The first oral relaxin receptor RXFP1 agonist for heart failure treatment: Translational studies from non-human primates to humans

Heart failure with reduced ejection fraction (HFrEF) remains a major clinical challenge, with considerable morbidity and mortality. Existing hemodynamic drug therapies often cause side effects like hypotension and reflex tachycardia, which can hinder optimal dosing. Relaxin, a pregnancy hormone, stimulates RXFP1 receptors in the kidneys, reducing systemic vascular resistance while increasing renal blood flow and renin release to maintain blood pressure. Prior clinical studies using injectable short- or long-acting relaxin analogues have not delivered sustained benefits. AZD5462, a novel oral small-molecule RXFP1 agonist designed for chronic use, was evaluated in translational studies involving non-human primates (NHPs) with HFrEF and in phase 1 trials in healthy humans. RXFP1 expression was confirmed in the renal glomeruli of both species. In NHPs with HFrEF, long-term administration of AZD5462 resulted in a ∼40% reduction in end-systolic volume and a 20% increase in left ventricular EF (LVEF) after 84 weeks, without significant effects on blood pressure or heart rate. In the phase 1 study, AZD5462 was generally well tolerated and showed a similar pharmacokinetic profile, with compatible renin discharge responses. These findings support AZD5462 as a promising novel therapy for chronic heart failure. A phase 2 study of AZD5462 is currently underway in patients with chronic heart failure.