according to the ALS/standard uptake ratio value (SUVR) composite end point demonstrated a statistically significant treatment benefit for the EE group compred with PE group at week 24 (0.15 [±0.05]; 95% CI, 0.06-0.25; P <.01) and week 48 (0.11 [±0.05]; 95% CI, 0.02-0.21; P = .02).

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"The findings of this post-hoc analysis are encouraging,” lead investigator Rix Brooks, MD, professor of neurology, University of North Carolina School of Medicine, said in a statement.¹ "These data reinforce the importance of continuing research that can further support an association between earlier use of Radicava and the potential impact on survival-related milestones in ALS."

This was not the first time findings showed a reduction in milestone-free time for patients with ALS on edaravone. Earlier this year, a real-world analysis of administrative claims that included milestones of canes/walker/wheelchairs (M1), artificial nutrition (M2), noninvasive ventilation (M3), invasive ventilation (M4), speech-generating devices (M5), and hospice (M6), showed similar results. Presented at the 2023 Muscular Dystrophy Association Clinical and Scientific Conference, the median treatment duration in the intravenous edaravone-treated group was 9.11 (IQR, 3.45-16.08) months.³

Differences between the 2 groups in cause-specific restricted mean time lost (RMTL) was estimated to examine the benefit of IV edaravone while considering mortality as the competing risk. In the post-index period, differences in RMTL in months indicated longer milestone-free time in cases than controls (M1: 2.50 [IQR, 0.93-4.07]; M2: 4.30 [IQR, 2.88-5.72]; M3: 2.92 [IQR, 1.56-4.28]; M4: 0.92 [IQR, 0.25-1.58]; M5: 3.37 [IQR, 2.27-4.46]; M6: 2.33 [IQR, 1.31-3.34]). For the majority of reported milestones, IV edaravone-treated cases had longer milestone-free time than non-IV treated controls for both commercial and Medicare Advantage insurance.

The original IV formulation of edaravone was FDA-approved in 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, which gained approval in 2022, 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.⁴

REFERENCES
1. 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 August 20, 2023. 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
2. 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
3. Ciepielewska M, Berry J, Hagan M, Zhang J, Liu Y. Longer milestone-free time to IV edaravone-treated vs IV edaravone-naïve amyotrophic lateral sclerosis patients: an administrative claims analysis. Presented at: 2023 MDA Clinical and Scientific Conference; March 19-22; Abstract 174.
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 August 20, 2023. https://www.prnewswire.com/news-releases/mitsubishi-tanabe-pharma-america-announces-fda-approval-of-radicava-ors-edaravone-for-the-treatment-of-als-301546937.html