{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T10:09:19Z","timestamp":1782727759547,"version":"3.54.5"},"reference-count":26,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2024,5,24]],"date-time":"2024-05-24T00:00:00Z","timestamp":1716508800000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004312","name":"Eli Lilly and Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004312","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,12,20]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Volenrelaxin is a half-life-extended recombinant human relaxin protein developed for improving kidney perfusion and cardiorenal function. This study assessed the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of volenrelaxin following single- and multiple-ascending doses (SAD and MAD) administration.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>In this Phase 1, four-part, randomized, double-blinded, placebo-controlled SAD and MAD study in healthy participants, SAD participants (n\u00a0=\u00a056) received an intravenous or subcutaneous dose of volenrelaxin or placebo in a dose-ascending manner. MAD participants (n\u00a0=\u00a077) received volenrelaxin or placebo subcutaneously once weekly for 5 weeks. Effective renal plasma flow (ERPF) and measured glomerular filtration rate (mGFR) were determined by para-aminohippurate and iohexol clearance, respectively.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Volenrelaxin demonstrated an extended half-life and increased acute and chronic placebo-adjusted ERPF change from baseline by 50% and 44%, respectively (P\u00a0&amp;lt;\u00a0.0001). mGFR was unchanged, while filtration fraction and afferent\/efferent renal arteriolar resistances were reduced. Systolic and diastolic blood pressures decreased, and pulse rate increased with increasing volenrelaxin exposures, demonstrating maximal model-derived placebo-adjusted changes (90% confidence interval) of \u20136.16 (\u20138.04, \u20134.28) mmHg, \u20136.10 (\u20137.61, \u20134.58) mmHg and +4.39 (+3.38, +5.39) bpm, respectively. Adverse events were mild, with no difference in orthostatic hypotension between volenrelaxin and placebo.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Volenrelaxin was well-tolerated, safe and suitable for weekly subcutaneous dosing. Volenrelaxin showed a sustained improvement in kidney perfusion upon repeated dosing, supporting further clinical development in chronic kidney disease and chronic heart failure.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Clinical trial registration<\/jats:title>\n                  <jats:p>NCT04768855.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/ndt\/gfae112","type":"journal-article","created":{"date-parts":[[2024,5,24]],"date-time":"2024-05-24T02:20:31Z","timestamp":1716517231000},"page":"109-122","source":"Crossref","is-referenced-by-count":11,"title":["Volenrelaxin (LY3540378) increases renal plasma flow: a randomized Phase 1 trial"],"prefix":"10.1093","volume":"40","author":[{"given":"Lai San","family":"Tham","sequence":"first","affiliation":[{"name":"Global Pharmacokinetics, Pharmacodynamics and Pharmacometrics, Lilly Centre for Clinical Pharmacology Pte Ltd , Singapore ,","place":["Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3126-3730","authenticated-orcid":false,"given":"Hiddo J L","family":"Heerspink","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen , Hanzeplein, Groningen ,","place":["Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6802-2623","authenticated-orcid":false,"given":"Xiaojun","family":"Wang","sequence":"additional","affiliation":[{"name":"Complications and Outcomes Research, Eli Lilly and Company , Indianapolis, IN ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Verdino","sequence":"additional","affiliation":[{"name":"Computational Science and Protein Engineering, Lilly Biotechnology Center , San Diego, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chadi G","family":"Saifan","sequence":"additional","affiliation":[{"name":"Global Patient Safety and Pharmacovigilance-Oncology, Abbvie , IL ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3111-9464","authenticated-orcid":false,"given":"Eric A","family":"Benson","sequence":"additional","affiliation":[{"name":"Complications and Outcomes Research, Eli Lilly and Company , Indianapolis, IN ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2977-1055","authenticated-orcid":false,"given":"Paul","family":"Goldsmith","sequence":"additional","affiliation":[{"name":"Exploratory Medicine and Pharmacology, Eli Lilly and Company , Bracknell ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenzhong","family":"Wang","sequence":"additional","affiliation":[{"name":"Complications and Outcomes Research, Eli Lilly and Company , Indianapolis, IN ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5285-0419","authenticated-orcid":false,"given":"Jeffrey M","family":"Testani","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, Yale University , CT ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"Haupt","sequence":"additional","affiliation":[{"name":"Diabetes