Enrollment Continuing in REFINE-ALS Biomarker Study for Radicava

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Thanks to the implementation of proactive safety measures for the COVID-19 pandemic, Mitsubishi Tanabe Pharma America (MTPA) has enrolled at least 33 adults with amyotrophic lateral sclerosis (ALS) in its ongoing REFINE-ALS biomarker study.

“ALS patient needs remain MTPA’s primary focus, so it was a priority to address the evolving concerns of the ALS community during the pandemic and offer appropriate alternatives for patients to participate in the REFINE-ALS study through a virtual setting,” Atsushi Fujimoto, MTPA’s president, said in a press release.

“The collective goal has always remained twofold — ensuring the safety of the participants while continuing to foster scientific research, including the use of optimized biomarker assays to obtain real-world data and help better understand this progressive disease,” Fujimoto added.

The implemented COVID-19 mitigation strategies and an update on REFINE-ALS’s progress were recently presented through two posters at the 32nd International Symposium on ALS/MND, held virtually Dec. 7–10.

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Conducted in collaboration with Massachusetts General Hospital’s Neurological Clinical Research Institute (NCRI), in Boston, the observational trial (NCT04259255) is designed to identify biomarkers in urine or blood that could be used to predict a patient’s response to MTPA’s Radicava (edaravone) in the real-world setting.

The therapy is approved for ALS in several countries, including the U.S., Canada, Switzerland, Japan, South Korea, and China. It works by reducing oxidative stress — an imbalance between the production of potentially harmful free radicals and a cell’s ability to detoxify them — which is thought to be one of the drivers of nerve cell death in ALS.

Radicava is administered directly into the bloodstream in 28-day cycles. The first cycle is characterized by 14 consecutive days of treatment, followed by a two-week treatment-free period. After that, treatment is given for 10 consecutive days of the next 14, followed by another two-week treatment-free period.

REFINE-ALS aims to enroll up to 300 ALS patients living in North America who will initiate Radicava treatment, which will consist of six cycles over 24 weeks (nearly six months).

Biomarker levels and ALS progression are being assessed before treatment initiation, at the start of the therapy, and at predetermined times throughout the treatment period. The therapy’s safety is also being evaluated.

As of April, more than 30 sites were actively recruiting adult patients; more information can be found here or at (617) 724-2609.

The COVID-19 pandemic hit North America only a few months after patient enrollment started in October 2019, ultimately affecting recruitment and in-person follow-up assessments of those who were able to enroll.

In the poster “COVID-19 mitigation strategies utilized in the Radicava/edaravone findings in biomarkers from ALS (REFINE-ALS) study” (abstract CLT-05), researchers presented data on the impact of COVID-19-related restrictions in the study’s progression and the strategies implemented to overcome them while ensuring patients’ safety.

COVID-19-related restrictions slowed clinical site openings, forced the temporary closure of some opened sites, slowed or halted patient recruitment, and prevented in-office visits for most of the enrolled participants.

In addition, “global supply chain limitations caused delays in the availability of laboratory kits for sample collection, and closure of research laboratories prevented processing of [such samples],” the researchers wrote.

To overcome these challenges, MTPA implemented mitigation strategies in January through revisions of the study’s protocol. These proactive measures included the option to participate virtually through telemedicine (medical care delivered virtually) and home health agencies instead of hospital or in-office visits.

“Workflows were developed to perform and document at-home visits by trained healthcare clinicians to collect blood samples, perform clinical assessments, and measure [lung function],” the researchers added.

Study investigators were informed of upcoming protocol changes through webinars in autumn 2020, and remote-visit training was conducted early this year.

“The COVID-19 mitigation strategies employed in the REFINE-ALS study may be applicable to other clinical studies in ALS and may help improve clinical trial procedures in future studies,” the researchers wrote.

Details on evaluated biomarkers and an overall study update were shared in the poster “Biomarker assays utilized in the Radicava/edaravone findings in biomarkers from ALS (REFINE-ALS) study” (abstract CLT-29).

Select biomarkers examined in the study, using the expertise of multiple specialty laboratories, include those involved in oxidative stress, inflammation, nerve cell damage or death, and muscle injury.

Epigenetic biomarkers, representing mechanisms that influence a gene’s activity without altering its underlying DNA sequence, are also being assessed, as well as a biomarker discovery panel called SOMAscan.

In addition, participants may choose to receive their genetic results for five genes — SOD1, TARDBP, C9ORF72, FUS, and VCP — whose mutations are associated with ALS. Advanced tele-genetic information will be made available for those who choose to receive this information.

MTPA is also exploring the best way to use biobank samples from matched, untreated ALS patients for biomarker comparisons.

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As of June, 33 patients had been enrolled in REFINE-ALS. Samples from the pre-treatment visit and the beginning of the first cycle from the first 16 participants were analyzed for all biomarkers as a pilot evaluation.

Results showed that all but two biomarker tests provided reliable results. The two exceptions included tests for two oxidative stress markers, for which a large proportion of the results were below the limit for detection. As such, these laboratory tests are being revised.

The company also developed a set of steps for data transfer and analysis to assess the therapy’s pharmacodynamics — effects on the body, or in this case, on the evaluated biomarkers — while within the treatment cycle and its association with clinical outcomes.

“The results of this study may help to identify biomarkers predictive of response to [Radicava] and biomarkers of pharmacodynamic response to [Radicava] that may elucidate biological mechanisms,” the researchers wrote.

“Researchers have faced many challenges over the last year, but our commitment to learning more about ALS and response to treatment with RADICAVA in a real-world setting has remained constant,” said James Berry, MD, the study’s principal investigator and the director of the NCRI.

“Our ongoing, adaptable collaboration with MTPA has allowed the REFINE-ALS study to continue enrollment and analyses of these complex biomarkers as a way to enhance understanding of ALS treatment,” Berry added.