AZD5462 Improves Cardiac Function in Phase 2b LUMINARA Trial

The oral relaxin agonist AZD5462 improved measures of cardiac function in patients with chronic heart failure, according to results from the phase IIb LUMINARA trial presented in a Hot Line session at the European Society of Cardiology (ESC) Congress 2026 in Munich, Germany, and published simultaneously in Circulation.¹

Relaxin, a pregnancy-associated peptide hormone with vasodilatory and end-organ protective properties, has long been of interest in heart failure, though earlier attempts to develop RXFP1 receptor agonists were limited by side effects linked to supraphysiological dosing.¹

The earlier relaxin therapeutic, serelaxin, an intravenous recombinant relaxin-2 formulation, illustrates this history. Serelaxin met its primary dyspnea end point in the phase 3 RELAX-AHF trial, but the follow-up RELAX-AHF-2 trial found no significant reduction in cardiovascular death or worsening heart failure compared with placebo.³ AZD5462, by contrast, is the first oral RXFP1 agonist to reach late-stage clinical testing.¹

James Januzzi, MD, presenter of LUMINARA and investigator at the Baim Institute for Clinical Research, Massachusetts General Hospital, Harvard Medical School, explained the rationale for revisiting this mechanism: "The pregnancy peptide hormone, relaxin, has been identified as having potentially advantageous properties in patients with heart failure," he said. "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."

LUMINARA Trial Design and Echocardiographic Results

This double-blind, dose-ranging phase 2b 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 therapy, including 235 patients with left ventricular ejection fraction (LVEF) 35% or lower and 140 patients with LVEF of 41% to 55%. Patients were randomly assigned in a 1:1:1:1 ratio to placebo or AZD5462 20 mg, 80 mg, or 360 mg once daily, and underwent echocardiography at baseline and after 24 weeks of treatment.¹

The primary endpoint in patients with LVEF ≤ 35% was change in end-systolic volume index (ESVi), a measure of adverse cardiac remodeling, from baseline to week 24; the primary endpoint in patients with LVEF of 41% to 55% was change in systemic vascular resistance index (SVRi), a measure of afterload, over the same period.¹

Among patients with LVEF ≤ 35%, AZD5462 had the most beneficial effect on cardiac function at the lowest dose, decreasing ESVi by 5.4 mL/m2 from baseline at 24 weeks (P = .054 vs placebo), with secondary end points, including change in LVEF, also greatest at the lowest dose.¹

In the cohort with LVEF of 41% to 55%, AZD5462 reduced SVRi by 19%, 21%, and 15% for the 20 mg, 80 mg, and 360 mg doses, respectively, at 24 weeks (all P ≤ .021).¹

AZD5462 Safety and the Relaxin Agonist Development History

The incidence of adverse events was low, with no evidence of excess adverse events among patients treated with AZD5462 compared with placebo.¹ Mild lowering of blood pressure was noted, but the incidence of significant hypotension did not differ between groups, and there was no evidence of significant volume overload, an issue previously seen with higher doses of relaxin-like drugs.¹

"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," Januzzi said. "Larger randomised trials with AZD5462 are now warranted, focused on outcomes."

References

1. European Society of Cardiology. Novel drug shows promise in an early phase trial in heart failure. Published August 30, 2026. Accessed August 30, 2026. https://www.escardio.org/news/press/press-releases/novel-drug-shows-promise-in-an-early-phase-trial-in-heart-failure/

2. Quintana-Hayashi MP, Connolly K, Millegård M, et al. Phase 2b trial of an oral relaxin family peptide receptor 1 agonist in patients with chronic heart failure: rationale and design. ESC Heart Fail. 2026. doi:10.1093/eschf/xvaf007

3. Metra M, Teerlink JR, Cotter G, et al. Effects of serelaxin in patients with acute heart failure. N Engl J Med. 2019;381(8):716-726. doi:10.1056/NEJMoa1801291