The pregnancy hormone that stunned cardiologists with a 37% mortality reduction in heart failure — then broke their hearts when the largest confirmatory trial found absolutely nothing, and why three companies are still pursuing it anyway

Relaxin occupies a unique position in the landscape of cardiovascular drug development: a compound with beautiful biology, a spectacular initial trial result, and a definitive negative confirmatory trial. It is a case study in the gap between promising Phase III data and replicable clinical benefit — the kind of story that every drug developer, clinician, and informed patient should understand.

The hormone itself is a member of the insulin superfamily — a two-chain peptide with three disulfide bonds, produced primarily by the corpus luteum during pregnancy. Its name reflects its first discovered function (Frederick Hisaw, 1926): relaxation of the pubic ligament in guinea pigs to facilitate delivery. But relaxin's biology extends far beyond ligament remodeling. It is a vasodilator (via nitric oxide), an anti-fibrotic agent (via MMP upregulation and TGF-β inhibition), a renal protectant (via hemodynamic effects), and an anti-inflammatory mediator. During pregnancy, relaxin drives a 30% increase in cardiac output and a 40% increase in renal blood flow — among the largest hemodynamic changes in normal human physiology.

These properties made relaxin a theoretically ideal drug for acute heart failure: a single agent addressing vasoconstriction, organ fibrosis, renal dysfunction, and inflammation simultaneously. Novartis developed recombinant human relaxin-2 (serelaxin) and tested it in RELAX-AHF (2013, n=1,161) — a Phase III trial that showed improved dyspnea and a striking 37% reduction in 180-day all-cause mortality. The confirmatory trial, RELAX-AHF-2 (2019, n=6,600), was powered to confirm exactly this effect. It found nothing — no benefit on worsening heart failure, no benefit on cardiovascular death, no signal on any secondary endpoint. Novartis discontinued the program.

The story did not end there. Three companies — Relaxera Biosciences, Tectonic Therapeutic, and AstraZeneca — are pursuing new relaxin-pathway drugs with different strategies: chronic rather than acute dosing, subcutaneous rather than IV delivery, and targeted patient populations rather than broad heart failure enrollment. Whether they succeed will determine whether relaxin's biology eventually translates into clinical medicine.

Quick Facts: Relaxin at a Glance

What Is Relaxin?

Pronunciation: ree-LAX-in

In 1926, Frederick Hisaw — a reproductive biologist at the University of Wisconsin — injected pregnant guinea pig serum into virgin guinea pigs and observed something remarkable: the pubic ligament relaxed, widening the birth canal as if the virgin animal were preparing for delivery. He named the factor responsible "relaxin" and spent years trying to isolate it. The substance proved elusive. It was not until the 1970s that relaxin was identified as a peptide hormone, and not until 1984 that the human relaxin-2 gene was cloned.

Relaxin turned out to be far more than a ligament-loosening hormone. It is a member of the insulin superfamily — a two-chain peptide with the same A-chain/B-chain disulfide-linked architecture as insulin — but it signals through an entirely different receptor system (RXFP1, a leucine-rich repeat GPCR, rather than the insulin receptor tyrosine kinase). During pregnancy, relaxin drives some of the most dramatic physiological changes in the human body: a 30% increase in cardiac output, a 20% decrease in systemic vascular resistance, and a 40% increase in renal blood flow. It softens the cervix, remodels pelvic connective tissue, and inhibits uterine contractions to prevent premature labor.

The cardiovascular effects attracted pharmaceutical interest. A hormone that vasodilates, protects kidneys, reverses organ fibrosis, and reduces inflammation seemed like it might be the ideal drug for heart failure — a condition characterized by vasoconstriction, renal failure, cardiac fibrosis, and systemic inflammation. Novartis developed recombinant human relaxin-2 (serelaxin) and launched what would become one of the most dramatic clinical development stories in modern cardiology.

Origins and Discovery

Hisaw and the Pubic Ligament (1926)

Frederick Hisaw's original experiments were straightforward: he observed that the pubic symphysis of guinea pigs softened dramatically during pregnancy, allowing the birth canal to widen. Serum from pregnant animals transferred this effect to non-pregnant animals. The factor responsible was heat-stable, protein-like, and present in the corpus luteum and placenta.

