Relaxin-receptor drug showed mixed Phase 2b signals in chronic heart failure

What happened

An oral drug designed to mimic signaling by the peptide hormone relaxin altered cardiovascular physiology in a randomized Phase 2b heart-failure trial, although the results differed between the study’s two patient cohorts.

Findings from LUMINARA were presented August 30 at the European Society of Cardiology Congress and published simultaneously in *Circulation*. The investigational drug, AZD5462, is a small molecule—not a peptide—but activates relaxin family peptide receptor 1, or RXFP1. Relaxin signaling can widen blood vessels and influence kidney function, making the pathway a longstanding but difficult target in heart failure.

In participants with mildly reduced or preserved left ventricular ejection fraction, all three AZD5462 doses produced statistically significant reductions in systemic vascular resistance, a measure of the resistance against which the heart pumps. In the reduced-ejection-fraction cohort, however, the most favorable ventricular-remodeling result occurred at the lowest dose and narrowly missed conventional statistical significance against placebo.

Two cohorts and two physiological endpoints

The AstraZeneca-funded trial enrolled 375 adults with stable chronic heart failure at 69 sites in 10 countries. Participants were receiving stable, maximally tolerated standard-of-care therapy and were randomly assigned, under double-blind conditions, to placebo or 20, 80 or 360 milligrams of AZD5462 once daily for 24 weeks.

Investigators divided participants by left ventricular ejection fraction, the proportion of blood pumped from the heart’s main chamber with each contraction. Cohort A included 235 people with an ejection fraction of 35% or less. Its primary endpoint was change in end-systolic volume index, which adjusts the blood remaining in the ventricle after contraction for body size and serves as a marker of cardiac remodeling.

Cohort B included 140 people with an ejection fraction from 41% through 55%. Its primary endpoint was change in systemic vascular resistance index, a measure of afterload.

Among participants in Cohort A, the 20-milligram dose produced the largest reported reduction in end-systolic volume index: 5.4 milliliters per square meter from baseline after 24 weeks. The comparison with placebo had a p-value of 0.054, just above the conventional 0.05 threshold. Secondary measures of cardiac function, including ejection fraction, also appeared most favorable at the lowest dose.

That non-monotonic dose pattern matters. A result concentrated at the lowest of three doses can reflect a genuine therapeutic window, but it can also arise from variability or multiple comparisons. The trial does not by itself resolve which explanation applies.

In Cohort B, systemic vascular resistance index fell by 19%, 21% and 15% with the 20-, 80- and 360-milligram doses, respectively. All three comparisons with placebo had reported p-values of 0.021 or lower. Those findings support biological activity at the intended pathway, but vascular resistance remains a physiological endpoint rather than direct evidence of improved survival or daily functioning.

Safety was encouraging but follow-up was limited

The investigators reported a low incidence of adverse events and no excess among AZD5462 recipients compared with placebo. Blood pressure fell mildly, but significant hypotension was not more frequent with the drug. Researchers also reported no evidence of clinically significant volume overload, a concern encountered with some earlier relaxin-pathway candidates.

A 375-person trial lasting 24 weeks cannot reliably characterize uncommon adverse effects or long-term safety. The available reports also do not establish whether treatment improves symptoms, exercise capacity, quality of life, hospitalization risk or mortality.

What the evidence means

LUMINARA provides controlled human evidence that an oral small molecule can engage a receptor normally activated by a peptide hormone and change relevant cardiovascular measurements on top of contemporary treatment. That is a meaningful development for a pathway previously pursued with injectable relaxin-based drugs.

It is not yet evidence that AZD5462 improves clinical outcomes. A larger trial would need prespecified patient-centered endpoints, longer follow-up and a dose strategy capable of confirming whether the low-dose ventricular signal is reproducible. Until then, the findings support continued development rather than clinical use.