PROJECT SUMMARY / ABSTRACT Metabolic reprogramming plays a critical role in immune cell activation, differentiation, and function in response to severe sepsis. Broad defects in leukocyte bioenergetics underlie the immunometabolic paralysis in sepsis. Dichloroacetate (DCA) is an investigational drug and the prototypic inhibitor of pyruvate dehydrogenase kinase (PDK) that inhibits the mitochondrial pyruvate dehydrogenase complex (PDC) by reversible phosphorylation. PDC catalyzes the rate-limiting step in aerobic glucose oxidation in mitochondria. Our Central Hypothesis is that DCA represents a novel, mechanism-based therapy that targets the underlying mitochondrial bioenergetic failure responsible for sepsis. Accordingly, to evaluate DCA’s safety and therapeutic potential more rigorously in septic shock, Medosome Biotec, in collaboration with the University of Florida, Wake Forest University, and Northwestern University, will evaluate various DCA intravenous dosages for the treatment of sepsis in pigs as a large animal model of sepsis. The Specific Aims (SA) of this STTR Phase I/Phase II Fast-track grant proposal focus on conducting pharmacokinetic, safety and efficacy experiments and establishing Chemistry, Manufacturing and Controls (CMC) information. Following a Pre-IND meeting with the Center for Drug Evaluation and Research (CDER), we will complete all IND-enabling studies (GLP, toxicity studies, etc.) required for the IND application and, upon approval, apply to initiate future clinical trials evaluating DCA as a treatment for sepsis.

PROJECT NARRATIVE Sepsis is the leading cause of death and readmissions in US hospitals. Currently the overall level of unmet need is high as there is a near absence of licensed sepsis-specific products. This may be in part because of the complexity of sepsis and lack of a clear target; furthermore the involvement of multiple organs poses a major hindrance. Recently, our understanding of the underlying mechanisms of severe sepsis has broadened, with the appreciation of how pathological perturbations in intermediary metabolism and bioenergetics of innate and adaptive immune cells and organs drive their fate and function and, hence, the host’s response to sepsis. Such metabolic reprogramming provides the impetus for emerging strategies, whereby targeting metabolism can affect the response of both immune cells and vital organ systems Our ultimate goal is to develop the investigational drug dichloroacetate (DCA) as a novel, mechanism-based intravenous therapy for human severe sepsis. DCA represents the first mechanism-based metabolic therapy for severe sepsis.