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. 2025 Aug 31.
doi: 10.1038/s41591-025-03939-6. Online ahead of print.

Effects of volenrelaxin in worsening heart failure with preserved ejection fraction: a phase 2 randomized trial

Barry A Borlaug #  1 , Jeffrey M Testani #  2 , Mark C Petrie  3 , Zhenzhong Wang  4 , Jonathan Cunningham  5 , Kirkwood F Adams Jr  6 , Offer Amir  7 , Jan Bělohlávek  8   9 , Edimar Bocchi  10 , Aguinaldo Freitas Jr  11 , Miguel Hominal  12 , Toshiaki Kadokami  13 , Bela Merkely  14 , Christopher A Miller  15   16 , Julio Nuñez  17   18 , Subodh Verma  19   20 , Mehmet Birhan Yilmaz  21 , Ena Oru  4 , Flora Sam  4
Affiliations

Effects of volenrelaxin in worsening heart failure with preserved ejection fraction: a phase 2 randomized trial

Barry A Borlaug et al. Nat Med. .

Abstract

Relaxin is a peptide hormone that may decrease circulatory congestion and improve kidney function. In this study, we conducted a double-blind, international, multicenter trial to test whether volenrelaxin, a long-acting form of human relaxin, can improve left atrial (LA) function, reduce congestion and improve kidney function in patients with heart failure and preserved ejection fraction (HFpEF). We randomly assigned patients with New York Heart Association (NYHA) class II-IV HFpEF and recent heart failure (HF) decompensation to 25-mg, 50-mg or 100-mg volenrelaxin or placebo administered subcutaneously once weekly. The primary outcome was the change in LA reservoir strain at 26 weeks, with key secondary endpoints including changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP), estimated glomerular filtration rate (eGFR) and safety. The trial was stopped early by the sponsor because of evidence for worsening congestion after 332 participants had been enrolled (mean age 74 years, 49% women, mean body mass index 30.6 kg m-2, 31.9% NYHA class III-IV). Compared to placebo, 25-mg volenrelaxin improved LA reservoir strain (+3.9%, 95% confidence interval (CI): 1.1-6.6, P = 0.006) but did not have effects on this outcome at 50-mg (+1.3%, 95% CI: -1.3 to 3.9, P = 0.332) or 100-mg (+0.9%, 95% CI: -1.8 to 3.6, P = 0.521) doses. At 26 weeks, volenrelaxin (pooling all dosages) increased NT-proBNP levels (+24.5%, 95% CI: 2.0-51.8) and had no significant effect on eGFR (+2.2 ml min-1 1.73 m-2, 95% CI: -1.8 to 6.3). Volenrelaxin was also associated with a non-significant increase in risk for HF hospitalization compared to placebo (hazard ratio = 2.64, 95% CI: 0.93-7.56, P = 0.070), along with signals for an increased number of cardiovascular and renal serious adverse events (odds ratio = 2.52, 95% CI: 0.95-6.68, P = 0.056). In conclusion, despite some evidence for improvement in LA function at a low dose, treatment with this long-acting form of human relaxin was associated with worsening congestion in patients with recently decompensated HFpEF. ClinicalTrials.gov identifier: NCT05592275 .

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Conflict of interest statement

