Does Edaravone Slow ALS Progression?

Disease progression in amyotrophic lateral sclerosis (ALS) patients who received edaravone (Radicava) plus standard therapy of riluzole (Rilutek) did not differ from patients treated with standard therapy alone, a prospective observational study showed.

ALS Functional Rating Scale-Revised (ALSFRS-R) scores were similar after long-term treatment with edaravone (-0.91 points per month, 95% CI -0.69 to -1.07) or standard therapy (-0.85 points per month, 95% CI -0.66 to -0.99, P=0.37), reported Simon Witzel, MD, of Ulm University in Germany, and co-authors in JAMA Neurology.

No significant differences in survival probability, time to ventilation, or change in disease progression were seen. Results did not depend on whether patients belonged to a subpopulation with expected drug efficacy based on earlier trial data.

Edaravone, a free radical scavenger, originally was marketed in Japan for the treatment of acute ischemic stroke and has since been repurposed for ALS.

The FDA approval of edaravone in 2017 was “somewhat of a surprise to many in the ALS scientific and clinical research communities but was seen by patients as new hope for slowing disease,” observed Jonathan Glass, MD, and Christina Fournier, MD, MS, both of Emory University in Atlanta, in an accompanying editorial.

Edaravone requires continued intravenous injections and costs upwards of $150,000 per year but never underwent trial in the U.S., Glass and Fournier pointed out. “The drug, tested only in Japan, had shown mixed results in two important clinical trials,” they wrote.

The first phase III trial of a diverse group of people with ALS in Japan did not meet its primary outcome on the 48-point ALSFRS-R, the editorialists noted. A post-hoc analysis, however, identified a subset of participants with higher functional status, shorter disease duration, and a moderate rate of disease progression who appeared to respond positively in the study.

In a smaller follow-up phase III trial with a selected subgroup of patients, decline on the ALSFRS-R was less in the edaravone-treated group than in the placebo group after 6 months. “Although the difference between active and placebo treatments reached statistical significance, the actual mean difference was about 2.5 points, a value of uncertain clinical significance,” Glass and Fournier wrote. “The more quantitative measures of respiratory function and muscle strength showed no effect of edaravone.”

Based on these findings, the European Medicines Agency has not approved edaravone. In Germany, the drug has been available under special access conditions.

Witzel and colleagues studied patients treated at 12 German ALS referral centers from June 2017 to March 2020. A total of 194 patients started intravenous edaravone treatment; 64% were men, and the median age when therapy started was about 58. Potential adverse effects emerged in 16% of patients, mainly infections at infusion sites and allergic reactions.

For the primary outcome, 116 patients treated with edaravone and riluzole for a median of 13.9 months were compared with 116 propensity score-matched patients treated with riluzole alone for a median of 11.2 months. The researchers also identified a subgroup of 64 edaravone-treated patients who would have been eligible for the selected population of higher functioning patients in the second Japanese trial.

Comparisons showed no differences in the slope of ALSFRS-R scores between edaravone and standard treatment in all groups, including the selected subgroup. “These findings show that treatment with long-term intravenous edaravone in addition to standard therapy for patients with ALS is feasible and relatively safe but may not provide a clinically relevant benefit,” Witzel and co-authors wrote.

The study’s main limitation is its observational design, the researchers acknowledged. “Although matching based on propensity scores replicates some characteristics of randomization, it cannot account for unknown confounders and thus does not yield the same level of evidence as randomized clinical trials,” they noted.