Radicava Slows Decline in ALS Patients With Poorer Lung Function
Early treatment with Radicava (edaravone) significantly slows disability progression compared with a six-month delay, including in amyotrophic lateral sclerosis (ALS) patients with poorer lung function, according to a new analysis of a Phase 3 clinical trial.
Patients switching from a placebo to Radicava after their lung function fell to well below normal levels still saw a significant change in their progression rate, highlighting the therapy’s beneficial effects in slowing functional decline regardless of patients’ lung capacity at treatment start.
These findings were detailed in the study “Edaravone efficacy in amyotrophic lateral sclerosis with reduced forced vital capacity: Post-hoc analysis of Study 19 (MCI186-19) [clinical trial NCT01492686],” published in the journal PLOS One.
Administered directly into the bloodstream, Radicava works by reducing oxidative stress, a type of cellular damage thought to contribute to nerve cell death in ALS.
Phase 3 Study 19 trial of Radicava
The therapy, developed by Japan-based Mitsubishi Tanabe Pharma, was approved for ALS in Japan and South Korea in 2015 and in the U.S. in 2017, based on findings from the Phase 3 Study 19 clinical trial (NCT01492686).
It enrolled 137 adults in Japan with ALS and normal lung function, who were randomly assigned to either Radicava or a placebo for 24 weeks (about six months).
Lung function was measured through forced vital capacity (FVC), which refers to the maximum amount of air a person can forcibly exhale after a deep breath. Values of at least 80% of predicted FVC are considered within normal range.
After this randomized period, 123 participants (65 in the Radicava group and 58 in the placebo group) chose to enter the trial’s open-label extension, in which all were given the therapy for an additional 24 weeks.
A total of 53 people originally assigned to Radicava and 40 in the placebo-to-Radicava group completed this extension part.
Top-line, six-month findings showed that Radicava-treated patients had a 33% significantly slower disability progression compared with those on a placebo, as assessed with the ALS Functional Rating Scale-Revised (ALSFRS-R). ALSFRS-R scores range from zero to 48, with lower scores indicating greater disability.
Extension study data suggested that people initially assigned to Radicava continued to show slower functional decline, while those switching from a placebo to the therapy started to experience benefits.
Notably, while all patients showed FVC values within the normal range at the study’s start, some experienced a drop below 80% during its first six months.
Patients with poorer lung function
Now, researchers at Mitsubishi Tanabe Pharma America and U.S. institutions evaluated whether Radicava was effective in those patients showing impaired lung function.
Participants were divided into two groups based on their FVC values at week 24. A total of 72 patients still had an FVC of at least 80%, while lung function in 51 others had dropped below that threshold.
The researchers then examined changes in ALSFRS-R scores from the study’s start (baseline) to week 24 (placebo-controlled trial portion), week 24 to week 48 (open-label extension portion), and from baseline to week 48 in these two groups.
Patients with impaired lung function after six months were more likely to be women, more often to have bulbar-onset disease, and to show a lower mean baseline ALSFRS-R score than those who maintained a normal lung function. Bulbar-onset disease first affects a person’s swallowing, chewing, and speech.
Within each group, baseline characteristics did not significantly differ between those initially assigned to Radicava and those given a placebo.
In both the trial’s placebo-controlled and open-label period, results showed a greater ALSFRS-R score decline among people in the reduced lung function group than in the normal lung function group, regardless of their assigned treatment.
But Radicava had a much greater impact among patients with poorer lung function — slowing functional decline by 44% in this group during the placebo-controlled trial, compared with 31% in the normal lung function group.
Similar findings were observed among patients originally assigned to a placebo who then switched to Radicava. These patients also experienced a significant reduction in their ALSFRS-R score slope after switching to Radicava, but the effects were more pronounced among those with impaired lung function.
These patients showed a 12% slower disability progression throughout the study, compared to what would be expected had they remained on a placebo — a drop of 15.2 points in the ALSFRS-R score versus an estimated 17.3-point drop.
In addition, at the study’s end, most patients still had ALSFRS-R scores greater than 24 (indicative of moderate disability), including those with poorer lung function. This highlighted that despite a decline in lung function, “these subjects appeared to have functionality in other domains of the ALSFRS-R (eg, gross motor, fine motor, and bulbar domains),” the researchers wrote.
These findings “confirm that ALS subjects having decreased vital capacity on placebo, receiving delayed [Radicava], may still benefit from a treatment that slows the loss of physical function,” the team added.
As such, Radicava “may be of benefit to the general ALS patient population, in terms of slowing the rate of loss of function, as measured by ALSFRS-R, independent of the respiratory status, as measured by FVC%p at the start of [Radicava] therapy,” the researchers wrote.
An appropriately controlled trial is needed to confirm these findings, the team added.