Volenrelaxin and the RELAXIN-LA Setback: Why Lilly's Long-Acting Relaxin Failed in HFpEF - and Where the RXFP1 Idea Goes Next (August 28, 2026)
Table of Contents
- A pregnancy hormone as a heart and kidney drug
- The half-life problem - and how volenrelaxin solves it
- Phase 1: the kidney-perfusion signal that launched the program
- RELAXIN-LA: a well-run HFpEF trial that went the wrong way
- Only the lowest dose helped - and the higher doses worsened congestion
- Why a vasodilating hormone can make HFpEF congestion worse
- Serelaxin, volenrelaxin, and the pattern in relaxin heart-failure trials
- Not a research chemical - and why that matters
- Where it fits on PepTracker
- Bottom line
A pregnancy hormone as a heart and kidney drug
Relaxin is one of the more intriguing hormones in human physiology. During pregnancy it widens blood vessels, increases the heart's output, boosts blood flow to the kidneys, and softens connective tissue - a coordinated set of effects that helps the body accommodate the demands of carrying a baby. For decades, cardiologists and nephrologists have wondered whether that same biology - vasodilation, anti-inflammation, anti-fibrosis, and improved kidney perfusion - could be borrowed to treat heart failure and chronic kidney disease, conditions defined in part by stiff vessels, inflammation, fibrosis, and failing organ blood flow. Volenrelaxin (development code LY3540378), an investigational once-weekly injectable from Eli Lilly, is the latest and most carefully engineered attempt to answer that question - and its story is a lesson in how a beautiful mechanism can still stumble in the clinic.
The half-life problem - and how volenrelaxin solves it
The central obstacle to using relaxin as a medicine has always been that it disappears fast. Native relaxin-2 clears from the bloodstream within hours, so sustaining its effects meant continuous delivery. The earlier recombinant human relaxin-2, serelaxin, had to be given as a multi-day intravenous infusion, and despite early promise it failed to improve outcomes in acute heart failure in the large RELAX-AHF-2 trial. Volenrelaxin is engineered to fix the delivery problem at its root. It fuses relaxin-2 to an albumin-binding VHH - a camelid single-domain antibody fragment - that grabs onto serum albumin, the most abundant protein in blood. Because albumin circulates for weeks, hitching a ride on it extends volenrelaxin's half-life to more than about 40 hours in animals while it remains a potent, selective agonist of the relaxin family peptide receptor 1 (RXFP1), with selectivity against the related receptors RXFP2, RXFP3 and RXFP4. The payoff: a single subcutaneous injection can sustain RXFP1 activation for a week, turning a fleeting hormone into a practical once-weekly drug.
Phase 1: the kidney-perfusion signal that launched the program
The early human data looked encouraging. In a randomized, placebo-controlled Phase 1 trial (published in Nephrology Dialysis Transplantation in 2024), volenrelaxin confirmed its extended half-life and, importantly, increased effective renal plasma flow (ERPF) - a direct measure of how much blood the kidneys receive - by roughly 50% acutely and 44% with repeated dosing versus placebo, with the improvement in kidney perfusion sustained across dosing. That is exactly the kind of physiology you would want in cardiorenal disease, and it gave Lilly a rationale to advance volenrelaxin into chronic kidney disease and heart failure. On paper, a long-acting relaxin that reliably opened up kidney blood flow looked like a genuinely novel tool.
RELAXIN-LA: a well-run HFpEF trial that went the wrong way
The pivotal test came in heart failure with preserved ejection fraction (HFpEF) - the form of heart failure in which the heart pumps normally but is stiff and cannot fill or relax well, and for which effective therapies remain limited. The Phase 2 RELAXIN-LA trial (funded by Eli Lilly and published in Nature Medicine in 2025) was a double-blind, international, multicenter study that randomized 332 patients with NYHA class II-IV HFpEF and a recent heart-failure decompensation to subcutaneous volenrelaxin at 25 mg, 50 mg, or 100 mg, or placebo, once weekly for 26 weeks. The primary endpoint was the change in left atrial (LA) reservoir strain - a sensitive echocardiographic gauge of how well the left atrium stretches and stores blood, which tends to fall as filling pressures rise. The hope was that relaxin's vasodilatory, congestion-relieving effects would improve LA function and kidney measures. Instead, the results split in an uncomfortable way.
Only the lowest dose helped - and the higher doses worsened congestion
For the primary endpoint, the 25 mg dose significantly improved LA reservoir strain versus placebo (+3.9%; 95% CI 1.1-6.6; p=0.006). But there was no significant effect at 50 mg or 100 mg - the opposite of the dose-response you would want to see. And the safety picture was worse than flat. Pooled across all doses, volenrelaxin significantly increased NT-proBNP - a biomarker of cardiac wall stress and congestion - by 24.5% (95% CI 2.0-51.8), with no significant improvement in kidney function (eGFR +2.2 ml/min/1.73 m2). Multiple independent measures pointed the same direction: higher estimated left atrial pressure, higher estimated plasma volume, and lower hematocrit and hemoglobin (hemodilution) - a coherent signature of worsening congestion. On the clinical side, volenrelaxin was associated with a non-significant but concerning increase in heart-failure hospitalization (hazard ratio 2.64; 95% CI 0.93-7.56; p=0.070) and signals for more cardiovascular and renal serious adverse events (odds ratio 2.52; 95% CI 0.95-6.68; p=0.056). Faced with evidence of harm, the sponsor stopped the trial early, before planned enrollment was complete.
