Development of a novel renalase agonist for the treatment of acute pancreatitis

Abstract Acute pancreatitis (AP) is one of the leading gastrointestinal diseases leading to hospital admissions worldwide, and of importance, there are no effective and approved drugs for AP. The condition's morbidity is significant and closely linked to the severity of the disease. Early severe complications of AP involve intense pain, persistent organ failure, and infections. The mortality rate for those with severe disease during hospitalization is about 20%. There is a pressing need for novel treatments for AP that can mitigate its severity, reduce pain, shorten hospital stays, and decrease both morbidity and mortality. Current therapies for AP are supportive rather than disease-specific, with a generic approach to pain management frequently involving opiates. A treatment that could reduce the severity of AP and control the undesired inflammation while simultaneously alleviating pain would make a substantial clinical impact, fulfill a significant unmet medical need, and reduce healthcare costs. Renalase (RNLS) is a novel plasma flavoprotein produced in the kidneys and other tissues with pro-survival and anti-inflammatory effects. Yale has designed and developed a sensitive ELISA assay that detects plasma RNLS and have shown levels significantly decline in animal models and patients with AP. In preclinical studies, effective treatment of AP is achieved by administering RNLS or a chemically synthesized peptide (BP-1002) that Bessor designed and developed with RNLS-like activity. BP-1002 significantly decreases AP injury and pain in rodent models in moderate and severe disease. The analgesic action is novel and non-opiate. An initial 4-day toxicology and toxicokinetic study in rats was completed with data indicating a promising margin of safety. Funds from this grant, along with those of private investors, will be used to complete all IND-enabling studies. These efforts include manufacturing of GMP BP-1002, confirmation of biological activity in vitro and in vivo, development of further phase appropriate analytical assays, formulation and stability studies, single and multi-dose toxicology and pharmacokinetics studies in rats and dogs, cardiovascular safety studies in dogs, identification of potential metabolites, and other necessary regulatory studies for an IND. The effects of BP- 1002 on inflammatory biomarkers will also be evaluated. With the completion of these studies, an IND will be filed.