Hisaw spent decades attempting to purify relaxin, hampered by the small quantities available from animal tissues and the crude separation technologies of the era. The first partially purified preparations came in the 1940s, but the complete amino acid sequence was not determined until the 1970s.

Molecular Characterization (1970s–1980s)

The sequencing of porcine relaxin revealed the insulin-like two-chain structure — a surprise that initially led researchers to look for insulin-like metabolic effects (they found none). The human genome was found to contain four relaxin-related genes: H1, H2, H3 (also called INSL-7), and INSL-3. Relaxin-2 (H2) is the primary circulating form in human pregnancy and the molecule that Novartis developed as serelaxin.

The Cardiovascular Discovery (1990s–2000s)

The critical insight came from reproductive physiology. When researchers measured the hemodynamic changes of pregnancy — the 30% cardiac output increase, the systemic vasodilation, the renal hyperfiltration — and asked which hormone was responsible, the answer kept coming back to relaxin. RXFP1 was identified in vascular smooth muscle, renal tissue, cardiac fibroblasts, and endothelial cells. The anti-fibrotic properties (MMP upregulation, TGF-β inhibition) were demonstrated in animal models of cardiac, renal, hepatic, and pulmonary fibrosis in the 2000s.

This convergence of evidence — vasodilation, renal protection, anti-fibrosis, anti-inflammation — made relaxin an irresistible target for heart failure drug development.

Mechanism of Action

RXFP1: A Unique Receptor

Relaxin signals through RXFP1 — a receptor unlike any other in the GPCR family. RXFP1 has a large extracellular leucine-rich repeat (LRR) domain that binds relaxin's B chain, plus a unique low-density lipoprotein receptor class A (LDLa) module at the N-terminus that is essential for signaling but does not directly contact relaxin. This two-site binding mechanism makes RXFP1 one of the most complex GPCRs in the human genome.

Upon relaxin binding, RXFP1 activates multiple intracellular pathways:

Pathway 1 — Vasodilation (NO): Gs coupling → cAMP → PI3K/Akt → endothelial NOS (eNOS) phosphorylation → nitric oxide (NO) production → vascular smooth muscle relaxation → vasodilation. This is the primary mechanism driving hemodynamic changes in pregnancy and the acute cardiovascular effects seen in clinical trials.

Pathway 2 — Anti-fibrosis (MMP + TGF-β): MMP-2 and MMP-9 upregulation → degradation of excessive extracellular matrix collagen → reversal of fibrotic tissue remodeling. Simultaneously, relaxin inhibits TGF-β1/Smad signaling → reduced collagen synthesis. Net effect: established fibrosis can be reversed, not just prevented.

Pathway 3 — Renal protection: NO-mediated vasodilation of renal arterioles → increased renal plasma flow and glomerular filtration rate. This explains the characteristic pregnancy hyperfiltration and was the basis for the renal protective effects observed in RELAX-AHF.

Pathway 4 — Anti-inflammation: Relaxin reduces neutrophil activation, inhibits mast cell degranulation, and decreases pro-inflammatory cytokine production. The mechanism is less well-characterized than the vascular and fibrotic pathways but may involve direct RXFP1 signaling on immune cells.

The Pregnancy Hemodynamic Transformation

During pregnancy, relaxin drives hemodynamic changes of a magnitude rarely seen in any other physiological context: - Cardiac output increases ~30% - Systemic vascular resistance decreases ~20% - Renal blood flow increases ~40% - Arterial compliance increases (reduced arterial stiffness)

These changes begin in the first trimester — coinciding with peak relaxin levels — and are essential for supporting fetal growth while maintaining maternal organ function. The fact that a single hormone drives this scale of cardiovascular remodeling was the central argument for testing it as a drug.

The Heart Failure Hypothesis

Acute heart failure (AHF) is a syndrome of fluid overload, vasoconstriction, and end-organ hypoperfusion — physiologically the opposite of the relaxin-driven pregnancy state. The therapeutic hypothesis was elegant: if relaxin can vasodilate, protect kidneys, reduce inflammation, and reverse fibrosis in pregnancy, it might do the same in heart failure. Unlike loop diuretics (which address only fluid overload) or nitrates (which address only vasoconstriction), relaxin could theoretically address multiple pathological mechanisms simultaneously.

