reviewed april 2026|next review october 2026|88 physicians psi has verified|7 published studies
Relaxin-2 (Serelaxin)
Relaxin-2 is a 6-kDa naturally occurring (the body's own) heterodimeric peptide hormone structurally related to insulin, with recombinant serelaxin having completed one of the most dramatic Phase II-to-Phase III clinical trial stories in cardiology before Novartis discontinued development in 2020.
Evidence landscape: 7 published studies
Published studies span cardiovascular pharmacology, pregnancy physiology, and fibrosis biology. Extensive Phase III human data exists.
- 1 Human
- 5 Animal
- 1 Reviews
Not FDA-approved. Serelaxin (recombinant human relaxin-2) completed Phase III trials for acute heart failure. RELAX-AHF-2 (n=6,600) did not meet its primary endpoint for cardiovascular death reduction. Novartis discontinued development in 2020.
Not available as a therapeutic product. Clinical development was discontinued. Relaxin-2 is a naturally occurring (the body's own) pregnancy hormone.
Relaxin-2 acts through the RXFP1 receptor producing vasodilation, anti-fibrotic effects, and anti-inflammatory activity. The Phase II RELAX-AHF trial showed a 37% reduction in 180-day cardiovascular mortality. The larger confirmatory Phase III trial failed to replicate this result.
PSI Assessment
Few clinical trial stories in cardiology are as dramatic as serelaxin. The Phase II RELAX-AHF trial showed a statistically significant 37% reduction in 180-day cardiovascular mortality in acute heart failure patients. The larger Phase III trial, RELAX-AHF-2, enrolled 6,600 patients and failed to confirm the benefit. Novartis discontinued development in 2020. The cardiovascular biology remains compelling: relaxin-2 produces vasodilation, reduces fibrosis, and improves renal blood flow through a mechanism entirely independent of standard heart failure drugs. Whether the Phase II result was a true signal or a statistical artifact remains one of the open questions in cardiology.
Phase II showed 37% mortality reduction. Phase III with 6,600 patients failed to confirm. The biology is compelling. The clinical program did not succeed.
The mechanism operates through the RXFP1 receptor (relaxin family peptide receptor 1), a leucine-rich repeat G-protein-coupled receptor. Activation triggers multiple signaling cascades: cAMP, nitric oxide/cGMP, and PI3K/Akt pathways. This produces systemic and renal vasodilation, reduces vascular stiffness, inhibits fibrosis via matrix metalloproteinase upregulation, and suppresses inflammatory cytokines. During pregnancy, these effects help the cardiovascular system adapt to increased blood volume.
What the evidence supports
Relaxin-2 is a potent vasodilator and anti-fibrotic hormone with an established role in pregnancy physiology. The Phase II RELAX-AHF trial showed a statistically significant 37% reduction in 180-day cardiovascular mortality in acute heart failure. Serelaxin was well tolerated across both Phase II and Phase III trials with hypotension as the dose-limiting effect.
What is not yet established
Clinical efficacy for acute heart failure after the Phase III RELAX-AHF-2 trial (n=6,600) failed to confirm the mortality benefit. Whether the Phase II result was a true signal or a statistical artifact remains genuinely uncertain. Future therapeutic development path after Novartis discontinued the serelaxin program in 2020.
Research Evidence
The findings below cover the RELAX-AHF trial program, the anti-fibrotic biology, and the pregnancy physiology that anchors the cardiovascular hypothesis.
Evidence by condition
Evidence dimensions across cardiovascular, anti-fibrotic, and pregnancy research. The acute heart failure application has the deepest evidence with Phase III trial completion.
| Condition | Mechanism | Animal evidence | Human evidence | Replication |
|---|---|---|---|---|
| Acute Heart Failure | ||||
| Pregnancy Physiology | ||||
| Anti-Fibrotic Biology | ||||
| Vascular Biology |
The Phase II RELAX-AHF trial demonstrated that serelaxin infusion in acute heart failure patients produced significant dyspnea relief and a 37% reduction in 180-day cardiovascular mortality compared to placebo.
This mortality signal was unexpected and generated significant excitement in the heart failure community. The result led to the larger confirmatory Phase III trial.
RELAX-AHF-2, the confirmatory Phase III trial enrolling 6,600 acute heart failure patients, did not meet its co-primary endpoints of cardiovascular death at day 180 or worsening heart failure at day 5.
The failure of the larger trial to confirm the Phase II mortality benefit led Novartis to discontinue clinical development. Whether the Phase II result was a true signal or statistical artifact is debated.
Relaxin-2 produces vasodilation, anti-fibrotic effects, and improved renal blood flow through RXFP1 receptor activation, with the biology validated across pregnancy physiology, cardiovascular, renal, and hepatic models.
The underlying biology is not disputed. The cardiovascular effects are real and reproducible. The clinical question is whether these biological effects translate to mortality benefit in acute heart failure.
1 Human|5 Animal|1 Reviews
View all 7 indexed studiesHow Relaxin-2 (Serelaxin) Works
Relaxin-2 is a naturally occurring (the body's own) 6-kDa heterodimeric peptide hormone. It activates the RXFP1 receptor, triggering cAMP, nitric oxide/cGMP, and PI3K/Akt signaling cascades that produce vasodilation, fibrosis reduction, and anti-inflammatory effects.