Competing interests: B.A.B. receives research support from the National Institutes of Health and the US Department of Defense; receives research grant funding from AstraZeneca, Axon, Corvia, Novo Nordisk and Tenax Therapeutics; has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD Biosciences, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly and Company, Imbria, Janssen, Merck, Novo Nordisk, NGM, NXT and VADovations; and is a named inventor (US patent no. 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. J.M.T. receives research support from Boehringer Ingelheim, Bristol Myers Squibb, Reprieve Inc., Sequana Medical, Abbott and Merck and has consulted for Boehringer Ingelheim, Bristol Myers Squibb, Cardionomic, MagentaMed, Reprieve Inc., FIRE1, Sequana Medical, Merck, Windtree Therapeutics, Precardia, Regeneron, BD Biosciences, Edwards Lifesciences, AstraZeneca, Corteria and Eli Lilly. M.C.P. receives grant funding from Boehringer Ingelheim, Roche, SQ Innovations, AstraZeneca, Novartis, Novo Nordisk, Medtronic, Boston Scientific and Pharmacosmos and has consulted and/or served on trial committees for Abbott, AbbVie, Akero, Applied Therapeutics, Alnylam, Amgen, AnaCardio, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Edwards Lifesciences, Corteria, Novartis, AstraZeneca, Novo Nordisk, Bayer, Horizon Therapeutics, GlaxoSmithKline, Moderna, Takeda, Cardiorentis, Pharmacosmos, Siemens, St. Jude, Eli Lilly and Company, Vifor, New Amsterdam, Medtronic, Moderna, Teikoku, LIB Therapeutics, 3R Lifesciences, Reprieve Inc., FIRE1, Corvia and Regeneron. He also serves as Director of Global Clinical Trials Partners. Z.W., E.O. and F.S. are employees of Eli Lilly and Company and hold Eli Lilly and Company stocks. F.S. is a named inventor of the patents filed by Eli Lilly and Company. J.C. has consulted for Edgewise Therapeutics, Occlutech, Roche Diagnostics and us2ai. K.F.A. has received research grants from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Cardurion Pharmaceuticals, Eli Lilly and Company, LivaNova, Merck, Novartis, Novo Nordisk, Otsuka, Pfizer and Roche Diagnostics and consulted for Amgen, AstraZeneca, Cytokinetics, Eli Lilly and Company, Novartis, Relypsa, Roche Diagnostics and Windtree Therapeutics. O.A. and his institution have served as national principal investigator and in advisory board meetings for Eli Lilly and Company. J.B. has received lecture honoraria from Abiomed, AstraZeneca, Boehringer Ingelheim, Getinge, Novartis and Resuscitec. E.B. has received consulting fees from AstraZeneca, Boehringer Ingelheim and Servier; subsidized travel/hotel/registration fees from Servier; membership in steering committees from Boehringer Ingelheim, Novartis and Servier; research grant support through the Heart Institute (Incor) from AstraZeneca, Bayer/Merck, Boehringer Ingelheim, Cardiol Therapeutics, Eurofarma, Janssen, Novartis and Pfizer; and honoraria from Abbott, AstraZeneca, Boehringer Ingelheim, Novartis, Servier and Viatris. A.F., M.H. and T.K. declare no funding or disclosures. B.M. reports lecture fees from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, Medtronic and Novartis and an institutional research grant from Novartis. C.M. has participated on advisory boards and/or consulted for AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, Novartis and PureTech Health; serves as an advisor for HAYA Therapeutics; has received speaker fees from AstraZeneca, Boehringer Ingelheim and Novo Nordisk; receives conference attendance support from AstraZeneca; and receives research support from Amicus Therapeutics, AstraZeneca, Guerbet Laboratories Limited, Roche and Univar Solutions B.V. J.N. reports research support from CIBER-Cardiovascular and reports honoraria for presentations or advisory boards from Alleviant, AstraZeneca, Boehringer Ingelheim, Bayer, Eli Lilly and Company, Novartis, Novo Nordisk, Pfizer, Roche, Rovi and Vifor CSL (outside the submitted work). S.V. holds a Tier 1 Canada Research Chair in Cardiovascular Surgery and reports receiving grants and/or research support and/or speaking honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, the Canadian Heart Research Centre, the Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly and Company, HLS Therapeutics, Humber River Health, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, S & L Solutions Event Management Inc., Sanofi and Sun Pharma. He is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. M.B.Y. has received institutional research fees from Albert Health, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Novartis and Novo Nordisk and travel support from Menarini.

References

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