Results from the post-hoc analysis, funded by Mitsubishi Tanabe Pharma America, were recently announced.
Mitsubishi Tanabe Pharma America (MTPA) recently announced data from a post-hoc analysis of the edaravone (Radicava) phase 3 double-blind trial (Study 19; NCT01492686) that examined the use of clinical staging systems to measure disease progression in amyotrophic lateral sclerosis (ALS).1 These data showed that The King’s and Milano-Torino (MiToS) staging systems were effective in assessing clinical progression of the disease.
The data showed that 42% of patients on edaravone experienced a progression in King’s stage (95% CI, 30.4–53.6) compared to 55.9% on placebo (95% CI, 44.1–67.6). An analysis of a ≥2-stage progression in MiToS stage showed no difference between treatment and placebo groups during double-blind treatment, but during the open-label period, more rapid progression was noted among patients in the placebo-edaravone arm than among those in the edaravone-edaravone arm (log-rank test, P <.001).2
Gustavo A. Suarez Zambrano, MD, Vice President of Medical Affairs, MTPA, said in a statement that "clinical staging systems have shown value in a variety of neurological diseases, but in ALS many studies have relied on a validated functional rating scale score... While this score is useful to assess change in a patient's functional status, we also recognize the potential benefit of utilizing clinical staging scales to evaluate other important disease progression milestones and provide complementary information.”
Principal author Ammar Al-Chalabi, MB, ChB, PhD, Professor of Neurology and Complex Disease Genetics, King’s College London, and colleagues analyzed data from the 127 patients enrolled in Study 19 who were randomized and completed double-blind treatment; 69 that received edavarone and 68 that received placebo. During this phase, 2 patients receiving edaravone and 8 patients receiving placebo discontinued treatment, principally due to disease progression. Approximately 80% of patients were King’s stage 1 or 2 at study entry, and all patients were at MiToS stage 0.
During the open-label extension, 93 patients completed treatment, 53 patients in the edaravone group (edaravone-edaravone) and 40 patients in the placebo group (placebo-edaravone). At the end of the open-label extension at 48 weeks, the discontinuation rate was 23% for edaravone-edaravone patients and 41% for placebo-edaravone patients.
In the placebo–edaravone group, 54 patients experienced a pattern of change in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score (defined as an event). In the MiToS analysis of time to any progression, through 48 weeks, 46 edaravone-edaravone patients and 50 placebo-edaravone patients experienced an event. In the MiToS analysis of time to progression by ≥2 stages, through 24 weeks, 7 edaravone-edaravone patients and 16 placebo-edaravone patients experienced an event.
Patients receiving placebo crossed over to open-label edaravone treatment at the end of the double-blind at 24 weeks. By the end of 48 weeks, a progression in King’s stage was experienced by 72.5% (95% CI; 62.3–82.6) edaravone-edaravone patients vs 79.4% (95% CI; 69.1–88.2) placebo-edaravone patients.
At end of 24 weeks, 46.4% (95% CI; 34.8–58.0) of edaravone patients experienced a progression in MiToS stage as compared to 47.1% (95% CI; 35.3–58.8) of placebo patients. During the open‐label phase, a statistically insignificant separation in Kaplan-Meier curves for any progression in MiToS stage was noted at the end of 48 weeks (log-rank test, P = .308), 66.7% (95% CI; 55.1–76.8) of edaravone-edaravone, compared to 73.5% (95% CI; 63.2–83.8) of placebo-edaravone.
Al-Chalabi and colleagues found that more rapid progression on the MiToS stage was observed in the placebo-edaravone arm than in the edaravone-edaravone arm in the open-label period (log-rank test, P <.001). Of those in the edavarone group, 2.9% (95% CI; 0.0–7.2) experienced a ≥2-stage progression in the MiToS stage by the end of 24 weeks as compared to 5.9% (95% CI; 1.5–11.8) in placebo. Greater separation was seen in the Kaplan-Meier curves by the end of 48 weeks for a ≥2-stage progression in MiToS (log-rank test, P <.001), with 10.1% (95% CI; 4.3–17.4) of edaravone-edaravone patients progressing vs 23.5% (95% CI; 13.2–33.8) of placebo-edaravone patients.
Another analysis also found that patients in lower King’s stages progressed at slower rates than patients in higher King’s stages. Statistically significant interactions between time since enrollment and King’s stage at baseline and also between time since enrollment and treatment were observed (P <.001 for both).
"The data presented showed that the King’s and MiToS staging systems provided utility in assessing clinical progression of ALS. These findings may support the use of staging systems as end points in ALS clinical trials and to understand the timing of benefit as measured by these scales,” Al-Chalabi and colleagues concluded.
1. Post-Hoc Analysis of ALS Treatment Study Looks at Multiple Staging Systems. News release. Mitsubishi Tanabe Pharma America, Inc. November 30, 2020. Accessed December 15, 2020. https://www.prnewswire.com/news-releases/post-hoc-analysis-of-als-treatment-study-looks-at-multiple-staging-systems-301181592.html
2. Al-Chalabi A, Chiò A, Merrill C, et al. Clinical staging in amyotrophic lateral sclerosis: analysis of Edaravone Study 19. J Neurol Neurosurg Psychiatry Res. Published online October 27, 2020. doi: 10.1136/jnnp-2020-323271