Why a vasodilating hormone can make HFpEF congestion worse
It may seem paradoxical that a vasodilator that boosts kidney blood flow could worsen congestion. But HFpEF is a disorder of exquisitely delicate fluid balance, and potent vasoactive and volume effects can cut both ways. The hemodilution seen in RELAXIN-LA (falling hematocrit and hemoglobin) suggests fluid retention or plasma-volume expansion rather than the decongestion investigators had hoped for; rising NT-proBNP and estimated LA pressure point to more wall stress, not less. The low-dose LA-strain signal without a congruent benefit at higher doses, set against biomarkers and hospitalization trends moving the wrong way, led the authors to a blunt conclusion: despite some evidence of improved LA function at the lowest dose, this long-acting form of human relaxin was associated with worsening congestion in patients with recently decompensated HFpEF, and the data do not support further evaluation of volenrelaxin in that population.
Serelaxin, volenrelaxin, and the pattern in relaxin heart-failure trials
Volenrelaxin is not the first relaxin approach to disappoint in heart failure. Serelaxin, the infused recombinant relaxin-2, generated excitement with an early trial before RELAX-AHF-2 showed no outcome benefit in acute heart failure. Now a re-engineered, long-acting relaxin has failed - and possibly harmed - in worsening HFpEF. Taken together, these results temper the enthusiasm for simply extending relaxin exposure as a cardiac strategy, and they underscore that biomarker or imaging signals (like the 25 mg LA-strain result) are not the same as clinical benefit. The more durable interest in relaxin may lie in the kidney: volenrelaxin's clearest positive human data remain its Phase 1 renal-plasma-flow results, and the relaxin/RXFP1 axis continues to attract study in chronic kidney disease and chronic heart failure, where the fluid dynamics differ from an acutely decompensated HFpEF population.
Not a research chemical - and why that matters
It is worth stating plainly: volenrelaxin is an investigational, prescription-stage biologic studied only within clinical trials. It is not approved by the FDA, EMA, or any regulator, and it is not a supplement or a research chemical. Anything sold online as 'volenrelaxin,' 'LY3540378,' or 'long-acting relaxin' is unverified and should be treated as such - particularly for a drug whose own Phase 2 trial was halted for safety concerns in the exact population that might be tempted to seek it out. Heart-failure and kidney-disease treatment decisions belong with a qualified clinician working from approved therapies and, where appropriate, monitored trials.
Where it fits on PepTracker
Volenrelaxin joins PepTracker Pro's growing map of engineered peptide and biologic therapies for cardiovascular-kidney-metabolic disease, and it introduces a mechanism the encyclopedia had not yet covered: relaxin/RXFP1 agonism. It sits alongside other cardiorenal and vasoactive entries - the vasodilatory cardiac peptide apelin, the activin-signaling inhibitor sotatercept used in pulmonary arterial hypertension, the angiotensinogen-silencing hypertension siRNA zilebesiran, the anti-IL-6 residual-inflammation antibody ziltivekimab, and the vasoactive intestinal peptide VIP. It also stands as a companion case study to the year's other high-profile 'engagement without benefit' stories, from ziltivekimab's ZEUS miss to eplontersen's CARDIO-TTRansform result - each a reminder that moving a biomarker is not the same as helping patients.
Bottom line
Volenrelaxin is a smartly engineered, once-weekly long-acting relaxin that did exactly what its designers intended biochemically - sustained RXFP1 activation and improved kidney perfusion in Phase 1 - yet still failed where it counted. In the Phase 2 RELAXIN-LA trial, only the lowest 25 mg dose improved left atrial strain, while pooled dosing raised NT-proBNP, showed no kidney-function benefit, and was associated with worsening congestion and more heart-failure hospitalizations, prompting early termination. For worsening HFpEF, the verdict is clear and negative. For the broader relaxin/RXFP1 idea, the door is not fully shut - the kidney-perfusion data keep chronic kidney disease and chronic heart failure on the table - but volenrelaxin is, above all, a crisp reminder that in cardiorenal medicine an elegant mechanism and a promising early signal have to survive contact with a rigorous outcomes-minded trial, and this one did not. This article is educational and not medical advice.
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Citations
- [1] Borlaug BA, Testani JM, Petrie MC, et al. Effects of volenrelaxin in worsening heart failure with preserved ejection fraction: a phase 2 randomized trial - Nature Medicine (2025) Source
- [2] Volenrelaxin in worsening HFpEF: a phase 2 randomized trial - PubMed Source
- [3] Volenrelaxin (LY3540378) increases renal plasma flow: a randomized Phase 1 trial - Nephrology Dialysis Transplantation (2024) Source
- [4] Development of a long-acting relaxin analogue, LY3540378, for treatment of chronic heart failure - PubMed Source
- [5] RELAXIN-LA Trial: Volenrelaxin Linked to Worsening Congestion in HFpEF - Radcliffe Cardiology Source
- [6] Volenrelaxin - Wikipedia Source
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