A phase 2 open-label study of epeleuton in patients with sickle cell disease

Abstract Background and Significance Sickle cell disease (SCD) is a rare inherited blood disorder caused by a single point mutation in the beta globin gene, leading to the production of sickle hemoglobin (HbS). HbS polymerizes when deoxygenated, resulting in dense dehydrated red blood cells (RBCs), membrane damage and the characteristic sickle shaped RBCs that are rigid and rapidly destroyed. This ultimately leads to a cascade of events which include hemolysis, inflammation, and vaso-occlusion, causing high morbidity and mortality. Despite years of intensive drug development, and the approval of gene therapy, there continues to be a need for new disease-modifying therapeutic options for SCD. Epeleuton is 15-hydroxy eicosapentaenoic acid (15(S)-HEPE) ethyl ester, a synthetic derivative of 15-HEPE, an endogenous w-3 fatty acid metabolite. Epeleuton improves the sickle RBC membrane, addressing a key driver of hemolysis and multicellular adhesion leading to vaso-occulsion. In preclinical studies in Townes humanized SCD mice, and in vitro studies with SCD RBCs, epeleuton acts as a disease-modifying therapy by simultaneously decreasing (a) red blood cell membrane defects and sickling, (b) systemic and local inflammatory activation, (c) endothelial adhesion and (d) organ damage. Objective To evaluate the pharmacodynamics, efficacy and safety of orally administered epeleuton in patients with SCD. Study Design and Methods This phase 2, open-label, multicenter study (NCT05861453) will enroll approximately 35 adult patients with a confirmed diagnosis of SCD (HbSS, HbSß0 thalassemia, HbSß+ thalassemia and HbSC) at 20 sites in the United States and Canada. Participants must have had 2-15 vaso-occlusive crises (VOCs) in the past 12 months hemoglobin of 5.0-10.5g/dL at screening, and a high adhesion index at screening defined as RBC laminin adhesion > 400 cells/mm2 in a microfluidic device. Concomitant treatment with a stable dose of hydroxyurea, crizanlizumab or l-glutamine is permitted during the study. Key exclusion criteria include receiving an RBC transfusion within three months of enrolment and prior hematopoietic stem cell transplant. Enrolled patients will receive epeleuton 2g BID (4g daily) for 16 weeks. The trial has a 28-day screening period, followed by a 16-week treatment phase and a 30-day post-treatment follow-up period. Study participants will attend the clinic on 6 occasions at screening, baseline, weeks 4, 8 and 16 (end-of-treatment) and the week 20 post-treatment follow-up visit. To date, 27 subjects have been enrolled. Study endpoints include change in annualized rates of VOC leading to a healthcare visit, changes in measures of RBC health and function including point of sickling, dense RBCs (%) and RBC deformability, and changes in measures of cellular adhesion. Conclusion: A therapy that can simultaneously impact multiple hallmark features of SCD including RBC morphology and function as well as cellular adhesion may have an important disease-modifying utility for patients with SCD. The results of this study are anticipated to confirm the potential of epeleuton to impact rates of VOC, multiple aspects of SCD pathophysiology, and to guide the design and conduct of a phase 2/3 study in patients with SCD