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 a therapeutic agent. Objective This protocol aims to 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 safety and tolerability 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 3 times daily over the 24-week treatment period. Clinical assessments include the mean monthly change of Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised total score. The biomarkers are selected to analyze the effect on oxidative stress and neuronal damage. The plasma biomarkers are 8-hydroxy-2′-deoxyguanosine (8-OHdG), 3-nitrotyrosine (3-NT), neurofilament light chain (NfL), phosphorylated neurofilament heavy chain (pNfH), homocysteine, and creatinine. The cerebrospinal fluid biomarkers are 8-OHdG, 3-NT, NfL, pNfH, and ornithine. The magnetic resonance biomarkers are 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 useful data to understand the characteristics of EPI-589. Trial Registration Japan Primary Registries Network jRCT2061210031; tinyurl.com/2p84emu6 International Registered Report Identifier (IRRID) DERR1-10.2196/42032

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

ObjectiveAutosomal recessive spinocerebellar ataxia type 9 (SCAR9) has received attention due to its potential response to coenzyme Q10 (CoQ10) supplementation; however, the response has so far been limited and variable.MethodsWe report a SCAR9 patient with severe hypophosphatemia who responded well to CoQ10 and phosphate repletion.ResultsA 70-year-old man (the offspring of a consanguineous marriage) presented with cerebellar ataxia and intense fatigue after exercise. Whole-exome sequencing identified a novel homozygous deletion mutation (NM_020247.5:c.1218_1219del) inCOQ8A. We thus diagnosed him with SCAR9. Supplementation of CoQ10 alleviated his symptoms, with the Scale for the Assessment and Rating of Ataxia (SARA) dropping from 16 to 14. During the course of the disease, he demonstrated continuous hypophosphatemia caused by renal phosphate wasting. Gait dysfunction due to weakness and eye movement was partially alleviated, and SARA dropped from 17 to 13 after phosphate repletion.DiscussionPhosphate repletion should be considered for patients with severe hypophosphatemia without any apparent subjective symptoms. In this case, phosphate repletion could have improved myopathy leading to partial improvement in the patient's symptoms. Further analyses regarding the association between COQ8A mutation and phosphate wasting are required to elucidate the detailed pathogenesis.Classification of EvidenceThis provides Class IV evidence. This is a single observational study without controls.