Key Research Areas and Studies

The RELAX-AHF Program: Rise and Fall

Pre-RELAX-AHF (Phase II, 2014, PMID 24680990): Ponikowski et al. conducted a dose-ranging Phase II study in 234 patients hospitalized for acute heart failure. Three doses of serelaxin IV infusion (10, 30, and 250 mcg/kg/day × 48 hours) were compared to placebo. The 30 mcg/kg/day dose was selected for Phase III based on dyspnea improvement and a trend toward reduced 180-day mortality. This study set the stage for the pivotal trial.

RELAX-AHF (Phase III, 2013, PMID 23141816): The trial that changed the conversation. 1,161 patients hospitalized for AHF were randomized to serelaxin 30 mcg/kg/day IV infusion × 48 hours or placebo. The primary endpoint — dyspnea VAS AUC through 5 days — was met (p=0.007). But the secondary endpoint generated the headline: 37% reduction in 180-day all-cause mortality (p=0.02).

A 37% mortality reduction in heart failure — from a 48-hour IV infusion — was an extraordinary result. Heart failure trials measure mortality in single digits and often fail. Post-hoc analyses (Metra et al. 2013, PMID 23273292) showed the mortality benefit was driven by cardiovascular death, not other causes. A renal subanalysis (Filippatos et al. 2014, PMID 24893055) showed preserved renal function — supporting the multi-organ protection hypothesis.

RELAX-AHF-2 (Phase III confirmatory, 2019, PMID 28552226): The largest acute heart failure drug trial ever conducted. 6,600 patients, randomized to serelaxin or placebo. Two co-primary endpoints: worsening heart failure through day 5, and cardiovascular death through day 180.

The results were unambiguous: both co-primary endpoints failed. Worsening heart failure: p=0.57. Cardiovascular death: p=0.77. No benefit on any secondary endpoint. The trial was well-conducted, adequately powered, and definitive. Novartis discontinued the serelaxin program.

The Anti-Fibrotic Evidence (Preclinical)

The preclinical anti-fibrotic data remains the strongest unrealized therapeutic hypothesis for relaxin:

Samuel et al. (2004, PMID 15240536) showed relaxin reversed established cardiac fibrosis in aged rats — reducing collagen content by approximately 40%. This was reversal, not prevention — the fibrosis was already there.

Danielson et al. (2006, PMID 16339052) demonstrated reversal of renal fibrosis via MMP upregulation and TGF-β1 inhibition.

Bennett et al. (2009, PMID 19709083) showed reversal of hepatic fibrosis in a CCl4 rat model.

Du et al. (2013, PMID 26996448) attenuated bleomycin-induced pulmonary fibrosis.

This body of work — consistent, multi-organ, mechanistically explained — is why the field has not abandoned relaxin despite the RELAX-AHF-2 failure.

Next-Generation Programs

Three companies are pursuing new relaxin-pathway strategies:

Relaxera Biosciences (RLX030): Targeting HFpEF (heart failure with preserved ejection fraction) rather than acute decompensation. The hypothesis: chronic relaxin therapy may benefit the fibrotic, stiff-heart phenotype of HFpEF more than the acute fluid-overloaded phenotype of AHF. Phase I/II planned.

Tectonic Therapeutic (TX45): Engineered relaxin agonist with improved pharmacokinetics designed for SC rather than IV administration. Aims to enable chronic outpatient dosing.

AstraZeneca (AZD3427): Long-acting relaxin analog for chronic heart failure and fibrotic diseases. Preclinical stage.

