Oral relaxin agonist AZD5462 improves cardiac function in heart failure patients

The oral relaxin agonist, AZD5462, improved cardiac function in patients with chronic heart failure, according to results presented in a Hot Line session today at ESC Congress 2026 and published simultaneously in Circulation.

Despite several guideline-directed medical therapies for heart failure, many patients continue to experience considerable disease burden. Presenter of the LUMINARA trial, Professor James Januzzi from the Baim Institute for Clinical Research, Massachusetts General Hospital, Harvard Medical School, Boston, USA, explained that there is a need to develop novel therapies that can be used on top of existing therapies to improve patient outcomes.

The pregnancy peptide hormone, relaxin, has been identified as having potentially advantageous properties in patients with heart failure. Earlier attempts to develop drugs that stimulate the relaxin receptor RXFP1 were unsuccessful due, in part, to challenges from side effects possibly related to supra-physiological dosing. However, data from preclinical and early clinical studies with the first oral RXFP1 agonist, AZD5462, have been promising."

Professor James Januzzi, Baim Institute for Clinical Research, Massachusetts General Hospital, Harvard Medical School, Boston, USA

Professor Januzzi and colleagues conducted the LUMINARA trial to evaluate the effects of AZD5462 on safety and echocardiographic parameters in patients with chronic heart failure and to find the most appropriate dose for future trials.

This double-blind, dose-ranging phase IIb trial was conducted at 69 sites in 10 countries. Eligible patients had chronic heart failure and were already receiving stable maximally tolerated standard-of-care therapies. The study included 235 patients with heart failure and left ventricular ejection fraction (LVEF) ≤35% and 140 patients with heart failure and LVEF 41–55%. Patients were randomized (1:1:1:1) to placebo or AZD5462 20 mg, 80 mg or 360 mg once daily. Patients underwent echocardiography to evaluate cardiac function at the start and after 24 weeks of treatment. The primary endpoint in patients with LVEF ≤35% was change in end systolic volume index from baseline to week 24, a measure of adverse cardiac remodelling. The primary endpoint in patients with LVEF 41–55% was change in systemic vascular resistance index from baseline to week 24, a measure of the resistance the heart has to pump against.

The researchers found that among those with an LVEF ≤35%, AZD5462 had the most beneficial effects on cardiac function at the lowest dose, decreasing the end systolic volume index by 5.4 mL/m2 from baseline at 24 weeks (p=0.054 vs. placebo). Effects on secondary endpoints, including change in LVEF, were also greatest at the lowest dose.

In the LVEF 41–55% cohort, AZD5462 reduced systemic vascular resistance index by 19%, 21% and 15% for doses 20 mg, 80 mg and 360 mg, respectively, at 24 weeks (all p≤0.021).

The incidence of adverse events was low with no evidence for excess of adverse events among those treated with AZD5462. Mild lowering of blood pressure was noted, but the incidence of significant hypotension was no different in those treated with AZD5462 compared with placebo. In addition, there was no evidence for significant volume overload as seen previously with higher doses of relaxin-like drugs.

Concluding, Professor Januzzi said: "Target engagement was demonstrated in both cohorts, with signs of improved cardiac function at the lowest AZD5462 dose when given on top of standard-care therapies. Larger randomized trials with AZD5462 are now warranted, focused on outcomes."