EpiSwitch Test May Help Classify ALS Patients: New Trial Data

Non-invasive test found to determine slow vs fast ALS progression

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by Steve Bryson, PhD |

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EpiSwitch, a non-invasive, blood-based test developed by Oxford BioDynamics, successfully stratified patients with amyotrophic lateral sclerosis (ALS) as fast versus slow progressors, according to an interim analysis of the REFINE-ALS study.

These findings highlight the potential of the biomarker test to better classify disease progression in ALS patients — which could help in improving diagnoses and advancing clinical trials.

“We are delighted with the initial interim results reported about the use of EpiSwitch in the REFINE-ALS trial,” Alexandre Akoulitchev, PhD, Oxford’s chief scientific officer, said in a company press release, adding, “Robust clinical biomarkers based on liquid biopsy [blood] have been long predicted to change the practice of medicine, and if proven, could become part of medical standards in XXI century.”

The trial was designed to identify biomarkers, including those measured with EpiSwitch, that may predict a response to the approved ALS therapy Radicava (edaravone), or Radicava ORS, an equivalent oral suspension formulation. It was conducted by Mitsubishi Tanabe Pharma America (MTPA), which is marketing the therapy in the U.S., in collaboration with Massachusetts General Hospital (MGH).

“We are encouraged by these initial findings,” said Gustavo A. Suarez Zambrano, MD, vice president of medical affairs at MTPA. “The EpiSwitch platform, as part of other biomarker analyses being conducted in REFINE ALS, will allow us to examine clinically meaningful systemic biomarkers in the REFINE-ALS clinical trial, and enhance our understanding of the role that Radicava (edaravone) might play in treating ALS.”

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Goal: better classifying ALS patients

In ALS, the loss of specialized nerve cells called motor neurons, which control voluntary movements, leads to muscle weakness and wasting, and eventually death from lung failure. Typically, ALS patients survive just 3–5 years after receiving a diagnosis. Some have a faster disease progression, with a shorter overall survival, of less than 15 months.

Because of the lack of clinically validated measures, a diagnosis of ALS usually takes about one year from symptom onset, which can delay timely treatment and limit enrollment of early-stage patients in clinical trials.

Oxford devised the EpiSwitch 3D genomics platform to help diagnose diseases and predict treatment response and outcomes, as well as monitor disease progression. The platform assesses epigenetic biomarkers, or changes in DNA that influence a gene’s activity without altering its DNA sequence.

In addition to patient stratification, EpiSwitch may reveal underlying biological mechanisms of disease beyond those found with other biomarkers, according to Oxford.

The REFINE-ALS trial (NCT04259255) is still enrolling participants across 25 study sites in the U.S. and Canada. It is seeking up to 300 ALS patients who received six cycles of edaravone, administered orally or directly into the bloodstream (intravenously), for a total of about six months.

The study’s regimen includes a first cycle of daily treatments for two weeks, then 14 days without treatment, followed by cycles of 10 consecutive days of treatment over two weeks, then another 14 days without treatment.

Researchers are testing participants’ blood and urine samples for biomarkers associated with inflammation, nerve damage, and oxidative stress — an imbalance in the body between harmful free radical production and antioxidants generated to detoxify them. Oxidative stress is thought to be a driver of motor neuron death in ALS, which is addressed by edaravone treatment.

The blood and urine samples are taken before edaravone treatment, or at baseline, and at time points throughout the trial.

Alongside established biomarkers and EpiSwitch, the SOMAscan platform also will be applied. This platform measures 7,000 biomarker proteins from a drop of blood or urine.

Participants will undergo regular clinical assessments to understand how these biomarkers are related to treatment and disease outcomes.

As previously reported, 50 people had been enrolled as of April this year, and their levels of biomarkers were matched to those of 36 patients participating in the Answer ALS study. Answer is an ongoing research program that intends to build the most comprehensive clinical, genetic, and molecular assessment of ALS.

At baseline, biomarker and clinical data from 40 REFINE-ALS participants demonstrated that the proportion of patients with fast-progressing ALS, as predicted by EpiSwitch, was higher among those in REFINE-ALS than in Answer ALS.

“We are very interested in investigating the biological impact of Radicava on this complex disease by using cutting-edge, meaningful biomarkers,” said James Berry, MD, REFINE-ALS’ lead investigator and director of the Neurological Clinical Research Institute at MGH.

“Non-invasive EpiSwitch biomarkers could enable us to successfully predict slow vs. fast progressors at baseline and compare the positive impact of treatment between REFINE-ALS and ANSWER-ALS [patient groups],” Berry said, adding that “further confirmatory data will be analyzed in the coming future.”

EpiSwitch also is intended to provide clinically meaningful patient stratifications in other conditions, such as neurological diseases, cancer, and autoimmune disorders.