Tells blood vessels to relax and connective tissue to become more flexible. During pregnancy, this helps the body adapt to increased blood volume. In heart failure, it reduces the stiffness and scarring that makes a failing heart work harder.
For a more detailed view of the biology, here is what researchers have observed at the molecular level.
Binds RXFP1 receptor, activating cAMP, NO/cGMP, and PI3K/Akt pathways. Produces vasodilation via endothelin-1 suppression and NO production. Anti-fibrotic effects via TGF-beta inhibition and MMP activation. Increases renal blood flow and natriuresis.
What is Relaxin-2 (Serelaxin) being studied for?
Researchers are studying Relaxin-2 (Serelaxin) across several health conditions. Each condition below is labeled with the strength of evidence that exists for that specific use, not for Relaxin-2 (Serelaxin) overall. This means a compound can have human studies for one condition but only animal data for another.
Acute Heart Failure
·Human TrialsPhase II RELAX-AHF showed 37% reduction in 180-day cardiovascular mortality. Phase III RELAX-AHF-2 (n=6,600) failed to confirm this benefit. Serelaxin was well tolerated with hypotension as the dose-limiting effect.
Limitations: The Phase III failure is definitive for the specific clinical program. Whether the Phase II mortality benefit was a true signal or statistical artifact remains debated. Development was discontinued.
Pregnancy Physiology
·Human TrialsRelaxin-2 has an established role in pregnancy: cervical softening, ligament relaxation, and cardiovascular adaptation to increased blood volume. This is well-characterized endocrine biology.
Limitations: The pregnancy role is physiological context rather than a therapeutic application. No therapeutic development targets pregnancy-specific uses.
Anti-Fibrotic Biology
·Animal StudiesRelaxin-2 reduces cardiac, renal, and hepatic fibrosis in animal models (animal research) through matrix metalloproteinase upregulation and TGF-beta inhibition.
Limitations: Anti-fibrotic effects are demonstrated in animal models only. No clinical program targets fibrosis specifically. The serelaxin program focused on acute heart failure rather than chronic fibrotic disease.
Vascular Biology
·Animal StudiesPotent vasodilator acting through RXFP1-mediated nitric oxide production and endothelin-1 suppression. Reduces vascular stiffness in animal models (animal research).
Limitations: Vasodilation was confirmed in human trials but did not translate to the primary mortality endpoint. Hypotension was the dose-limiting effect.
Safety and Regulatory Status
FDA Status: Not FDA-approved. Clinical development discontinued after Phase III failure. Serelaxin was well tolerated in trials with hypotension as the primary safety concern.
Availability: Not available as a therapeutic product. Novartis discontinued development in 2020. Relaxin-2 is a naturally occurring (the body's own) pregnancy hormone.
Class context: The serelaxin program failed on efficacy, not safety. The drug was well tolerated in a 6,600-patient Phase III trial. Simplified relaxin analogs (like B7-33) remain under investigation by other research groups.
Serelaxin was well tolerated in large clinical trials. The program was discontinued due to efficacy failure, not safety concerns. Hypotension was the dose-limiting adverse effect.
Peptide Structure
Technical molecular data for researchers and clinicians.
Questions and Comparisons
Questions the evidence raises for a Relaxin-2 (Serelaxin) discussion.
Comparison and Related Research
Relaxin-2 is compared with other cardiovascular peptides and anti-fibrotic compounds.
Related compounds
Frequently Asked Questions
References
Each citation links to the original study on PubMed, the U.S. National Library of Medicine database.
- 1.Phase III trial evaluating intravenous serelaxin (recombinant relaxin-2) in 1,161 patients hospitalized for acute heart failure. Serelaxin improved dyspnea over the first 5 days compared to placebo and showed a reduction in 180-day cardiovascular death, establishing the clinical potential of relaxin-2 in cardiac emergencies.Teerlink JR et al., 2009 in Lancet. View on PubMed
- 2.Larger Phase III trial of serelaxin in 6,545 acute heart failure patients, designed to confirm the mortality benefit seen in RELAX-AHF. The primary endpoint of 180-day cardiovascular death was not met, although serelaxin was well tolerated. This trial demonstrated the challenge of translating early positive signals into confirmed survival benefits.Metra M et al., 2017 in Lancet. View on PubMed
- 3.Comprehensive review of the anti-fibrotic properties of relaxin-2 across multiple organ systems. The evidence showed that relaxin-2 reduces collagen deposition and tissue fibrosis in models of cardiac, pulmonary, renal, and hepatic fibrosis, mediated through its receptor RXFP1 and downstream signaling pathways.Samuel CS et al., 2011 in Br J Pharmacol. View on PubMed
- 4.Systematic review of relaxin-family peptide receptor biology and cardiovascular effects. Relaxin-2 acts through RXFP1 to promote vasodilation, reduce vascular stiffness, and inhibit fibrosis. The review established the biological rationale for therapeutic development in heart failure and vascular disease.Du XJ et al., 2010 in Pharmacol Rev. View on PubMed
Medical Disclaimer
This content is for educational and informational purposes only and does not constitute medical advice. The information presented reflects published research as indexed by PSI and should not be used to make treatment decisions. Always consult a qualified healthcare provider before starting, stopping, or modifying any treatment.