Radicava Effective in Slowing Progression Across Year of Use, Trial Data Show

Inês Martins, PhD avatar

by Inês Martins, PhD |

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Radicava (edaravone), an approved treatment for amyotrophic lateral sclerosis (ALS), can be taken for up to one year without losing its effectiveness, and benefits patients who delay its start — say, after six months of placebo in a clinical trial, a post hoc analysis of that Phase 3 study suggests.

These findings were in “Long‐term edaravone efficacy in amyotrophic lateral sclerosis: Post‐hoc analyses of Study 19 (MCI186‐19),” a study published in the journal Muscle Nerve.

Radicava, developed by Mitsubishi Tanabe Pharma America (MTPA), is a free radical scavenger designed to reduce oxidative stress — an imbalance between the production of potentially harmful free radicals and a cell’s antioxidant defenses — which is thought to be one of the causes of nerve cell death in ALS.

The treatment was approved in the U.S. in 2017 based on findings from Study 19 (NCT01492686), a double-blind Phase 3 clinical trial in Japan that assessed the safety and efficacy of Radicava in people with ALS.

Its 137 participants were randomly given either Radicava or a placebo, both via intravenous (IV, into-the-vein) infusions, for 24 weeks. Results showed that those on Radicava experienced a significantly slower decline (by 33%) in their ability to perform everyday activities, compared to those on placebo.

Physical abilities were assessed using the ALS functional rating scale-revised (ALSFRS-R), which measures the ability to perform such daily functions such as speech, swallowing, and dressing. Patients on placebo lost an average of 7.5 ALSFRS-R points over six months, while those on Radicava lost 5 points during the same period, a difference in decline of 2.5 ALSFRS-R points.

After six months, patients had the opportunity to enter an open-label extension part of the study, where all would be treated with Radicava for an additional 24 weeks (about six more months) to explore its long-term safety and efficacy.

In total, 123 patients enrolled here, 65 previously on Radicava and 58 from the placebo group. Extension study findings suggested that those staying with Radicava continued to experience slower disease progression, while those previously on placebo started to benefit from the treatment.

The lack of a placebo  group throughout the entire study’s 48 weeks — serving as a comparative control group — limited the conclusions that could be drawn. This led researchers at MTPA to conduct a post hoc analysis, meaning an analysis done after a study has finished, to better understand Radicava’s long-term efficacy in ALS.

Using data from the double-blind first part of Study 19, and assuming that ALSFRS-R declined in a linear manner over time, researchers estimated likely progression in patients on placebo and on Radicava for the first 24 weeks. They then used that estimate to predict progression within each group — with no change in treatment status — over the next six months.

Finally, they compared this projected progression with the actual rate of progression among patients using Radicava for the entire 48 weeks, and for those who switched to Radicava from placebo for weeks 24 to 48.

The analysis helped them to compare projected disease progression without Radicava for 48 weeks with actual progression with Radicava’s use for 48 weeks (about 1 year), and against actual progression in those with six months of placebo followed by 24 weeks of Radicava.

Had patients remained on placebo for 48 weeks, their projected decline would reach 13 ALSFRS-R points, the analysis showed. This decline was significantly greater than the actual decline seen in Radicava-treated patients for 48 weeks, who experienced an 8-point reduction. (The analysis’ projected decline over about one year of Radicava’s use was 8.6 points.)

This point gap amounted to a 38% difference in disease progression among those treated continuously with Radicava, and those who would have remained on placebo for 48 weeks (the projected group).

The projected decline in a 48-week placebo group was also greater than the actual decline experienced by those who switched to Radicava for a final 24 weeks. Their ALSFRS-R scores were 10.9 points lower than at the study’s start.

The rate of progression was also similar between the continuous Radicava and placebo-Radicava switch groups, “supporting treatment benefit of edaravone in ALS patients who begin receiving treatment later in their disease course,” the researchers wrote.

Among study limitations noted was the assumption that ALSFRS-R scores decline in a linear manner, which may not be true in early and late disease stages. This should be addressed in future studies of Radicava’s long-term use, the team recommended.

“Compared with placebo, these analyses suggest that edaravone is beneficial in ALS patients even after 6 [months] of receiving placebo, and efficacy is maintained for up to 1 year,” the researchers wrote. “Ongoing and planned studies will further our understanding of the long‐term safety and efficacy of edaravone in patients with ALS.”

Another post-hoc analysis of Study 19 was shared at a Virtual Clinical Trial Session of the recent MDA Conference, in the presentation “Post hoc analysis of edaravone Study 19: efficacy in bulbar onset ALS patients with and without reduced pulmonary function.”

This analysis supported the effectiveness of one year of treatment regardless of whether ALS symptoms first occur in the neck or face (bulbar-onset disease) or in the limbs (limb-onset).

Patients with bulbar-onset also benefitted from a year of Radicava regardless of their forced vital capacity (FVC, a measure of lung function) being above or below 80% at the start of treatment.

“ALS patients with bulbar-onset disease receive a significant benefit from initiating edaravone treatment regardless of whether they have baseline FVC ≥80% or <80%,” the researchers wrote.