Abstract 16840: A Novel Long-Acting CRF2 Receptor Agonist COR-1167 Improves Cardiac and Renal Function on Top of Furosemide in a Sheep Model of Pacing Induced Heart Failure

Abstract

Urocortin-2 (UCN-2), a member of the corticotrophin releasing factor family, has cardiovascular protective effects mediated via activation of CRF2 receptors. Exploratory studies in ovine heart failure (HF) and in HF patients demonstrated that acute intravenous (IV) infusion of UCN-2 (1-4hrs), on top of standard of care, temporarily improved cardiac function. However, the short t 1/2 of recombinant UCN-2 (~15 min) limits its therapeutic utility. A stable CRF2 peptide agonist was developed, named COR-1167, that is potent and selective for CRF2 versus CRF1 receptors and it was tested chronically in vivo. Adult female sheep were anesthetized, and instrumented with 7F His bundle electrodes, arterial, venous and Swan-Ganz catheters, pressure transducers, and flow probes. After recovery, HF was induced by rapid cardiac pacing that was maintained during the study. COR-1167 (5 μg/kg/day SC) in combination with furosemide (0.35 mg/kg/day IV) versus furosemide alone was administered for 5 days and cardiorenal parameters were constantly monitored in conscious sheep. Furosemide had no effect on cardiac function while it increased urine Na + , when compared to pre-treatment measurements. Compared to furosemide, COR-1167 plus furosemide significantly enhanced cardiac and renal function parameters (Table). Mean + SEM for Days 1-5 (CV, biomarker and renal parameters), F (n=5-7), F + COR-1167 (n=6-7), Repeated Measures ANOVA; *BW Day 0 minus Day 5 = BW change, Unpaired t test. COR-1167 cardiorenal benefits occurred within 2 hours of the first dose and were sustained, without changing SBP. It increased natriuresis and decreased net fluid balance (water intake minus urine volume) and BW (reflecting a reduction in congestion). In conclusion, chronic CRF2 receptor activation by COR-1167 significantly improved both cardiac and renal function on top of furosemide in ovine HF and potentially is a unique therapy for HF patients.