The protocol of EPI-589 early Phase 2 Investigator-initiated Clinical trial for ALS (EPIC-ALS): A multi-center, open-labeled, 24-week, single-group, exploratory trial to evaluate the efficacy, safety, and biomarker effects of EPI-589 in amyotrophic lateral sclerosis (Preprint)

Abstract

BACKGROUND Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, with its currently approved drugs, including riluzole and edaravone, showing limited therapeutic effects. Therefore, safe and effective drugs are urgently necessary. EPI-589 is an orally available, small molecule, novel redox-active agent characterized by highly potent protective effects against oxidative stress with high blood–brain barrier permeability. Given the apparent oxidative stress and mitochondrial dysfunction involvement in the pathogenesis of ALS, EPI-589 may hold promise as therapeutic. OBJECTIVE Here we describe the design and rationale for the EPI-589 early Phase 2 Investigator-initiated Clinical trial for ALS (EPIC-ALS). METHODS EPIC-ALS is an explorative, open-labeled, single-arm trial that evaluates the efficacy, safety, and biomarkers of EPI-589 in patients with ALS. This trial consists of 12-week run-in, 24-week treatment and 4-week follow-up periods. Patients will receive 500 mg of EPI-589 three times daily over the 24-week treatment period. Efficacy assessments include the mean monthly change of Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised total score. The biomarkers were selected to analyze the effect on oxidative stress and neuronal damage. The plasma biomarkers include 8-hydroxy-2’-deoxyguanosine, 3-nitrotyrosine, neurofilament light chain (NfL), phosphorylated neurofilament heavy chain (pNfH), homocysteine, and creatinine. The cerebrospinal fluid biomarkers include 8-hydroxy-2’-deoxyguanosine, 3-nitrotyrosine, NfL, pNfH, and ornithine. The magnetic resonance biomarkers include fractional anisotropy in the corticospinal tract and N-acetylaspartate in the primary motor area. RESULTS This trial began data collection in September 2021 and is expected to be completed in October 2023. CONCLUSIONS This study can provide data regarding the safety, efficacy, and biomarkers of EPI-589. These data will be useful to understand the characteristics of EPI-589. CLINICALTRIAL JRCT ID: jRCT2061210031; https://rctportal.niph.go.jp/en/detail?trial_id=jRCT2061210031