Volenrelaxin
Medium EvidenceAn investigational, once-weekly injectable long-acting analogue of the human hormone relaxin-2 from Eli Lilly, engineered as a selective agonist of the relaxin family peptide receptor 1 (RXFP1) and studied for chronic kidney disease and heart failure. Natural relaxin is a peptide hormone with vasodilatory, anti-inflammatory and anti-fibrotic effects, but it clears from the body within hours; volenrelaxin fuses relaxin-2 to an albumin-binding VHH (single-domain antibody) fragment that latches onto serum albumin to extend its half-life beyond ~40 hours in animals, allowing once-weekly subcutaneous dosing. In a randomized Phase 1 trial it increased effective renal plasma flow (a marker of kidney perfusion) by roughly 44-50% versus placebo, supporting development in chronic kidney disease and heart failure. However, in the Phase 2 RELAXIN-LA trial (n=332) in people with worsening heart failure with preserved ejection fraction (HFpEF), the program hit a wall: although the lowest 25 mg dose modestly improved the primary imaging endpoint (left atrial reservoir strain), the pooled higher doses were associated with WORSENING congestion - rising NT-proBNP, more estimated plasma volume, and a numerically higher rate of heart-failure hospitalizations - prompting the sponsor to stop the trial early, and the authors concluded the data do NOT support further evaluation of volenrelaxin in worsening HFpEF. Volenrelaxin is an investigational prescription-stage medicine studied only in clinical trials - it is not approved anywhere and is not a supplement or research chemical.
What It Is
Volenrelaxin (development code LY3540378) is Eli Lilly's investigational long-acting analogue of relaxin-2, a naturally occurring human peptide hormone best known for its role in pregnancy, where it relaxes blood vessels, increases cardiac output and boosts kidney blood flow. Relaxin signals mainly through the relaxin family peptide receptor 1 (RXFP1) and produces vasodilatory, anti-inflammatory and anti-fibrotic effects that made it an attractive candidate for cardiovascular and kidney disease - but native relaxin has a very short circulating half-life (hours), which limited earlier attempts such as serelaxin (recombinant human relaxin-2), an intravenous infusion that ultimately failed to improve outcomes in acute heart failure (the RELAX-AHF-2 trial). Volenrelaxin was designed to solve the half-life problem: it fuses relaxin-2 to an albumin-binding VHH (a camelid single-domain antibody fragment) that binds tightly to circulating serum albumin, extending the in vivo half-life to more than ~40 hours in rats and monkeys while remaining a potent, selective RXFP1 agonist (with selectivity against the related receptors RXFP2, RXFP3 and RXFP4). This engineering allows once-weekly subcutaneous dosing that sustains RXFP1 activation - a more practical delivery than an inpatient infusion. In a randomized Phase 1 study (published in Nephrology Dialysis Transplantation, 2024), volenrelaxin demonstrated an extended half-life and increased placebo-adjusted effective renal plasma flow (ERPF) from baseline by about 50% acutely and 44% with repeated dosing, with sustained improvement in kidney perfusion - results the developers said supported further study in chronic kidney disease (CKD) and chronic heart failure. The pivotal test in HFpEF, however, was disappointing. The Phase 2 RELAXIN-LA trial (funded by Eli Lilly; published in Nature Medicine, 2025) was a double-blind, international, multicenter study that randomized 332 patients with New York Heart Association (NYHA) class II-IV HFpEF and a recent heart-failure decompensation to subcutaneous volenrelaxin 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 measure of LA function - at 26 weeks. The 25 mg dose significantly improved LA reservoir strain versus placebo (+3.9%; 95% CI 1.1-6.6; p=0.006), but the 50 mg and 100 mg doses showed no significant effect. More concerning, pooled across all doses volenrelaxin significantly INCREASED NT-proBNP (a congestion/wall-stress biomarker) by 24.5% (95% CI 2.0-51.8) with no significant improvement in estimated glomerular filtration rate (eGFR, +2.2 ml/min/1.73 m2), and it was associated with a non-significant 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). Multiple independent measures - higher estimated LA pressure, higher estimated plasma volume, and lower hematocrit and hemoglobin (hemodilution) - pointed to worsening congestion, so the sponsor terminated the trial before planned enrollment was complete. The authors concluded that despite the low-dose signal on LA function, this long-acting relaxin worsened congestion in recently decompensated HFpEF and the data do not support further evaluation of volenrelaxin in that population. Volenrelaxin illustrates a recurring theme in cardiorenal drug development - a biologically compelling, well-engineered peptide hormone with promising early perfusion data can still fail (or even harm) in a rigorously run outcomes-oriented trial - and its relaxin/RXFP1 mechanism remains of interest in kidney disease even as the HFpEF path has closed. It is investigational, has no regulatory approval anywhere, and head-to-head or outcome benefits are unproven.
