Development of PAR2 Pepducins as a Novel NASH Treatment

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Non-alcoholic steatohepatitis (NASH) is characterized by fatty changes in the liver with inflammation and hepatocellular injury that in advanced stages leads to fibrosis, cirrhosis and high mortality rates. NASH is frequently associated with other common metabolic abnormalities, such as insulin resistance and visceral obesity. Liver transplantation is currently the only effective therapeutic approach for severe NASH or other forms of liver fibrosis with no approved drug treatments to date. Protease-activated receptor-2 (PAR2) is a signaling receptor that is highly abundant in liver stellate cells, hepatocytes and inflammatory cells which controls fibrotic, inflammatory and metabolic processes that lead towards severe NASH and liver cirrhosis. The cell-penetrating, lipidated PAR2 inhibitor OA-235i, was developed using our proprietary PepducinTM technology. PepducinTM technology offers a unique opportunity to target the intracellular surface of recalcitrant G-protein coupled receptors (GPCRs) such as PAR2 with exquisite specificity, potency and long half-lives, with prolonged drug exposure to the target tissue, namely liver. OA-235i is an advanced anti-fibrotic/anti- inflammatory drug candidate that blocks PAR2 signaling in hepatic stellate, inflammatory cells and hepatocytes. In the past 3 years, with Fast-Track support from the NIDDK, Oasis Pharmaceuticals successfully formulated and produced cGMP OA-235i at 97-98% purity and high stability. In in vivo efficacy studies, OA- 235i significantly reduced fatty liver steatosis/lobular inflammation/ballooning injury (NAS score) and ALT levels by 50% and gave complete suppression of AST in mouse models of diet-induced NASH to the same level of protection afforded by PAR2-deficiency. OA-235i afforded highly significant suppression of weight gain, liver weight, TGs, steatosis and development of liver tumor foci in a 6-month DEN-NASH model in mice fed a HFD. Delayed OA-235i treatment gave a significant 44-49% suppression of severe liver fibrosis induced by 8-weeks of CCl4 exposure. In 7-28 day repeat-dose safety/toxicology studies, OA-235i was safe and tolerated in dogs and in rat GLP studies with no evidence of liver, heart, kidney, lung, bone marrow, or other organ toxicity or any laboratory abnormalities at high multiples of the therapeutic dose. The translational studies in this Phase 2b application provide a rapid clinical validation and accelerate the commercialization of OA-235i for the treatment of NASH patients in collaboration with Duke Medical Center and Tufts Medical Center. Aim 1 will complete the IND Data Package for OA-235i in year 1 of funding with submission of the IND to the FDA as the first milestone. In years 2-3, Aim 2 will conduct a Phase I-single ascending dose (SAD) study in 17 normal healthy volunteers (NHV) and NASH patients followed by multi ascending 7-day repeat dose study (MAD) in 15 NHV/NASH subjects as the second major milestone. This First-in-Human study will establish the safe dose range, tolerability and PK/PD efficacy of OA-235i using ex vivo PAR2 assays and biomarkers and will inform the design and endpoints of Phase 2 studies to be conducted in the NASH population. 1