Long-Term IV Edaravone Not Associated With Disease-Modifying Benefit in ALS


Despite not providing additional, clinically relevant benefit for patients with amyotrophic lateral sclerosis as an add-on to standard therapy, the intravenous treatment was feasible and well tolerated.

Simon Witzel, MD, neurology department, Ulm University

Simon Witzel, MD

Data from a recent study suggest long-term intravenous (IV) edaravone may not provide clinically relevant benefits as an add-on to standard therapy of riluzole in patients with amyotrophic lateral sclerosis (ALS). Although, the treatment was found to be feasible, safe, and mainly well-tolerated in the cohort study. 

The multicenter, propensity score-matched cohort study included a total of 324 patients, 194 of whom started IV edaravone treatment, with investigators analyzing approximated 2400 edaravone treatment cycles corresponding to 190 treatment–years. Participants receiving edaravone had a median age of 57.5 years (interquartile range [IQR], 50.7-63.8) and 125 participants (64%) were men. At the start of treatment, patients receiving edaravone had a median disease duration of 16.5 months (IQE, 10.6-24.2) and 186 patients (97%) were administered riluzole. 

When evaluating disease progression in 116 patients treated with edaravone for a median follow-up period of 13.9 months (IQR, 8.9-13.9), investigators found no difference in 116 control patients treated with standard therapy for a median of 11.2 months (IQR, 6.4-20.0), with decreases in ALS Functional Rating Scale-Revised (ALSFRS-S) scores of –0.91 points per month (95% CI, –0.69 to –1.07) and –0.85 points (95% CI, –0.66 to –0.99; P = .37), respectively. 

When evaluating secondary end points, investigators, led by Simon Witzel, MD, neurology department, Ulm University, in Ulm, Germany, found no significant decreases in survival probability, time to ventilation, or change in disease progression between the 2 cohorts. Short-term beneficial effects of IV edaravone treatment were demonstrated in the previous MCI-186 ALS19 study (NCT01492686) in an efficacy-expected subpopulation (EESP), which did not affect results in the current study. Upon evaluation of subgroups, defined by applying inclusion criteria from the MCI-186 ALS19 study, investigators found no difference in outcomes for patients treated with edaravone and matched patients in both the eligible (EFAS) and ineligible (non-EFAS) groups.  

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“Evidence for the efficacy of edaravone in long-term use is scarce, to our knowledge,” Witzel et al wrote. “Our study investigated propensity score-matched controls participating in a single observational study to achieve the best possible comparability and ensure identical medical care structure during follow-up. Propensity score matching replicates some characteristics of randomized clinical trials and can improve effectiveness analysis under nonrandomized conditions.” 

There were 30 documented cases (16%) of potential treatment-associated adverse effects (AEs), 20 of which (67%) occurred during the first 24 weeks of treatment. AEs were divided into potential drug-associated AEs (n = 24 [EFAS: 12 events; non-EFAS: 12 events]; P = .07) and infusion-related AEs (n = 6 [EFAS: 3 events; non-EFAS: 3 events]; P = .40). Potential drug-associated AEs included allergic reactions (4 events), orthostatic dysregulations (4 events), fatigue (4 events), eczema or dermatitis (3 events), gait disturbance (2 events), among others. Infusion related events included port infections (5 events) and thrombophlebitis (1 event). 

“Our study reports adverse effects consistent with those observed in the edaravone development program and in the post-marketing experience and does not point toward more serious safety concerns for long-term treatment compared with short-term treatment,” Witzel et al wrote. “Our study population included European patients treated up to 32 months and a relevant number of patients in more advanced disease stages and with impaired respiratory function, a population that has rarely been evaluated. Although edaravone treatment as mainly well-tolerated, allergic reactions and infections at the infusion site associated with hospitalization in single cases suggested a residual treatment risk, which, in terms of infusion-related events, was already suggested by previous work.”

The study was conducted between June 2017 and March 2020 at 12 academic ALS referral centers, all associated with the German Motor Neuron Disease Network. A total of 1440 patients were originally screened, with 738 included in propensity score matching.

Limitations were attributed to the study’s observational design and nonrandomized treatment allocations. Additionally, only partial genetic information was available and therefore not included, and incomplete data collection for some patients may have affected accounting for potential AEs. Analysis of disease progression rates may have also been influenced by heterogenous follow-up intervals. To account for the 12-week observation period in a real-world setting from the MCI-186 ALS19 study, investigators adjusted EESP criteria by assigning patients who met 5 of the 6 criteria to the EFAS subgroup. This may therefore not fully match the MCI-186 ALS19 population. 

Witzel S, Maier A, Steinbach R, et al. Safety and effectiveness of long-term intravenous administration of edaravone for treatment of patients with amyotrophic lateral sclerosis. JAMA Neurol. Published online January 10, 2022. doi:10.1001/jamaneurol.2021.4893
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