Relaxin-2
Relaxin-2, and serelaxin as its recombinant form
Written by Aaron CuhaReviewed Sep 2026
Also known as: Serelaxin, H2 relaxin, Recombinant human relaxin-2, RLX030
The pregnancy hormone that opens the circulation. A 1,161 patient phase 3 trial reported 42 deaths against 65 on placebo at 180 days as an additional endpoint, and the 6,545 patient confirmatory trial found cardiovascular death of 8.7 percent against 8.9 percent, hazard ratio 0.98. Serelaxin was never approved and development for acute heart failure stopped.
Overview
Relaxin-2 is a two-chain peptide hormone of the insulin superfamily, made by the corpus luteum and the placenta, and it is the reason a pregnant woman's cardiac output rises and her blood vessels and kidneys relax. That physiology is not in question and it is a perfectly good reason to have wondered whether the same hormone could help a failing heart.
Serelaxin is recombinant human relaxin-2, and its story is the clearest example on this site of why a confirmatory trial exists.
RELAX-AHF, published in the Lancet in 2013, randomised 1,161 patients hospitalised with acute heart failure to a 48 hour infusion of serelaxin at 30 micrograms per kilogram per day or placebo. It hit one of its two primary dyspnoea endpoints, a visual analogue scale area under the curve improvement of 448 mm times hours (95 percent CI 120 to 775, p = 0.007), and missed the other, the Likert scale, at 27 percent against 26 percent (p = 0.70). It showed no effect on cardiovascular death or readmission at 60 days, hazard ratio 1.02. Then, among prespecified additional endpoints, there were 42 deaths at day 180 on serelaxin against 65 on placebo, hazard ratio 0.63 (95 percent CI 0.42 to 0.93, p = 0.019). A mortality signal in acute heart failure is rare enough that this result reshaped the field's expectations.
RELAX-AHF-2, published in the New England Journal of Medicine in 2019, was built to confirm it. Same drug, same dose, same 48 hour infusion, same entry criteria, 6,545 patients in the intention to treat analysis. Cardiovascular death at 180 days: 8.7 percent on serelaxin, 8.9 percent on placebo, hazard ratio 0.98 (0.83 to 1.15), p = 0.77. Worsening heart failure at day 5: 6.9 percent against 7.7 percent, hazard ratio 0.89 (0.75 to 1.07), p = 0.19. No difference in all-cause death, in rehospitalisation, or in length of stay.
A later adjudication of every death in RELAX-AHF-2 found no effect of serelaxin on any category of cause of death. Development for acute heart failure was discontinued. Serelaxin is not approved anywhere.
Mechanism of action
Relaxin-2 acts at RXFP1, a G protein-coupled receptor, and produces systemic vasodilation, increased cardiac output, increased renal blood flow and increased arterial compliance, largely through nitric oxide and cyclic AMP dependent pathways, together with anti-fibrotic signalling that has been the focus of most later work. It is a two-chain molecule held together by disulfide bonds, built like insulin, which is why it is hard and expensive to manufacture and why simplified single-chain analogues were designed. The clinical rationale in acute heart failure was that the haemodynamic profile of pregnancy, more flow at lower vascular resistance with preserved renal perfusion, is close to what you would want in a congested, hypertensive, mildly renally impaired patient. The rationale held up. The outcome did not.
Human evidence
Two phase 3 randomised trials in acute heart failure totalling almost 7,700 patients. The first was positive on one dyspnoea endpoint with an unexpected mortality signal; the second, four times larger, was negative on both primary endpoints.
- RELAX-AHF, 1,161 patients: dyspnoea visual analogue scale area under curve improved by 448 mm times hours (p = 0.007); the co-primary Likert endpoint missed (p = 0.70).
- RELAX-AHF additional endpoint: 42 deaths against 65 by day 180, hazard ratio 0.63 (0.42 to 0.93, p = 0.019). This was not a primary endpoint and was not the trial's design purpose.