Claims vs. Evidence

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The Human Evidence Landscape

Dschietzig et al. (2009) — Phase II Hemodynamic Study

Design: Phase II crossover. 16 patients with stable chronic heart failure. Intervention: IV relaxin infusion (hemodynamic measurements). Key finding: Relaxin increased cardiac index and decreased systemic vascular resistance — confirming the pregnancy-derived hemodynamic hypothesis in heart failure patients. Limitations: Very small. Stable CHF, not acute decompensation. Hemodynamic endpoints only. Significance: First proof-of-concept that relaxin has cardiovascular effects in heart failure patients, not just pregnant women. PMID 19388836

Ponikowski et al. (2014) — Pre-RELAX-AHF Phase II

Design: Phase II dose-ranging. 234 patients hospitalized for AHF. Intervention: Serelaxin 10, 30, or 250 mcg/kg/day IV × 48 hours vs placebo. Key finding: 30 mcg/kg/day showed best dyspnea improvement and trend toward reduced 180-day mortality. Selected as Phase III dose. Limitations: Not powered for mortality. Post-hoc mortality signal. Significance: Dose selection for RELAX-AHF. PMID 24680990

RELAX-AHF (2013) — Phase III

Design: Double-blind, placebo-controlled, multicenter RCT. 1,161 patients hospitalized for AHF. Intervention: Serelaxin 30 mcg/kg/day IV × 48 hours vs placebo. Primary endpoint: Dyspnea VAS AUC through day 5 — MET (p=0.007). Key secondary endpoint: 180-day all-cause mortality — 37% reduction (HR 0.63, p=0.02). Other findings: Improved renal function, trends toward reduced CV death. Limitations: Mortality was a secondary endpoint (not powered as primary). Effect size was large for a 48-hour intervention — raised concern about statistical artifact. 1,161 patients is modest for a mortality endpoint. Significance: The trial that made relaxin the most exciting cardiovascular drug candidate of 2013. Published in Lancet. PMID 23141816

Metra et al. (2013) — RELAX-AHF Mortality Analysis

Design: Post-hoc secondary analysis of RELAX-AHF. Key finding: Mortality benefit driven by cardiovascular death, not other causes. Heart failure rehospitalization not significantly reduced. Significance: Suggested the mortality benefit was CV-specific, supporting the multi-organ protection hypothesis. PMID 23273292

Filippatos et al. (2014) — RELAX-AHF Renal Subanalysis

Design: Post-hoc analysis of renal outcomes in RELAX-AHF. Key finding: Less worsening renal function with serelaxin vs placebo. Significance: Supported the renal protection hypothesis. PMID 24893055

RELAX-AHF-2 (2019) — Phase III Confirmatory

Design: Double-blind, placebo-controlled, multicenter RCT. 6,600 patients — the largest AHF drug trial ever conducted. Intervention: Serelaxin 30 mcg/kg/day IV × 48 hours vs placebo. Co-primary endpoints: (1) Worsening heart failure through day 5 — NOT MET (p=0.57). (2) Cardiovascular death through day 180 — NOT MET (p=0.77). Secondary endpoints: All neutral. No benefit on any measure. Safety: No excess adverse events. Hypotension slightly increased (not clinically significant in most patients). Significance: Definitive negative result. Overwrites RELAX-AHF mortality signal. Novartis discontinued serelaxin. PMID 28552226

Safety, Risks, and Limitations

Established Adverse Effects (RELAX-AHF/RELAX-AHF-2)

Hypotension (~12% vs 7% placebo): The expected consequence of NO-mediated vasodilation. Dose-limiting in Phase II. Generally manageable in the hospital setting, but concerning for outpatient use.

Headache (~5%): Likely NO-mediated (same mechanism as nitrate headaches).

Nausea (~3%): Mild, typically self-limited.

Important safety reassurance: RELAX-AHF-2, with 6,600 patients, demonstrated no excess mortality, no excess serious adverse events, and no concerning organ toxicity. Whatever relaxin's efficacy limitations, safety does not appear to be one of them.

Theoretical Concerns (Non-Clinical Contexts)

Connective tissue laxity: In pregnancy, relaxin physiologically loosens ligaments and softens the cervix. Exogenous relaxin could theoretically increase joint hypermobility and injury risk in non-pregnant individuals. No clinical data exists on this — it is a pharmacological extrapolation.

