Results of cohort study did not differ in subgroup with efficacy expected

Edaravone added to standard therapy with riluzole did not change rates of disease progression for patients with amyotrophic lateral sclerosis (ALS) compared with riluzole alone, an observational cohort study found.

Disease progression on the ALS Functional Rating Scale–Revised (ALSFRS-R) for patients treated for a median of 13.9 months with riluzole plus edaravone (-0.91 points/month, 95% CI −0.69 to −1.07) did not differ from that for patients treated for a median of 11.2 months with riluzole only (−0.85 points/month, 95% CI −0.66 to −0.99, P=0.37), reported Simon Witzel, MD, of Ulm University in Germany and co-authors.

“Our effectiveness analyses do not support the association of edaravone treatment with a clinically relevant benefit on disease progression,” the researchers wrote in JAMA Neurology.

A 2017 Japanese trial (MCI186-ALS19) had suggested slowing of disease progression at 24 weeks based on the ALSFRS-R, but included only patients with expected efficacy who had disease progression less than 2 years, preserved respiratory function, minor functional impairment, and moderate disease progression (i.e., earlier, milder disease).

In the present study, results “did not depend on whether patients belonged to the subpopulation with expected drug efficacy with respect to the MCI186-ALS19 study,” Witzel and co-authors noted.

The researchers used data from 12 German academic ALS research centers, studying 324 patients with probable or definite ALS with disease onset from December 2012 to April 2019. Of this group, 194 patients started intravenous edaravone treatment cycles (10 infusion days in 14 days, then 14 days off), and of these, 130 were propensity-matched with 130 ALS patients receiving standard therapy. (Edaravone was available under special access conditions in Germany.)

The disease progression analysis included 116 propensity-matched patients in each group. Of these, Witzel and co-authors identified a subgroup of 64 treated patients who would have qualified to be included among the early onset, high-functioning participants enrolled in the MCI186-ALS19 trial.

Among patients starting edaravone, 64% were men and the median age was 57.5; median disease duration was 16.5 months. Median baseline score ALSFRS-R was 37 (scores can range from 0 to 48), and median disease progression was -0.58 points/month.

By study end, 47% who started edaravone were continuing therapy, 26% had discontinued therapy, and 17% had died, while 10% were lost to followup.

Other study results included:

  • The 18-month survival probability was 75% in both the edaravone and control group, and did not differ between the subgroups defined by restrictive criteria.
  • Median ventilation-free survival after baseline did not differ for the edaravone (21.7 months, 95% CI 15.0-28.3) or control patients (19.7 months, 95% CI 15.2-24.1, P=0.40).
  • Potential treatment-related adverse events were seen in 16% of edaravone-treated patients and included allergic reactions, orthostatic difficulties, and fatigue as well as infusion-related events. Safety events were consistent with those observed during edaravone development and post-marketing, the authors noted.

“Supported by additional real-world studies, our results raise doubts whether patients with ALS benefit from long-term intravenous edaravone treatment,” Witzel and co-authors wrote. “This doubt is particularly important in light of the time-consuming and challenging intravenous application.”

An oral formulation of edaravone has been developed but first must be studied in clinical trials, they added.

Edaravone is an antioxidant free radical scavenger initially investigated as a protective agent for ischemic stroke. The ALS efficacy-expected-subpopulation was first identified in subgroup analysis of the otherwise negative phase III Japanese study called MCI186-ALS16. The study failed to meet its primary outcome overall, which was functional decline at 24 weeks measured with the ALSFRS-R.

The subsequent MCI186-ALS19 phase III study had fewer patients and more restrictive inclusion criteria, and did find a difference between active treatment and placebo groups. This was among the data used in the FDA decision to approve the medication for ALS in 2017, although approval was not limited to patients meeting the more restrictive criteria.

In an accompanying editorial, Jonathan Glass, MD, and Christina Fournier, MD, MS, both of Emory University in Atlanta, called the present study’s results “both impressive and believable,” and pointed out that the approximately 2.5 point ALSFRS-R score difference seen in MCI186-ALS19 was of uncertain clinical significance.

Marketing drugs that do not show incontrovertible clinical benefit may do more harm than good, they suggested, noting that:

  • Unproven drugs for neurodegenerative disease are frequently costly and burdensome for patients and toxic effects may outweigh any benefit.
  • Patients may choose to not participate in future clinical trials, hoping this “new” drug is providing proven benefit.
  • Resources may be diverted from interventions that could actually be helpful.
  • False hope based on unrealistic expectations and conflicting messages among clinicians and regulatory agencies may breed mistrust in science and the healthcare system.

“The case of edaravone is particularly troubling,” Glass and Fournier wrote. “This drug, requiring continued intravenous injections and costing upwards of $150,000 per year, never underwent trial in the United States.” The European Medicines Agency has not approved edaravone and is requiring a larger and longer trial, they noted.

“The desperate search for new ALS therapies and the desire to bring new drugs to market are understandable,” the editorialists wrote. “Unfortunately, many patients and patient advocates blame the U.S. FDA for the lack of new drugs, unfairly tagging the agency as an obstacle to effective therapies.”

“However, there are no examples of potentially game-changing ALS therapies that have not come to market owing to U.S. FDA barriers,” Glass and Fournier pointed out. “Our lack of effective therapies for ALS and other devastating neurodegenerative diseases reflects a lack of a clear understanding of underlying biological mechanisms and true druggable targets.”

Limitations include an observational study design with non-randomized treatment allocation. In addition, genetic information was not used in propensity matching for the outcomes analysis.

  1. Edaravone added to standard therapy with riluzole did not change rates of disease progression for patients with amyotrophic lateral sclerosis (ALS) compared with riluzole treatment alone, an observational cohort study found.

  2. Results did not depend on whether people with ALS belonged to a subpopulation with expected drug efficacy.

Paul Smyth, MD, Contributing Writer, BreakingMED™

Witzel reported grants from the Charcot Foundation for ALS Research and the Medical Faculty of Ulm University outside the submitted work.

Glass and Fournier had no disclosures.

Cat ID: 130

Topic ID: 82,130,730,130,192,925