The Orally Available Ghrelin Receptor-Agonist AC01 Improves Systolic Function in HFrEF Mice and Nonhuman Primates

Heart failure with reduced ejection fraction (HFrEF) is characterized by impaired cardiac contractility. AC01, a small-molecule ghrelin receptor agonist, enhances contractility in cardiomyocytes. This study evaluated the in vivo hemodynamic effects of AC01 in a mouse HFrEF model and in cynomolgus monkeys. In HFrEF mice, intravenous AC01 significantly increased cardiac output, stroke volume, and ejection fraction versus vehicle, without any apparent detriment to diastolic function. Pressure-volume loop analysis demonstrated load-independent inotropic effects. In monkeys, oral AC01 increased cardiac output and stroke volume while reducing heart rate, without lowering central aortic pressure. These effects were sustained over 14 days of oral dosing. Additionally, AC01 improved autonomic balance by increasing parasympathetic and decreasing sympathetic activity. Overall, AC01 produced rapid, consistent, and sustained improvements in systolic function across species, supporting its potential as a novel, load-independent inotropic therapy for heart failure.