Regulatory Status
Not approved by the FDA, EMA or any regulator. Volenrelaxin is an investigational long-acting relaxin analogue (RXFP1 agonist) in clinical development by Eli Lilly. After a Phase 1 trial showed increased renal plasma flow, the Phase 2 RELAXIN-LA trial in worsening HFpEF (published in Nature Medicine, 2025) was terminated early because of worsening congestion, and the investigators concluded the data do not support further evaluation of volenrelaxin in that population. Available only within clinical trials.
Effective: 2025
View FDA SourceWhy Researchers Study It
Volenrelaxin is one of the most instructive recent tests of whether the pregnancy hormone relaxin - with its natural ability to widen blood vessels, calm inflammation, reduce fibrosis and boost kidney blood flow - can be turned into a durable cardiorenal medicine. Relaxin biology is genuinely appealing: during pregnancy the hormone increases cardiac output and renal plasma flow and softens connective tissue, exactly the kind of physiology that heart-failure and kidney-disease patients could benefit from. The problem has always been delivery - native relaxin lasts only hours, and the earlier recombinant relaxin serelaxin required continuous IV infusion and failed to improve outcomes in acute heart failure (RELAX-AHF-2). Volenrelaxin attacks that limitation by fusing relaxin-2 to an albumin-binding single-domain antibody so a single weekly injection sustains RXFP1 activation, and its Phase 1 renal-plasma-flow data (about +44-50%) revived hope that a practical, long-acting relaxin could help chronic kidney disease and heart failure. Researchers study it both for that promise and for its cautionary Phase 2 result: in RELAXIN-LA, a well-run HFpEF trial, higher doses paradoxically WORSENED congestion (rising NT-proBNP, hemodilution, more HF hospitalizations) and the study was stopped early - a reminder that a compelling mechanism and a good biomarker (LA strain at the lowest dose) do not guarantee clinical benefit, and that potent vasoactive/volume effects can cut both ways in the delicate fluid balance of HFpEF. Its trajectory helps define whether the relaxin/RXFP1 axis has a future in kidney disease even as the HFpEF door has closed, and it stands alongside other engineered long-acting peptide and antibody approaches to cardiovascular-kidney-metabolic disease.
Proposed Mechanisms
- RXFP1 agonism: volenrelaxin is a long-acting analogue of the human hormone relaxin-2 that binds and activates the relaxin family peptide receptor 1 (RXFP1), reproducing endogenous relaxin signaling while remaining selective against the related receptors RXFP2, RXFP3 and RXFP4.
- Vasodilation and increased renal perfusion: RXFP1 activation promotes vasodilation (partly via nitric oxide and endothelin pathways) that widens blood vessels and increases blood flow - in a Phase 1 trial volenrelaxin raised effective renal plasma flow by roughly 44-50% versus placebo, the basis for its interest in kidney disease.
- Anti-fibrotic and anti-inflammatory effects: relaxin signaling has been shown to reduce tissue fibrosis and inflammation in preclinical models, effects that motivated its study in organ diseases marked by fibrotic remodeling such as heart failure and chronic kidney disease.
- Albumin-binding half-life extension: volenrelaxin fuses relaxin-2 to an albumin-binding VHH (camelid single-domain antibody) fragment that binds tightly to circulating serum albumin, extending its in vivo half-life beyond ~40 hours in animals and enabling once-weekly subcutaneous dosing rather than the continuous IV infusion required by earlier recombinant relaxin (serelaxin).
- Potential congestion liability: in worsening HFpEF, higher volenrelaxin doses were paradoxically associated with WORSENING congestion - increased NT-proBNP, higher estimated left atrial pressure and plasma volume, and hemodilution (lower hematocrit/hemoglobin) - suggesting that sustained relaxin-driven hemodynamic and volume effects can be detrimental in fluid-overloaded patients, the finding that ended the RELAXIN-LA trial early.
