Exploratory Phase 2 clinical trial of EPI-589 for ALS is ongoing

Also called (R)-troloxamide quinone, EPI-589 is designed to reduce oxidative stress

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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A small Phase 2 clinical trial is evaluating the safety and tolerability of investigational treatment candidate EPI-589 in adults with amyotrophic lateral sclerosis (ALS).

The EPIC-ALS trial (jRCT2061210031), being conducted in Japan, will also assess exploratory effectiveness outcomes after six months of treatment. Data collection began in September 2021 and is expected to finish in October.

The trial’s design was recently described in, “An Exploratory Trial of EPI-589 in Amyotrophic Lateral Sclerosis (EPIC-ALS): Protocol for a Multicenter, Open-Labeled, 24-Week, Single-Group Study,” which was published in JMIR Research Protocols

EPI-589, also called (R)-troloxamide quinone, is a brain-penetrant small molecule given orally that’s designed to reduce oxidative stress, a type of cellular death implicated in the progression of ALS and other neurodegenerative diseases.

Oxidative stress is marked by an imbalance between toxic reactive oxygen species and the antioxidant defense systems needed to fight them.

The treatment works to boost or speed up processes involved in controlling oxidative stress and enhance energy metabolism in cells’ mitochondria, the cellular energy production centers that become dysfunctional in ALS.

It was originally developed by BioElectron Technology Corporation (previously Edison Pharmaceuticals) for inflammatory neurodegenerative diseases, including ALS and Parkinson’s disease. Under an agreement with BioElectron, Sumitomo Pharma holds the licensing rights for EPI-589 in Japan and North America and is providing the EPI-589 to be used in the trial. BioElectron was acquired by PTC Therapeutics in 2019.

In ALS cell models, EPI-589 was more potent than edaravone — sold as Radicava, an approved ALS treatment with an antioxidant mechanism — at protecting against oxidative stress and mitochondrial dysfunction.

Additional preclinical studies showed dose dependent effects of EPI-589 on slowing motor deterioration in an ALS mouse model, where it also reduced biomarkers of oxidative stress and nerve cell damage.

A Phase 1 study found EPI-589 at doses up to 1,500 mg per day to be well tolerated in healthy adults, prompting the launch of a Phase 2 trial (NCT02460679), which evaluated its safety in 19 adults with ALS.

The results showed EPI-589 at a dose of 500 mg twice per day was safe and well tolerated.

Signs of clinical effectivenesss were also observed, including a reduction in disease-associated biomarkers in the blood and the cerebrospinal fluid (CSF), which surrounds the brain and spinal cord.

Results also suggested EPI-589 may slow disease progression, as assessed with the ALS Functional Rating Scale-Revised (ALSFRS-R), and lead to improvements in grip strength and swallowing.

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Clinical trial to test EPI-589’s safety, tolerability

The ongoing exploratory Phase 2 trial seeks to evaluate EPI-589’s safety and tolerability at a dose of 500 mg three times a day among 10 adults with ALS. Participants are being recruited from three centers in Japan.

Eligible participants, ages 18-79, have had an onset of ALS within 1.5 years of screening. Patients on Rilutek (riluzone) must be on a stable dose and regimen for at least a month before enrolling. Using other medications that may also have an antioxidant mechanism, such as Radicava, is not permitted.

The trial will last 40 weeks — a 12 week run-in period, 24 weeks (six months) of treatment, and a four week follow-up. The run-in period is designed to assess each patient’s baseline clinical status before treatment.

During the treatment phase, patients will take 500 mg EPI-589 — two 250 mg oral tablets — three times a day at least an hour before eating.

The trial’s main goal is safety, which will be evaluated with side effects, lab tests, vital signs, heart tests, and monitoring for suicidality.

Disease progression will be monitored by a change in ALSFRS-R scores as well as time to death, tracheostomy, or use of whole-day ventilation support. Additional physical findings will include tests of lung function, muscle strength, functional ability, and health-related quality of life.

Blood and CSF biomarkers, including markers of oxidative stress and nerve cell damage will also be assessed, as will MRI disease markers.

“As the primary objective of this trial is to evaluate safety and tolerability, placebo-controlled trials will be needed to confirm the efficacy,” the researchers wrote. “This pilot trial will provide insights into the variability of efficacy endpoints and the feasibility of the next large randomized controlled trial.”