A review of Radicava (edaravone), an approved amyotrophic lateral sclerosis (ALS) treatment, found the medication generally well tolerated in real-life use by patients in six countries, matching reports from clinical trials.
But its effectiveness at delaying disease progression was less evident, with findings of greatest efficacy coming from Asia and more studies needed elsewhere, its researchers wrote.
The study, “Post-Marketing Experience of Edaravone in Amyotrophic Lateral Sclerosis: A Clinical Perspective and Comparison With the Clinical Trials of the Drug,” was published in the journal Cureus.
Radicava, marketed by MT Pharma, works to limit motor nerve cell death — a hallmark of ALS — by reducing oxidative stress, in which potentially harmful free radicals overwhelm a cell’s antioxidant defenses.
The treatment was approved in Japan and South Korea in 2015, and based on results of a Phase 3 trial (NCT01492686) in Japan was approved by the U.S. Food and Drug Administration (FDA) in 2017, making it the first new ALS treatment available to patients there in over two decades. Radicava is also approved for use in Canada, Switzerland, and a number of other countries, but in Europe it is likely only available through compassionate use programs.
Some studies into Radicava’s efficacy have faced criticism. A separate Phase 3 study in Japan (NCT00330681, also called the MCI-186 trial) failed to demonstrate a significant difference between the treatment and a placebo. Later trials showed Radicava slowed decline in physical function in treated patients, especially those in early disease stages, but they did not evaluate whether it could improve survival.
Because these trials also took place in Japan, “studies around the world might draw different conclusions with a more diverse population,” the researchers wrote. They also were interested in whether Radicava, used as an add-on therapy with riluzole — the first approved ALS treatment — might show better benefit.
Scientists at the California Institute of Behavioral Neurosciences and Psychology reviewed past studies of Radicava, as well as data on how it has performed in the clinic in six countries: Kuwait, South Korea, Argentina, the United States, Israel, and Italy.
From 20 papers that met their criteria, the researchers examined how Radicava is reported to benefit physical function. Measures examined included the revised amyotrophic lateral sclerosis functional rating scale (ALSFR-R; evaluates speech, swallowing, ability to dress and eat with utensils, etc.), forced vital capacity (FVC, a standard measure of respiratory health), survival rate, and if an added benefit existed with Radicava plus riluzole.
Studies preceding the MCI-186 study showed reductions in ALSFRS-R decline and in markers of oxidative stress. Those conducted after that MCI-186 trial — called post-hoc studies— as well as an extension study to MCI-186 in Japan, also showed significant decreases in the rate of physical function decline with Radicava’s use, particularly among early stage patients.
Analyses of real-life, or post-marketing, use took into account safety, ALSFRS-R scores, and changes in FVC.
In Korea, patients using Radicava showed more “modest” FVC declines than were reported among Japanese patients in the Phase 3 study, and a slower rate of decline in ALSFRS-R scores among limb-onset ALS patients (those whose disease begins with weakness in the arms and legs).
In Kuwait, an observational study of 17 ALS patients using Radicava showed ALSFRS-R scores declining by modest amounts — amounts lesser than those reported among patients in the trials. These changes may have been influenced by riluzole, as use of other treatments was allowed. Changes in FVC were not found to be statistically significant.
While treatment appeared to be of some benefit to those in Korea and Kuwait, 22 patients in Israel failed to demonstrate significant differences in various ALS measures when treated with Radicava. These people were compared with 71 patients not using Radicava; all were on a stable riluzole dose for at least six months. The researchers observed, however, that none of the Israeli patients met the original trials’ criteria, which targeted patients more likely to benefit from Radicava, such as early stage disease.
Two Italian studies, with a combined 262 ALS patients, also found no differences in declines in ALSFRS-R or FVC scores (measuring in disease progression and respiratory function) among those given Radicava and those not treated with this medication.
A survey given 67 physicians in the United States covered 3,007 patient prescribed Radicava over the year following its U.S. launch, with a majority (67%) using it as an add-on to riluzole. Effectiveness was not a focus of this survey, although the California researchers noted “[d]rug ineffectiveness was reported in more than 50 cases.”
A study in 16 patients in Argentina — where Radicava’s use is limited “mainly because the insurance companies do not cover it” — also supported Radicava being generally safe and well-tolerated. It largely looked at treated patients’ characteristics, and noted only that two patients stopped using Radicava’s over the study’s four years (2016–April 2020) “due to dissatisfaction.”
The research team noted that both in the MCI-186 trial and in these real-world experiences, most patients were also using riluzole. Further research, they wrote, should examine possible additive effects of these two treatments.
“Edaravone has been demonstrated as an effective drug for patients with ALS at an early stage in clinical trials,” the investigators wrote. Varying outcomes drawn from other studies, however, such as the more moderate benefits seen in Korea and Kuwait, and the lack of clinical benefit seen in Italy and Israel, point toward a need for more research.
“This is why,” the investigators concluded, “more post-marketing experience with edaravone and its impact in the clinical setting need to be reported to get a better perspective of edaravone’s effectiveness.”
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