- RELAX-AHF-2, 6,545 patients: cardiovascular death at 180 days 8.7 percent against 8.9 percent, hazard ratio 0.98, p = 0.77.
- RELAX-AHF-2: worsening heart failure at day 5, 6.9 percent against 7.7 percent, hazard ratio 0.89, p = 0.19. No difference in all-cause death, rehospitalisation or length of stay.
- Adjudicated cause-of-death analysis of RELAX-AHF-2 found no effect of serelaxin on any category of death.
- Both trials were funded by Novartis or its affiliate. Development for acute heart failure was discontinued.
What this does not tell you: There is no human evidence for relaxin-2 outside acute heart failure that resolves to a controlled trial here, and the acute heart failure question has been answered negatively at scale. The anti-fibrotic properties that attract interest in scarring, kidney disease and scleroderma are supported by animal and cell work, not by outcome trials. The long-acting fusion programme has completed a phase 2 study whose results are not summarised here, and a phase 1 renal perfusion study in the same programme was terminated early for recruitment reasons.
Reading the research record
This page exists to stop one specific misuse of the literature.
RELAX-AHF reported fewer deaths at 180 days on serelaxin, hazard ratio 0.63, p = 0.019. That number is real, it is published in the Lancet, and it is still quoted. It was a prespecified additional endpoint in a trial designed to measure breathlessness, in 1,161 patients, in a trial that showed no effect on its own 60 day cardiovascular death and readmission endpoint. That is exactly the kind of finding a confirmatory trial exists to test.
The confirmatory trial enrolled 6,545 patients and found nothing. Not a smaller effect. Hazard ratio 0.98 with a confidence interval sitting squarely across one. The investigators then adjudicated every death to look for any subgroup or mechanism that might explain the earlier signal, and found no effect on any category of cause of death.
Anyone citing the 2013 mortality result without the 2019 result is misleading you, whether or not they mean to. The honest one-line summary of relaxin-2 in heart failure is that it was tested properly, twice, and it did not work.
What remains alive is the fibrosis and vascular biology, where relaxin's effects are real in animals and where simplified analogues and long-acting fusions are still in development. Those are open questions. The acute heart failure question is closed.
The evidence, charted
Fig. 1 · evidence composition
3of 5 citations (60%) are in people
Counted from the citation list on this page. The Human count is the same number shown in the badge at the top. Both understate any literature larger than the sources we cite.
Fig. 2 · evidence over time
Evidence spans 5 distinct years, 2013 to 2025, counted from the citation list on this page.
Fig. 3 · legal status at a glance
US
Not approved
UK
Not approved
AU
Not approved
CA
Not approved
Not approved in any of the four jurisdictions shown. A jurisdiction's classification is a regulatory fact, not a verdict on the science; see Legal status below for the full text and any notes.
Fig. 4 · dose response
No human dose response curve exists
We draw this figure where the data supports it. For this compound in humans it does not, so the panel stays empty rather than borrowing an animal curve and implying it transfers.
Key studies & citations
- Human2013
Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial
1,161 patients hospitalised with acute heart failure randomised 1:1 to a 48 hour infusion of serelaxin at 30 micrograms per kilogram per day or placebo within 16 hours of presentation. Serelaxin improved the visual analogue scale dyspnoea endpoint by 448 mm times hours (95 percent CI 120 to 775, p = 0.007) but had no effect on the co-primary Likert endpoint (27 percent against 26 percent, p = 0.70). There was no effect on cardiovascular death or readmission at 60 days (hazard ratio 1.02, 0.74 to 1.41) or on days alive out of hospital. Among prespecified additional endpoints, 42 deaths occurred by day 180 on serelaxin against 65 on placebo, hazard ratio 0.63 (0.42 to 0.93, p = 0.019). Funded by Corthera, a Novartis affiliate company. Registered as NCT00520806.