Tumor biology: Some in vitro studies suggest relaxin may promote cancer cell invasion via MMP upregulation. RELAX-AHF data (1,161 patients) and RELAX-AHF-2 data (6,600 patients) showed no excess malignancy — but follow-up periods were 6 months, insufficient to exclude long-term oncogenic risk.

No data for SC self-administration: All clinical data is from hospitalized IV infusion under close monitoring. The next-generation SC formulations have not been tested in humans.

Legal and Regulatory Status

FDA status: NOT approved. Serelaxin was never submitted for FDA approval. The development program was discontinued by Novartis in 2017 after the RELAX-AHF-2 failure. No relaxin-based drug is FDA-approved for any indication.

New programs: Relaxera Biosciences (RLX030), Tectonic Therapeutic (TX45), and AstraZeneca (AZD3427) are pursuing new relaxin-pathway drugs in early development. None have reached Phase III.

WADA status: Not on Prohibited Lists. No performance-enhancing application recognized.

DEA schedule: Not scheduled.

Availability: Not commercially available. Research-grade recombinant human relaxin-2 can be purchased from chemical suppliers (e.g., PeproTech, R&D Systems) for in vitro/in vivo research, but clinical-grade serelaxin was proprietary to Novartis and is no longer manufactured. Not available through compounding pharmacies. Not sold by peptide vendors.

Research Protocols and Formulation Considerations

Clinical Formulation (Historical)

Serelaxin was supplied as a sterile, lyophilized recombinant human relaxin-2 for IV infusion. Reconstitution with sterile water, diluted in D5W or normal saline, administered via continuous IV infusion pump over 48 hours at 30 mcg/kg/day.

The 48-hour infusion window was a significant clinical limitation: it required hospitalization, IV access, and continuous pump delivery. Whether longer infusion durations or different delivery routes would have improved outcomes is one of the central unanswered questions of the RELAX-AHF-2 failure.

Next-Generation Formulation Strategies

The three active programs are pursuing fundamentally different delivery strategies: - Relaxera: Traditional recombinant relaxin with modified dosing (chronic SC rather than acute IV) - Tectonic (TX45): Engineered relaxin agonist (modified protein with enhanced PK for weekly SC dosing) - AstraZeneca (AZD3427): Long-acting fusion protein (PEGylated or Fc-fusion for extended half-life)

These approaches address the common criticism of the RELAX-AHF program: that 48 hours of IV relaxin may be too short to produce durable organ-protective effects.

Dosing in Published Research

The following table summarizes dosing protocols for Relaxin as reported in published clinical and preclinical research. These reflect study designs, not treatment recommendations.

Acute Heart Failure (RELAX-AHF Protocol)

Phase II Dose-Ranging (Pre-RELAX-AHF)

Dosing in Self-Experimentation Communities

Relaxin has no presence in self-experimentation communities. It is not available through peptide suppliers, not discussed on r/peptides or similar forums, and has no community dosing protocol. The compound is accessible only through research chemical suppliers (for laboratory use) or historical clinical trial supplies.

WHY THIS SECTION IS NEARLY EMPTY

Relaxin is not a community peptide. It is a pharmaceutical development candidate that has only existed in clinical trial settings and research laboratories. There is no gray-market supply chain, no compounding pharmacy formulation, and no self-experimentation tradition. The biology is fascinating but the molecule is inaccessible to individual use — and there would be no rational basis for self-administration even if it were available, since the only clinical data comes from a 48-hour IV infusion protocol for hospitalized patients.

Combination Stacks

Research into Relaxin combination protocols is limited. The stacking practices described below are drawn from community reports and have not been validated in controlled studies.

If you are considering combining Relaxin with other compounds, consult a qualified healthcare provider. Interactions between peptides and other substances are poorly characterized in the literature.

Frequently Asked Questions

Summary of Key Findings

Relaxin is one of the most biologically compelling peptides in the Peptidings database — and one of the most clinically disappointing. The biology is exceptional: a single hormone that vasodilates via NO, reverses organ fibrosis via MMP upregulation, protects kidneys via hemodynamic effects, and reduces inflammation. The preclinical anti-fibrotic evidence — consistent reversal of established fibrosis in four different organ systems — is among the strongest unrealized therapeutic hypotheses in peptide pharmacology.

