An innovative non-thiazolidinedione pan-PPAR agonist therapeutic for Alcoholic Hepatitis

PROJECT SUMMARY Alcoholic Hepatitis (AH) is a severe and acute form of alcohol-mediated liver disease, affecting ~34% of heavy alcohol drinkers, and presents a healthcare burden of ~$2.2 billion/yearly. AH sufferers have a short life expectancy, with about ~70% dying in the first six months after presentation. Re-hospitalization occurs in nearly 40% of the patients within 90 days of their first hospital discharge, further driving upward the costs associated with this deadly disease. As a weak alternative to expensive and unsustainable liver transplants, the first-line pharmaceutical intervention for AH is based on corticosteroids’ administration, in a vain attempt to reduce inflammation and liver fibrosis. Unfortunately, corticosteroids do not improve patients' survival and are linked to several secondary complications including infections, gastrointestinal bleeding, acute pancreatitis, and renal failure. Moreover, patients that develop an infection after corticosteroid treatment show a significantly higher mortality rate. For patients for whom steroids are contraindicated, the alternative treatment option is pentoxifylline, a phosphodiesterase inhibitor that is clinically ineffective in AH patients, as reported in the STOPAH-1 multi-center clinical trial. Pleiogenix is developing a unique oral (qd) therapeutic approach for AH based on the novel, orally-active, non-thiazolidinedione pan-PPAR agonist (PLG888), optimized to selectively modulate the activities of all three PPAR isoforms. PLG888’s unique structural design enables full agonism of PPAR along with partial agonism towards PPAR and PPAR overcoming side effects (e.g. edema, weight gain, fractures) associated with full PPAR and PPAR activation. Preliminary data obtained in non-alcoholic steatohepatitis mice, obese Rhesus monkeys, and multiple clinical trials in patients with type 2 diabetes (T2D) indicate that PLG888 1) reduces the activities of the key markers of liver damage, including alanine transaminase (ALT) and aspartate transaminase (AST), 2) reduces C-reactive protein, and 3) increases adiponectin (up to 200%), positively improving liver steatosis, fibrosis, and ballooning. The goal of this SBIR Phase I project is to assess the feasibility of using PLG888 as a novel oral (qd) treatment for AH. The following aims are proposed. In AIM 1, Pleiogenix will execute a dose-finding and prevention study in a validated mouse model of AH, generated through chronic and binge ethanol feeding; plus LPS administration to create a second hit, to increase liver damage. In AIM 2, the most efficacious dose identified in AIM 1 will be used to evaluate a larger cohort of mice to conduct a preclinical study to test the efficacy and safety of PLG888 in reducing the detrimental effects of ethanol. Cardiac toxicity, in particular, will be evaluated. In combination with previously executed toxicology and safety data derived from completed clinical trials in subjects with T2D, the successful conclusion of this SBIR Phase I study will validate the proposed pan-PPAR agonist, as a safe and effective intervention for the treatment of subjects with AH, paving the way to clinical trials to define dose-ranging in moderate and severe AH patients.