Evidence Snapshot
| Study Type | Model | Outcome | Link |
|---|---|---|---|
| Phase 1 randomized, placebo-controlled trial (renal plasma flow) | Adults dosed with subcutaneous volenrelaxin (LY3540378) vs placebo, single and repeated dosing, with measurement of effective renal plasma flow (ERPF) and pharmacokinetics; published in Nephrology Dialysis Transplantation (2024). | Volenrelaxin demonstrated an extended half-life and increased placebo-adjusted ERPF from baseline by about 50% acutely and 44% with repeated dosing, with sustained improvement in kidney perfusion - supporting further development in chronic kidney disease and chronic heart failure. | Source |
| Phase 2 randomized, double-blind, placebo-controlled trial in worsening HFpEF (RELAXIN-LA) | 332 adults with NYHA class II-IV heart failure with preserved ejection fraction and a recent heart-failure decompensation, randomized to subcutaneous volenrelaxin 25 mg, 50 mg or 100 mg or placebo once weekly for 26 weeks; primary endpoint change in left atrial (LA) reservoir strain at 26 weeks; funded by Eli Lilly and published in Nature Medicine (2025). | Mixed/negative: the 25 mg dose significantly improved LA reservoir strain vs placebo (+3.9%; 95% CI 1.1-6.6; p=0.006) but 50 mg and 100 mg showed no significant effect; pooled dosing significantly raised NT-proBNP (+24.5%; 95% CI 2.0-51.8) with no eGFR benefit (+2.2 ml/min/1.73 m2). | Source |
| Phase 2 safety and congestion signals (RELAXIN-LA) | Safety and hemodynamic/volume analyses from the RELAXIN-LA HFpEF population at the three volenrelaxin doses vs placebo. | Volenrelaxin was associated with a non-significant increase in heart-failure hospitalization (HR 2.64; 95% CI 0.93-7.56; p=0.070) and more cardiovascular/renal serious adverse events (OR 2.52; 95% CI 0.95-6.68; p=0.056); higher estimated LA pressure and plasma volume and lower hematocrit/hemoglobin indicated worsening congestion, and the sponsor terminated the trial early. | Source |
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Safety & Cautions
- Volenrelaxin is an investigational medicine with no regulatory approval anywhere; it is not a supplement or research chemical, and any product sold as 'volenrelaxin', 'LY3540378' or 'long-acting relaxin' outside a regulated clinical trial is unverified and unsafe.
- Its lead Phase 2 trial (RELAXIN-LA) in worsening HFpEF was stopped early because higher doses were associated with WORSENING congestion - rising NT-proBNP, higher estimated plasma volume and left atrial pressure, hemodilution, and a numerically higher rate of heart-failure hospitalization - and the authors concluded the data do not support further evaluation in that population.
- Only the lowest 25 mg dose improved the primary imaging endpoint (left atrial reservoir strain); the higher 50 mg and 100 mg doses did not, and an imaging/biomarker signal is not the same as a proven clinical benefit.
- Relaxin is a potent vasoactive and volume-affecting hormone, so its effects can be harmful in fluid-overloaded or recently decompensated heart-failure patients; the earlier recombinant relaxin serelaxin also failed to improve outcomes in acute heart failure (RELAX-AHF-2).
- Its potential future is now mainly in chronic kidney disease and chronic heart failure research based on renal-plasma-flow data, not worsening HFpEF; long-term efficacy and safety in any indication are unproven.
- Decisions about heart failure or kidney disease treatment should be made with a qualified clinician; this information is educational and not medical advice.
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Citations
- [1] Effects of volenrelaxin in worsening heart failure with preserved ejection fraction: a phase 2 randomized trial (RELAXIN-LA) - Nature Medicine (2025) PubMed
- [2] Effects of volenrelaxin in worsening heart failure with preserved ejection fraction: a phase 2 randomized trial - PubMed PubMed
- [3] Volenrelaxin (LY3540378) increases renal plasma flow: a randomized Phase 1 trial - Nephrology Dialysis Transplantation (2024) PubMed
- [4] Development of a long-acting relaxin analogue, LY3540378, for treatment of chronic heart failure - PubMed PubMed
- [5] RELAXIN-LA Trial: Volenrelaxin Linked to Worsening Congestion in HFpEF - Radcliffe Cardiology PubMed
- [6] Volenrelaxin - Wikipedia PubMed
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