An innovative, non-thiazolidinedione pan-PPAR agonist therapeutic for alcoholic hepatitis: IND-enabling safety and toxicological evaluation

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% of patients dying in the first six months after diagnosis. The high mortality rate of AH is largely due to lack of effective treatments for AH (e.g. corticosteroids) which do not increase patients’ survival and are linked to several secondary complications. Currently, the only effective cure for AH is early orthotopic liver transplantation which is not easily accessible, is extremely expensive, and requires life-long immunosuppression associated with long-term side effects. Pleiogenix proposes a unique 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. This unique agonism profile, especially the partially PPAR agonism of PPAR overcomes the side effects (e.g. edema, weight gain, fractures) associated with full PPAR and PPARδ activation. Proof-of-concept data from Phase I of this project has revealed that PLG888 significantly increased the survival of ethanol-treated mice (NIAAA model), when compared to the clinical standard of care. Additionally, PLG888 significantly decreased liver transaminases (ALT and AST), inflammatory cytokines (TGFβ and TNFα), fibrosis markers, biliary hyperplasia, lobular inflammation and steatosis, without affecting total body weight or heart weight. The goal of this SBIR Phase II project is to establish the GLP safety and toxicology profile of PLG888 in rats and dogs. This project will also conduct polymorph and salt screening of PLG888 and characterize new forms, exhibiting enhanced thermodynamic stability and patentability. The successful completion of this proposed SBIR Phase II study will provide virtually all IND-enabling safety data, and also complete the IND-enabling CMC work pertaining to the chemical synthesis of PLG888. The successful execution of this proposed SBIR Phase II project will enable Pleiogenix to pursue a a) Phase IIb SBIR award to perform 3-month GLP-toxicity studies (rats, dogs) and to b) file an IND for AH indication to initiate clinical development of PLG888 for AH.