AstraZeneca’s oral relaxin agonist improved cardiac function in patients with chronic heart failure in a Phase IIb trial.
In data from the LUMINERA trial (NCT06299826) presented at the European Society of Cardiology (ESC 2026) meeting, which took place in Munich, Germany from 28 to 31 August, three doses of AZD5462 were pitted against placebo in 235 patients with heart failure and left ventricular ejection fraction (LVEF) ≤35% and 140 patients with heart failure and LVEF 41–55% who were already receiving stable, maximally tolerated standard-of-care (SoC) therapies.
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In patients 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.
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 20mg, 80 mg and 360mg, respectively, at 24 weeks.
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.
Adverse events (AEs) were low in all patients, with mild lowering of blood pressure noted, but the incidence of significant hypotension was no different in those treated with AZD5462 compared with placebo.
Relaxin is a pregnancy hormone produced by the placenta to relax joints and prepare the body for childbirth.
AZD5462 is an oral, small-molecule selective agonist of the relaxin family peptide receptor 1 (RXFP1).
Despite several guideline-directed medical therapies for heart failure, many patients continue to experience considerable disease burden.
Trial investigator, Professor James Januzzi from the Baim Institute for Clinical Research, Massachusetts General Hospital, Harvard Medical School, Boston, said that, as a result, there is a need to develop novel therapies to be used in combination.
Januzzi said: “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”
The relaxin pathway has faced its challenges in previous studies, with investigators noting there was no evidence for significant volume overload as seen previously with higher doses of relaxin-like drugs.
Both Eli Lilly and AstraZeneca dropped development of their respective relaxin receptor-targeting drugs, volenrelaxin and AZD3427.
According to GlobalData analysis, Eli Lilly’s Jardiance (empagliflozin), Lexicon Pharmaceuticals and Viatris’ Inpefa (sotagliflozin), and Novartis’ Entresto (sacubitril/valsartan) will continue to fuel growth in the heart failure market, which is due to grow from $13.5bn in 2022 to $33.9bn in 2032 across the seven major markets (7MM: United States, France, Germany, Italy, Spain, United Kingdom and Japan).
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