Edaravone effective in small subset of ALS patients

By Marilynn Larkin

NEW YORK (Reuters Health) - Edaravone is effective in a carefully selected subset of patients with amyotrophic lateral sclerosis (ALS) but is unlikely to be helpful in a wider patient population, researchers in Japan say.

The U.S. Food and Drug Administration approved the drug, marketed by Mitsubishi Tanabe Pharma Corporation as Radicava, on May 5, with an orphan drug designation (http://bit.ly/2qnEdFe.)

In an earlier phase III study, edaravone efficacy was similar to placebo. However, a post-hoc analysis suggested a greater effect in patients in the early stage of disease who met specific criteria: ALS grade 1 or 2 in the Japan ALS Severity Classification; scores of at least two points on all 12 items on the 48-point ALS Functional Rating Scale (ALSFRS-R); forced vital capacity of at least 80%; definite or probable ALS according to revised El Escorial criteria; and disease duration of no more than two years.

To confirm the post hoc finding, Dr. Makoto Akimoto of Mitsubishi Tanabe Pharma Corporation in Tokyo and colleagues conducted a randomized, double-blind, parallel-group phase III study of patients from 31 hospitals in Japan who met these inclusion criteria.

For the efficacy analysis, 66 patients received 60 mg intravenous edaravone and 68 received placebo for six cycles (four weeks per cycle with two weeks on, two weeks off) over six months.

As reported in The Lancet Neurology, online May 15, the change in ALSFRS-R score was -5.0 in the edaravone group and -7.50 in the placebo group.

Adverse events were reported in 84% of patients in both groups, including serious events in 16% of patients taking edaravone and 24% of those taking placebo. One patient receiving edaravone and four receiving placebo had adverse events that led to study withdrawal.

Should clinicians now be prescribing edaravone for their ALS patients? “I would suggest that we should not,” editorialist Dr. Orla Hardiman of Trinity College Dublin, Ireland, told Reuters Health.

“The cohort of ‘responders’ was very small and the study was conducted in a single population,” she said by email. “Moreover, analysis of the Irish ALS Register suggests that less than 7% of ALS patients in Ireland would fulfill the inclusion criteria.”

“However,” she added, “the FDA approval did not stipulate that the drug should only be provided to likely responders, suggesting that the real-world experience of edaravone use would likely reflect the initial study, in which no difference between treated and untreated patients could be discerned.”

“The treatment is both expensive and burdensome for patients,” Dr. Hardiman continued. “The economic cost of this must be set against the potential benefit within the larger population of patients with ALS.”

In addition, she observed, the study “described a change in the slope of decline as measured by the ALSFRS , but did not provide any details regarding survival” nor benefits to the patients who experienced this effect.

Dr. Hardiman added, “This does not mean we should dismiss the potential of edaravone as a therapeutic agent in ALS, and in this regard, the studies performed by Mitsubishi should be welcomed.”

“The recognition of ‘responders’ and ‘nonresponders’ in ALS therapeutics is a novel development to be encouraged,” she noted. “But more work is required” to ensure the drug is properly positioned for selected patients.

Dr. Sami Saba, a neurologist specializing in neuromuscular medicine and electromyography at Lenox Hill Hospital in New York City, told Reuters Health, “Overall, this study shows a modest slowing of progression over six months in those with early/mild ALS. Specifically, those who received the drug declined 2.5 points fewer on the 48-point scale than those who received placebo.”

“To put it in a different way,” he said by email, “those who got the drug took six months, on average, to get to the same level of disability as those who did not receive the drug did in four months.”

“The drawbacks of this study are its short duration and very specific population; furthermore the absolute effect was relatively small,” he continued.

“However . . . this treatment may have a meaningful impact on the lives of those who are diagnosed early enough to benefit from its effects,” he noted. While the effect may be modest on a numerical scale, he said, it could reflect a meaningful difference in the real world, such as being able to feed oneself or not.

Additional studies are needed to determine whether the effects are long-lasting or impact overall survival. Still,” he concluded, “this is a promising result despite the limitations.”

The study was funded by Mitsubishi Tanabe Pharma Corporation. Six coauthors are employees and the rest have received fees from the company.

The author did not respond to requests for a comment.

SOURCE: http://bit.ly/2qBJ98X and http://bit.ly/2pE6AlB

Lancet Neurol 2017.

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