Early treatment with Radicava (edaravone) significantly lowers the cumulative risk of death, need for mechanical and permanent ventilation, and hospitalization in adults with amyotrophic lateral sclerosis (ALS), a post hoc analysis of a Phase 3 clinical trial suggests.
While the trial “was not designed with survival as an endpoint, this post-hoc analysis allows us to explore insights on the results of early treatment intervention on survival-related events due to ALS progression,” Atsushi Fujimoto, the president of Mitsubishi Tanabe Pharma America (MTPA), the therapy’s developer, said in a press release.
These events include “death, hospitalization, ventilation and tracheostomy,” Fujimoto added.
Appropriately controlled future studies, however, are needed to confirm these findings, researchers noted.
These results were presented by Benjamin Rix Brooks, MD, an ALS specialist at the Atrium Health Neurosciences Institute of the Carolinas Medical Center, in an oral presentation at the 2021 MDA Virtual Clinical and Scientific Conference.
Radicava works by reducing oxidative stress — an imbalance between the production of potentially harmful free radicals and the cells ability to detoxify them — which is thought to be one of the causes of nerve cell death in ALS.
The therapy was approved in the U.S. in 2017 based on findings from a Phase 3 clinical trial, called Study 19 (NCT01492686), which evaluated its safety and effectiveness in 137 adults with ALS living in Japan.
Participants were randomly assigned to either Radicava or a placebo, both via intravenous (into-the-vein) infusions, for 24 weeks (about six months). Results showed that Radicava-treated patients had a 33% significantly slower functional decline, compared with those on a placebo.
A total of 123 patients completing these six months chose to enter the study’s open-label extension, in which all received Radicava for an additional 24 weeks (totaling for some up to one year of treatment).
Extension study data suggested that people initially assigned to Radicava continued to experience slower disease progression, while those previously on placebo started to benefit from the treatment.
Now, a post hoc analysis looked at how earlier versus later initiation of Radicava affected the risk of death, tracheostomy, permanent assisted ventilation, and hospitalization due to ALS progression in Study 19 participants.
Tracheostomy is a surgical procedure that creates an opening in the windpipe for mechanical ventilation. A post hoc analysis is that done after a study has finished to help “develop insights to the [therapy’s] clinical effect that may be relevant” to patients, said Brooks, who is also the medical director of the Carolinas Neuromuscular/ALS-MDA Care Center.
Six deaths were reported at the trial’s end: two people (2.9%) on continuous Radicava treatment and four (5.9%) initially assigned to placebo. All occurred during its extension part.
Patients always on Radicava were also found to have a 52% lower risk of death and a 56% lower cumulative risk of death, tracheostomy, and permanent assisted ventilation, compared with those starting on Radicava six months later.
These differences did not reach statistical significance, meaning that the data were insufficient to provide strong evidence that these differences were associated with Radicava and not due to chance.
But the cumulative risk of death, tracheostomy, permanent assisted ventilation, and hospitalization was found to be significantly reduced (by 53%) among patients on continuous Radicava, compared with those first given a placebo.
This provides “evidence that early intervention with intravenous [Radicava] was associated with a statistically significant reduction in the combined endpoint of cumulative occurrence of death, tracheostomy, permanent assisted ventilation, and hospitalization in patients with ALS,” Brooks said.
Among the analysis’ limitations, the neurologist noted the lack of a placebo group throughout the entire trial — serving as a comparative control group — and the fact that the post hoc analysis was not originally powered to assess these cumulative risks.
“No clinical conclusions can be drawn from these results alone without additional, appropriately-controlled clinical observation studies,” he said, and “further research is recommended to confirm these findings and [is] ongoing.”
Notably, real-world studies have challenged Radicava’s efficacy in this patient population, further supporting the need for additional clinical trials and those including patients from different countries.
MTPA is evaluating an oral formulation of Radicava in adults with ALS living in the U.S. and Japan in a Phase 3 clinical trial (NCT04165824) and its open-label extension study (NCT04577404), anticipated to finish by September 2023.
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