Long-term add-on treatment with intravenous (IV) edaravone is not associated with any change in the progression of amyotrophic lateral sclerosis (ALS), new research shows.
These findings contradict those from the drug trial the US Food and Drug Administration (FDA) based its approval on in 2017. That trial showed short-term benefit for patients with ALS who took edaravone versus placebo.
In a new multicenter cohort study of 324 patients with ALS, disease progression was similar between those who received edaravone plus riluzole for about a year and those who received standard therapy of riluzole only. Time to ventilation and survival were also similar between the groups.
"What's most important is that patients should be well educated about the current state of studies and the remaining questions regarding the benefit of edaravone," study investigator Simon Witzel, MD, an attending physician at the Ulm University neurology clinic in Germany, told Medscape Medical News.
Whether the findings will directly affect clinical practice remains to be seen, Witzel said.
"We should not conclude that this drug is definitely not of worth for the ALS field or for patients with ALS. But we should be cautious and do well-designed placebo-controlled, long-term trials to clearly show if there is a benefit or not," he added.
The findings were published online January 10 in JAMA Neurology.
ALS is a progressive neurodegenerative disease that causes muscle atrophy, respiratory failure, and death. Riluzole is the only drug to be approved for ALS by all major regulatory authorities, but its effect on survival is small. New treatments for this disorder are needed, the investigators note.
The FDA approved edaravone for ALS in 2017 on the basis of the 6-month MCI-186 ALS19 trial, which was conducted in Japan "in a subpopulation in which efficacy [for edaravone] was expected," the current researchers note.
For the new real-world study, investigators examined effects of IV edaravone as it is administered in clinical practice. They enrolled patients who met the El Escorial criteria for probable or definite ALS and who presented at one of 12 academic referral centers in Germany.
Using propensity-score matching, the investigators compared patients who received edaravone plus riluzole with those who received riluzole alone. Baseline was start of edaravone treatment for the active group and first on-site visit for the control group.
The primary outcome was disease progression during follow-up, as measured by ALS Functional Rating Scale-Revised (ALSFRS-R) points lost per month. Secondary outcomes were survival probability, ventilation-free survival, and change in disease progression rate from before baseline to treatment. Investigators also assessed treatment adherence.
The IV edaravone group included 194 patients (64% men; mean age, 57.5 years). Median ALSFRS-R score at baseline was 37, and median pre-baseline disease progression was −0.58 points per month.
Investigators successfully matched 130 of these patients with individuals who acted as controls. Median treatment time was 13.9 months in the edaravone group and 11.2 months for the standard-therapy group.
No Significant Effect
During follow-up, the rate of disease progression was −0.91 points per month in the edaravone group versus −0.85 points per month in the standard treatment group. The between-group difference was not statistically significant.
When investigators compared participants who would have been eligible to participate in the MCI186-ALS19 study with those who would not have been eligible, they again found no significant difference.
Results for secondary outcomes were similar. There was no difference between change in disease progression before baseline and disease progression during treatment. Survival probability and the rate of ventilation-free survival also did not differ significantly between the edaravone and standard therapy groups.
Approximately 16% of all participants had adverse events potentially related to treatment. The most common adverse events were allergic reactions, orthostatic dysregulation, and fatigue. Six patients had infusion-related events.
In the edaravone group, 26% discontinued treatment. Reasons for discontinuation included the patient's decision, insurance coverage, and adverse events.
"One of the main messages might be that studies that are largely based on the drop of the ALSFRS-R score over a short study period, like only 6 months, could end up raising more questions than they answer," said Witzel.
The known weaknesses of the ALSFRS-R score become less prominent in longer trials, he added.
In an accompanying editorial, Jonathan D. Glass, MD, and Christina N. Fournier, MD, both of Emory University in Atlanta, Georgia, note these new data "add to the unfortunate experience in ALS clinical trials, in which exciting results in small trials are not reproducible in larger, appropriately powered trials," the editorialists write.
Observational trials such as the current study are not accorded the same weight as prospective, placebo-controlled trials, but the current study's rigor is impressive and lends credibility to the findings, they add.
Commenting on the findings for Medscape Medical News, Richard S. Bedlack, MD, PhD, professor of neurology and director of the ALS clinic at Duke University School of Medicine, Durham, North Carolina, said there is "always going to be potential biases in real-world studies."
The large patient population, prospective design, and propensity-score matching are significant strengths of the current study, said Bedlack, who was not involved with the research.
"But the bottom-line is, without another randomized, double-blind, placebo-controlled trial, I will never truly know whether this drug works or in whom." Yet the FDA approval of edaravone "removed any incentive for the company that owns it to ever sponsor another trial," Bedlack said.
Edaravone requires many IVs, 14 consecutive days of infusion, and has a significant rate of adverse events, he noted.
"It's easy for me to see why so few of my patients seem to be interested in this, and I think this study is going to make even less of them interested," said Bedlack.
Slow enrollment, "noisy" clinical scales, and a lack of pharmacodynamic biomarkers are among the difficulties that ALS researchers face, he added.
"Given all this, it's not surprising that replication, which is one of the fundamental principles of good science, is quite rare in ALS trials," he noted. The field must reconcile the need for replication with the humanitarian need for new treatments, Bedlack concluded.
The study was conducted without outside funding. Witzel has reported receiving grants from the Charcot Foundation for ALS Research and the Medical Faculty of Ulm University for research unrelated to this study. Bedlack has reported previously receiving consulting income from Mitsubishi Tanabe Pharma America, which owns edaravone.
JAMA Neurol. Published online January 10, 2022. Abstract, Editorial
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Headshot 1: Courtesy of Simon Witzel, MD
Headshot 2: Courtesy of Duke University
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Cite this: Long-Term Adjunctive Edaravone for ALS: Latest Findings - Medscape - Jan 17, 2022.