The Lancet - Human2019
Effects of Serelaxin in Patients with Acute Heart Failure
RELAX-AHF-2, the confirmatory trial, and it failed. 6,545 patients in the intention to treat analysis, same drug, dose, 48 hour infusion and entry criteria as RELAX-AHF. Death from cardiovascular causes at 180 days occurred in 285 of 3,274 patients (8.7 percent) on serelaxin and 290 of 3,271 (8.9 percent) on placebo, hazard ratio 0.98 (0.83 to 1.15), p = 0.77. Worsening heart failure at day 5 occurred in 6.9 percent against 7.7 percent, hazard ratio 0.89 (0.75 to 1.07), p = 0.19. No significant difference in all-cause death at 180 days, in cardiovascular death or rehospitalisation, or in length of the index hospital stay. Adverse event rates were similar. Funded by Novartis. Registered as NCT01870778.
New England Journal of Medicine - Human2020
Cause of Death in Patients With Acute Heart Failure: Insights From RELAX-AHF-2
An adjudicated analysis of every death in RELAX-AHF-2, run specifically to understand why the two trials disagreed. By 180 days 11.5 percent of patients had died, 38 percent of those deaths from heart failure. Unlike in RELAX-AHF, there was no apparent effect of serelaxin on any category of cause of death. Patients aged 75 or over died more often (14.2 percent against 8.8 percent) and more often from non-cardiovascular causes. Patients with preserved ejection fraction had less heart failure mortality (30 percent against 40 percent) and more non-cardiovascular mortality (36 percent against 20 percent).
JACC: Heart Failure - Review2016
Serelaxin and acute heart failure
A review written in the window between the two phase 3 trials, which is exactly why it is worth reading. It records what the field believed about serelaxin on the strength of RELAX-AHF, before the confirmatory result arrived and removed it.
Heart - Animal2025
A novel long-acting relaxin-2 fusion, AZD3427, improves cardiac performance in non-human primates with cardiac dysfunction
The current direction of the field, and it is preclinical. A long-acting relaxin-2 fusion protein improved cardiac performance in non-human primates with induced cardiac dysfunction. Non-human primates are the closest animal model available and this is still an animal result. AZD3427 has since completed a phase 2 study of 260 participants with heart failure and pulmonary hypertension (NCT05737940, AstraZeneca, completed August 2025); a separate phase 1 renal perfusion study was terminated early after recruitment difficulties (NCT06611423).
Cardiovascular Research
Frequently asked questions
Does relaxin help heart failure?
No, on the evidence that exists. Serelaxin, recombinant human relaxin-2, was tested in 6,545 patients with acute heart failure in RELAX-AHF-2 and missed both primary endpoints: cardiovascular death at 180 days was 8.7 percent against 8.9 percent on placebo. Development was discontinued and it is not approved anywhere.
But I read that it reduced deaths. Was that wrong?
It was a real result in the earlier and much smaller RELAX-AHF trial, 42 deaths against 65 at 180 days, and it was an additional endpoint in a trial designed to measure breathlessness. The larger confirmatory trial did not reproduce it, and an adjudication of every death in that trial found no effect on any cause of death category. Both facts belong in any accurate description.
Is serelaxin approved anywhere?
No. It is not approved by the FDA, the MHRA, the TGA or Health Canada, and the acute heart failure programme ended after the confirmatory trial.
What about relaxin for fibrosis or scarring?
That is where the live science is, and it is preclinical. Relaxin has genuine anti-fibrotic activity in animal models, which is why simplified single-chain analogues such as B7-33 exist. None of that has been shown to help a person in a controlled trial.
Is anything still in development?
Yes. Long-acting relaxin-2 fusion proteins, most visibly AZD3427, which improved cardiac performance in non-human primates and has completed a 260 participant phase 2 study in heart failure with pulmonary hypertension. A separate phase 1 renal perfusion study in the same programme was terminated early because of recruitment difficulties. Nothing is approved.
Is relaxin what makes joints loose in pregnancy?
That association is widely repeated and this page does not verify it. What the trials here establish is the cardiovascular and renal side of relaxin physiology, which is what made it a heart failure candidate, and what the outcome trials found when it was given as a drug.