Development of D6PV- a novel ApoC-II peptide mimetic therapeutic

PROJECT SUMMARY The goal of the current study is to complete IND enabling studies to develop a therapeutic based on D6PV, a novel ApoC-II peptide mimetic, by conducting toxicology studies and manufacturing GMP drug substance and drug product for future Phase 1 trials in normal healthy volunteers. Successful completion of aims proposed here will result in the development of a novel peptide mimetic as an intravenous formulation with a rapid onset of action for the treatment of hospitalized patients with acute pancreatitis to rapidly reduce triglycerides to prevent or treat hypertriglyceridemia, and therefore will reduce the length of stay in the hospital and reduce or eliminate the morbidity and mortality. A safety assessment will be completed in IND enabling studies and a NOAEL (no adverse effect load) determined to support first-in-human dosing. This will enable Protean Bio to advance D6PV for Phase 1 clinical trials in normal healthy volunteers to evaluate the pharmacokinetics, safety and tolerability of D6PV after single and multiple ascending dosing regimens. Once completed and demonstrated to be safe in humans, D6PV is anticipated to progress to Phase 2 trials in hospitalized AP patients for proof- of-concept (i.e., efficacy) for reducing triglycerides in < 4 hours after administration as an intravenous dose. AP is one of the most common diagnosis for GI-related hospitalization with significant morbidity and at an annual cost of $2.6B. Severe Hypertriglyceridemia (SHTG) is a leading cause for AP and is known to occur in up to 38% of patients with plasma triglyceride (TG) levels of 3000-5000 mg/dL. Although there are several approved products (e.g., Vascepa®, Epanova®) and new modalities (nucleic acid drugs, antibodies) in Phase 2/3 trials for the treatment of SHTG, they have a delayed onset of action, rendering them unsuitable for rapidly lowering triglycerides in hospitalized AP patients. Therefore, there is a clear unmet need for rapidly addressing elevated TG in AP patients in an acute, hospitalized setting to reduce pain and progression of pancreatic necrosis, organ failure and mortality. Superior ex vivo results were confirmed in in vivo studies in mice models of HTG, demonstrating a ~80% reduction of plasma HTG in 3 hours post dosing and ~85% decrease in plasma ApoC-III; the latter due to displacement by D6PV and subsequent clearance. In this Direct to Phase II grant, we propose to complete engineering validation of the non-GMP manufacturing process, complete IND- enabling studies in rat and dog, and manufacture GMP drug substance and drug product.