Biomarkers May Determine ALS Progression, Edaravone Response

REFINE-ALS trial is designed to ID biomarkers to predict response to Radicava

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Continuous monitoring of certain biomarkers in people with amyotrophic lateral sclerosis (ALS) may inform about the risk of disease progression and the response to edaravone, according to interim data from the ongoing REFINE-ALS biomarker study.

Mitsubishi Tanabe Pharma America (MTPA), the developer of edaravone, recently shared these findings at the 2022 annual Northeast Amyotrophic Lateral Sclerosis (NEALS) meeting, which ran Nov. 1–3 in Clearwater, Florida. The presentation was titled, “Interim Analysis of the Radicava/Edaravone Findings in Biomarkers from ALS (REFINE-ALS) Study” (Abstract 110).

“The REFINE-ALS study has enabled us to examine meaningful biomarkers to enhance our understanding of the complexities of ALS and the role that edaravone might play in treatment of the disease,” Gustavo A. Suarez Zambrano, MD, vice president of Medical Affairs at MTPA, said in a press release.

Edaravone 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 believed to be a key driver of nerve cell death in ALS.

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Radicava is the first approved form of edaravone and is administered directly into the bloodstream (intravenous infusion) in 28-day cycles. In the first cycle, patients receive daily infusions over 14 days, 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 weeks of no treatment.

Edaravone is also available in a more convenient oral formulation called Radicava ORS, which is administered by mouth or a feeding tube, but in a similar dosing schedule.

The observational REFINE-ALS trial (NCT04259255), conducted in collaboration with Neurological Clinical Research Institute (NCRI) at Massachusetts General Hospital (MGH) in Boston, is designed to identify biomarkers that could predict a person’s response to Radicava or Radicava ORS.

It’s recruiting up to 300 participants at sites in the U.S. and Canada who received six cycles of oral or intravenous edaravone as part of their clinical care, totaling about six months of treatment.

As part of the trial, blood and urine biomarkers associated with oxidative stress, inflammation, and nerve damage — biological processes known to occur in ALS – are being monitored before starting treatment (baseline), at the start of treatment, and then at specific times throughout the trial.

In addition to known biomarkers, two biomarker discovery panels, called EpiSwitch and SOMAscan, are also being used. EpiSwitch will assess for epigenetic biomarkers, or changes in the DNA that influence a gene’s activity without altering the underlying DNA sequence. SOMAscan is a platform that allows 7,000 biomarker proteins from a drop of blood or urine to be quantified.

To understand how these biomarkers relate with disease outcomes, patients will be assessed for a number of clinical measures, including disease progression, quality of life, respiratory function, muscle strength, and survival.

As of April, 50 patients had been enrolled and their biomarker levels were matched to those of 36 participants of the Answer ALS study, an ongoing research program that’s building a comprehensive collection of data from ALS patients.

Biomarker and clinical data from 40 participants showed that, at the start of the study, the proportion of patients with fast progressing disease, as predicted with the EpiSwitch, was higher among those in REFINE-ALS than in Answer ALS.

Consistent with a more aggressive and rapidly progressing disease, the REFINE-ALS population also had higher levels of neurofilament light chain (NfL), a marker of nerve cell damage, than those in Answer ALS. This biomarker’s levels correlated with the rate of disease progression, assessed with the ALS Functional Rating Scale-Revised (ALSFRS-R).

However, despite the higher proportion of fast progressors and the higher NfL levels at baseline in REFINE-ALS patients, the disease progressed at the same rate in both groups, the researchers found.

“We are encouraged by these initial findings and look forward to gathering more biomarker data on these important assessments and sharing our key learnings with the ALS community,” Zambrano said.

James Berry, MD, director of the NCRI and the trial’s lead researcher noted that there’s been “a heightened interest in leveraging biomarker research in ALS to evaluate potential relationships between changes in biomarkers and disease progression and treatment outcomes.”

“The results from REFINE-ALS may help provide further insight into the biological effect of edaravone treatment of ALS using biomarkers. Our hope is that continued ALS biomarker research will serve as an important tool for understanding treatment effects in ALS,” Berry said.