Project Grant R43AA029931

A NOVEL THERAPY FOR ACUTE ALCOHOLIC HEPATITIS - EACH YEAR APPROXIMATELY 5 MILLION PEOPLE IN THE US DEVELOP ACUTE ALCOHOLIC HEPATITIS (AH), A SYNDROME OF PROGRESSIVE INFLAMMATORY LIVER INJURY. IN MOST PATIENTS WITH AH, THE ILLNESS IS MILD. HOWEVER, IN PATIENTS WITH SEVERE ACUTE AH, RISK OF EARLY DEATH IS HIGH AND INTENSIVE MANAGEMENT IS REQUIRED WITH MINIMAL PHARMACOLOGICAL AGENTS AVAILABLE. SEAL ROCK THERAPEUTICS IS DEVELOPING SRT-015, A POTENT AND SELECTIVE INHIBITOR OF THE ACTIVATED ASK1 KINASE TO ADDRESS THIS UNMET NEED. ASK1 IS PRESENT IN ALL CELLS AND ACTIVATED IN RESPONSE TO STRESS FACTORS INCLUDING REACTIVE OXYGEN SPECIES (ROS), CYTOKINES AND LPS. SRT-015 DEMONSTRATES DIRECT ANTI-INFLAMMATORY, ANTI-FIBROTIC AND ANTI-APOPTOTIC ACTIVITY IN VITRO ON STIMULATED HUMAN IMMUNE CELLS, FIBROBLASTS AND HEPATOCYTES, RESPECTIVELY. SRT-015 TREATMENT WAS ALSO PROVEN EFFICACIOUS IN VIVO USING ACUTE AND CHRONIC LIVER DISEASE MOUSE MODELS AND DEMONSTRATED SAFE IN GLP TOXICOLOGY STUDIES. IN A PHASE 1 CLINICAL TRIAL SRT-015 WAS WELL TOLERATED WITH NO DOSE-LIMITING TOXICITIES. SRT-015 IS A POSSIBLE THERAPEUTIC FOR MULTIPLE LIVER DISEASES INCLUDING AH. IN THIS SBIR R43, WE WILL CONDUCT IND-ENABLING EFFICACY STUDIES OF SRT-015 FOR TREATMENT OF SEVERE AH. THESE STUDIES ARE DESIGNED TO DETERMINE THE MINIMAL EFFICACIOUS EXPOSURE, DEFINE CLINICALLY RELEVANT BIOMARKERS, AND CHARACTERIZE CHANGES IN THE MICROBIOTA AND INTESTINAL PERMEABILITY AFTER SRT-015 TREATMENT IN AN AH ANIMAL MODEL AIM 1: ESTIMATE OF MINIMAL EFFICACIOUS EXPOSURE OF SRT-015 AND EFFICACY BIOMARKERS IN A CHRONIC ETHANOL PLUS BINGE THERAPEUTIC AH ANIMAL MODEL. WE WILL BE USING THE MOUSE CHRONIC LIEBER-DECARLI ETHANOL LIQUID DIET (8 WEEKS) PLUS BINGE ETHANOL MODEL THAT BEST REFLECTS HUMAN AH DISEASE. THE MINIMUM EFFICACIOUS DOSE WILL BE IDENTIFIED USING THREE DOSE LEVELS OF SRT-015 TREATMENT ADMINISTERED DURING THE FINAL FOUR WEEKS OF CHRONIC ETHANOL FEEDING AND BIOMARKERS FOR FIBROSIS, INFLAMMATION AND HEPATOXICITY EVALUATED. AIM 2: EVALUATION OF INTESTINAL PERMEABILITY, BACTERIAL TRANSLOCATION AND INTESTINAL DYSBIOSIS AFTER SRT-015 TREATMENT IN A THERAPEUTIC AH ANIMAL MODEL. TO COMPLEMENT AND EXTEND THE EFFICACY DATA, A FULL CHARACTERIZATION OF SRT-015 EFFECTS ON INTESTINAL INFLAMMATION AND GUT BARRIER FUNCTION WILL BE CONDUCTED. DEMONSTRATING PRECLINICAL EFFICACY OF SRT-015 IN A CHRONIC PLUS BINGE THERAPEUTIC AH MODEL WILL BE CRITICAL TO CONDUCT CLINICAL TRIALS IN AH PATIENTS. ONCE APPROVED, SRT-015 IS ANTICIPATED TO GREATLY IMPROVE THE LIVES OF PATIENTS WITH SEVERE AH.