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LUMINARAHeart FailureCirculationOpen Access
Oral Relaxin Receptor Agonist AZD5462 in Chronic Heart Failure: The LUMINARA Trial
Oral Relaxin Receptor Agonist AZD5462 in Participants With Chronic Heart Failure: Primary Results From the LUMINARA Trial
View Full PaperWhy the trial?
Relaxin has appealing haemodynamic and anti-fibrotic properties, but intravenous serelaxin failed to improve outcomes and no oral agent had enabled chronic dosing. LUMINARA tested whether the once-daily oral relaxin agonist AZD5462 benefits patients with heart failure.
Does AZD5462 improve end-systolic volume index and systemic vascular resistance index in adults with chronic heart failure?
Population
375 adults with chronic HF: LVEF <=35% (cohort A, n=235) or 41-55% (cohort B, n=140)
Comparison
AZD5462 20, 80, or 360 mg once daily vs placebo (1:1:1:1)
Design
International multicenter double-blind placebo-controlled dose-ranging trial
Follow-up
24 weeks (primary endpoints assessed at week 25)
Key result
Oral AZD5462 20 mg yielded a placebo-adjusted end-systolic volume index change of -5.4 mL/m2 (95% CI, -10.9 to 0.1; P=0.054) in HFrEF, and reduced systemic vascular resistance in HFmrEF (P<0.05).
Authors
Discussion
Key questions
Member takes
Where experts stand
Experts see LUMINARA as encouraging early-phase evidence that oral relaxin receptor agonism can alter hemodynamics in chronic heart failure, but the primary remodeling endpoint narrowly missed significance, leaving the field waiting for a larger outcomes trial.
Most experts frame LUMINARA as a promising mechanistic signal rather than a practice-changing result. The vascular resistance findings in the higher-LVEF cohort drew more confidence than the remodeling data in the reduced-EF cohort, where the primary endpoint fell just short of statistical significance. The live question is whether a larger outcomes trial will confirm that chronic oral relaxin agonism translates into clinical benefit on top of modern guideline-directed therapy.
Agreement
Multiple clinicians agreed that AZD5462 was well tolerated and showed encouraging hemodynamic effects across a wide LVEF range, but that the primary remodeling endpoint in HFrEF narrowly missed significance, making an outcomes trial the necessary next step.
2 clinicians say this directly
2 takes classified by contention axis so far — the map appears as more land.
Still unclear
Whether the non-monotonic dose-response in the HFrEF cohort reflects a real pharmacologic pattern or noise from a small trial. Whether the cleaner vascular resistance signal in the higher-LVEF group will hold up in a powered outcomes study. What dose should be carried forward into a phase 3 trial.
Key expert perspectives
Ahmed BennisHeart Failure / Cardiomyopathy · Centre Hospitalier Universitaire Hassan IIEndpoint critiqueAug 30Vascular resistance signal is cleaner than the remodeling signal, and the dose-response is not monotonic
The vascular resistance data in HFmrEF looked stronger and cleaner than the remodeling data in HFrEF. In Cohort A the dose-response was not monotonic, with only the lowest dose trending toward benefit. He called it early mechanistic data worth watching in a larger outcomes trial.
C. Michael GibsonInterventional / Structural Cardiology · Beth Israel Deaconess Medical CenterResults readoutAug 30AZD5462 improved remodeling and hemodynamics despite high baseline guideline-directed therapy use
Highlighted that the oral RXFP1 agonist improved cardiac remodeling and hemodynamics versus placebo in HFrEF patients who were already on high rates of background guideline-directed medical therapy. Discussed the findings with the presenting investigator.
Andrew P. AmbrosyHeart Failure / Cardiomyopathy · Kaiser Permanente San Francisco Medical CenterContextAug 30Congratulated investigators and pointed to the accompanying editorial
Offered congratulations to the LUMINARA team and directed attention to the corresponding editorial published in Circulation.
Distilled from their postX post
Overview
Oral relaxin agonism shows early hemodynamic signals across HF phenotypes; larger outcome trials needed before practice consideration.
Key Points
- To evaluate the safety, tolerability, and hemodynamic effects of the oral relaxin family peptide receptor 1 agonist AZD5462 in individuals with chronic heart failure across varying ejection fraction levels.
- International, multicenter, double-blind, placebo-controlled dose-ranging trial (NCT06299826) conducted across 57 sites in 10 countries.
- Randomized 235 participants with LVEF ≤35% (cohort A) and 140 participants with LVEF 41% to 55% (cohort B) 1:1:1:1 to AZD5462 (20, 80, or 360 mg) or placebo once daily.
- Assessed primary endpoints of changes in end-systolic volume index for cohort A and systemic vascular resistance index for cohort B after at week 25 of treatment.
- In cohort A (LVEF ≤35%), treatment with AZD5462 20 mg showed a placebo-adjusted end-systolic volume index change from baseline of −5.4 mL/m² (95% CI, −10.9 to 0.1; P=0.054) at week 25.
- In cohort B (LVEF 41%–55%), AZD5462 treatment led to significant placebo-adjusted reductions in systemic vascular resistance index at week 25 across all dose groups (all P<0.05).
- Oral AZD5462 was well tolerated compared with placebo when added to baseline guideline-directed medical therapy.
Evidence details
What drove the result?
| Outcome | AZD5462 | Placebo |
|---|---|---|
| End-systolic volume index change, cohort A (20 mg dose) | ||
| Placebo-adjusted -5.4 mL/m2 (95% CI -10.9 to 0.1; P=0.054) · missed significance | ||
| Systemic vascular resistance index, cohort B | ||
| Significant placebo-adjusted reductions across all dose groups (all P<0.05) |
Limitations & tradeoffs
Safety
reported as well tolerated vs placebo; event counts not reported.
Design limitations
primary endpoints are hemodynamic surrogates, not clinical outcomes.
Statistical certainty
the cohort A remodeling endpoint missed statistical significance (P=0.054), and dose-ranging cohorts were small (235 and 140 patients split across four arms).
Representation
participants were predominantly male (88% in cohort A, 69% in cohort B).
Structured PICO
Does AZD5462 improve end-systolic volume index and systemic vascular resistance index in adults with chronic heart failure?
P
Population
375 adults with chronic heart failure and LVEF ≤35% or 41-55% randomized to once-daily oral AZD5462 or placebo for at week 25.
I
Intervention
AZD5462 (relaxin family peptide receptor 1 agonist) 20, 80, or 360 mg oral once daily for at week 25
C
Comparator
Placebo
O
Outcome
Changes in end-systolic volume index (cohort A) and systemic vascular resistance index (cohort B) after at week 25surrogate
Oral AZD5462 was well tolerated and demonstrated encouraging effects on cardiovascular hemodynamic measures in patients with chronic heart failure across a wide range of ejection fractions.
Main Result
Mean Difference: -5.4 (95% CI -10.9–0.1)
p-value: p=0.054
Coverage & sources
Journal, society, and media accounts. Useful signal, not independent expert judgment.
Cite This Study
Januzzi et al. (2026) conducted an RCT in Chronic heart failure (n=375). AZD5462 vs. Placebo was evaluated on Changes in end-systolic volume index (cohort A) and systemic vascular resistance index (cohort B) after at week 25 (MD -5.4, 95% CI -10.9 to 0.1, p=0.054). Oral AZD5462 20 mg yielded a placebo-adjusted end-systolic volume index change of -5.4 mL/m2 (95% CI, -10.9 to 0.1; P=0.054) in HFrEF, and reduced systemic vascular resistance in HFmrEF (P<0.05).