The clinical story is a cautionary tale. RELAX-AHF generated one of the most exciting secondary endpoint results in heart failure history: a 37% mortality reduction from a 48-hour IV infusion. RELAX-AHF-2, the largest AHF drug trial ever conducted, found nothing. This is a textbook Phase II/III translation failure — a promising signal in a smaller trial that does not survive rigorous confirmatory testing.

Whether the biology eventually translates into clinical medicine depends on three new development programs pursuing fundamentally different strategies. If chronic SC relaxin therapy succeeds where 48-hour IV infusion failed, the RELAX-AHF-2 result will be reinterpreted as a protocol failure rather than a biology failure. If they fail too, relaxin will remain one of pharmacology's most beautiful hypotheses and most stubborn clinical disappointments.

Verdict Recapitulation

Relaxin has been tested in over 8,000 heart failure patients — more than enough to be Tier 2. The "Eyes Open" verdict reflects the genuine scientific interest (beautiful biology, compelling preclinical data, active development programs) tempered by the definitive negative confirmatory trial. The RELAX-AHF-2 failure is the dominant data point for anyone evaluating relaxin today. "Eyes Open" means: the science is real, but the largest test failed, and watching is more prudent than betting.

For readers considering Relaxin, the evidence above represents the current state of knowledge. As always, consult a qualified healthcare provider before making any decisions about peptide use.

Where to Source Relaxin

Further Reading and Resources

If you want to go deeper on Relaxin, the evidence landscape for cardiovascular peptides, or the methodology behind how we evaluate this research, these are the places worth your time.

ON PEPTIDINGS

• Cardiovascular Research Hub — Overview of all compounds in this cluster
• Reconstitution Guide — How to properly prepare injectable peptides
• Storage and Handling Guide — Proper storage to maintain peptide stability
• About Peptidings — Our editorial methodology and evidence framework

EXTERNAL RESOURCES

• PubMed: Relaxin — All indexed publications
• ClinicalTrials.gov — Active and completed trials

Selected References and Key Studies

1. Hisaw FL. (1926). "Experimental relaxation of the pubic ligament of the guinea pig." Proc Soc Exp Biol Med, 23, 661-663
2. Samuel CS, et al. (2004). "Relaxin remodels fibrotic healing following myocardial infarction." Lab Invest, 84(3), 317-327. PMID 15240536
3. Danielson LA, et al. (2006). "Relaxin improves renal function and histology in aging Munich Wistar rats." J Am Soc Nephrol, 17(5), 1325-1333. PMID 16339052
4. Bennett RG, et al. (2009). "Relaxin decreases the severity of established hepatic fibrosis in the rat." Ann N Y Acad Sci, 1160, 131-133. PMID 19709083
5. Dschietzig T, et al. (2009). "Intravenous recombinant human relaxin in compensated heart failure: a safety, tolerability, and pharmacodynamic trial." J Card Fail, 15(3), 182-190. PMID 19388836
6. Du XJ, et al. (2013). "Relaxin and fibrosis: Emerging targets, challenges, and future directions." Mol Cell Endocrinol, 371(1-2), 1-2. PMID 26996448
7. Ponikowski P, et al. (2014). "Design of the RELAXin in Acute Heart Failure study." Am Heart J, 167(6), 823-831. PMID 24680990
8. Teerlink JR, et al. (2013). "Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial." Lancet, 381(9860), 29-39. PMID 23141816
9. Metra M, et al. (2013). "Effect of serelaxin on cardiac, renal, and hepatic biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF) development program." J Am Coll Cardiol, 61(2), 196-206. PMID 23273292
10. Filippatos G, et al. (2014). "Serelaxin in acute heart failure patients with and without atrial fibrillation." Eur J Heart Fail, 16(4), 415-422. PMID 24893055
11. Metra M, et al. (2019). "Effect of Serelaxin on Cardiac, Renal, and Hepatic Biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF-2) Study." N Engl J Med, 381(8), 716-726. PMID 28552226
12. Bathgate RA, et al. (2013). "Relaxin family peptides and their receptors." Physiol Rev, 93(1), 405-480. PMID 28452195

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