and Metabolic Research, Eli Lilly and Company , Indianapolis, IN ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8442-9362","authenticated-orcid":false,"given":"Flora","family":"Sam","sequence":"additional","affiliation":[{"name":"Diabetes and Metabolic Research, Eli Lilly and Company , Indianapolis, IN ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David Z I","family":"Cherney","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Nephrology, University Health Network , Toronto, Ontario ,","place":["Canada"]},{"name":"Department of Medicine, University of Toronto , Toronto, Ontario ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,5,23]]},"reference":[{"key":"2025010614204936300_bib1","doi-asserted-by":"publisher","first-page":"254","DOI":"10.21037\/cdt-20-291","article-title":"Overview of the socio-economic consequences of heart failure","volume":"11","author":"Hessel","year":"2021","journal-title":"Cardiovasc Diagn Ther"},{"key":"2025010614204936300_bib2","doi-asserted-by":"publisher","first-page":"e1001699","DOI":"10.1371\/journal.pmed.1001699","article-title":"Heart failure care in low- and middle-income countries: a systematic review and meta-analysis","volume":"11","author":"Callender","year":"2014","journal-title":"PLoS Med"},{"key":"2025010614204936300_bib3","doi-asserted-by":"publisher","first-page":"e93","DOI":"10.1161\/CIR.0000000000001123","article-title":"Heart disease and stroke statistics-2023 update: a report from the American Heart Association","volume":"147","author":"Tsao","year":"2023","journal-title":"Circulation"},{"key":"2025010614204936300_bib4","doi-asserted-by":"publisher","first-page":"e009776","DOI":"10.1161\/CIRCHEARTFAILURE.122.009776","article-title":"Improvement in renal function during the treatment of acute decompensated heart failure: relationship with markers of renal tubular injury and prognostic importance","volume":"16","author":"Natov","year":"2023","journal-title":"Circ Heart Fail"},{"key":"2025010614204936300_bib5","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1093\/ndt\/gfn679","article-title":"The role of hypotension in the development of acute renal failure","volume":"24","author":"Vincent","year":"2008","journal-title":"Nephrol Dial Transplant"},{"key":"2025010614204936300_bib6","doi-asserted-by":"publisher","first-page":"R267","DOI":"10.1152\/ajpregu.00156.2011","article-title":"Maternal vasodilation in pregnancy: the emerging role of relaxin","volume":"301","author":"Conrad","year":"2011","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"2025010614204936300_bib7","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1016\/j.jacc.2012.11.005","article-title":"Effect of serelaxin on cardiac, renal, and hepatic biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF) development program: correlation with outcomes","volume":"61","author":"Metra","year":"2013","journal-title":"J Am Coll Cardiol"},{"key":"2025010614204936300_bib8","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/S0140-6736(12)61855-8","article-title":"Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial","volume":"381","author":"Teerlink","year":"2013","journal-title":"Lancet North Am Ed"},{"key":"2025010614204936300_bib9","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1056\/NEJMoa1801291","article-title":"Effects of serelaxin in patients with acute heart failure","volume":"381","author":"Metra","year":"2019","journal-title":"N Engl J Med"},{"key":"2025010614204936300_bib10","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1111\/1755-5922.12231","article-title":"Serelaxin in acute heart failure: most recent update on clinical and preclinical evidence","volume":"35","author":"Ghosh","year":"2017","journal-title":"Cardiovasc Ther"},{"key":"2025010614204936300_bib11","doi-asserted-by":"publisher","first-page":"1965","DOI":"10.1111\/bph.16055","article-title":"Development of a long-acting relaxin analogue, LY3540378, for treatment of chronic heart failure","volume":"180","author":"Verdino","year":"2023","journal-title":"Br J Pharmacol"},{"key":"2025010614204936300_bib12","doi-asserted-by":"publisher","first-page":"3192","DOI":"10.1681\/ASN.2005090950","article-title":"Influence of recombinant human relaxin on renal hemodynamics in healthy volunteers","volume":"17","author":"Smith","year":"2006","journal-title":"J Am Soc Nephrol"},{"key":"2025010614204936300_bib13","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1016\/j.kint.2019.09.013","article-title":"The renal hemodynamic effects of the SGLT2 inhibitor dapagliflozin are caused by post-glomerular vasodilatation rather than pre-glomerular vasoconstriction in metformin-treated patients with type 2 diabetes in the randomized, double-blind RED trial","volume":"97","author":"Van Bommel","year":"2020","journal-title":"Kidney Int"},{"key":"2025010614204936300_bib14","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1161\/CIRCULATIONAHA.113.005081","article-title":"Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus","volume":"129","author":"Cherney","year":"2014","journal-title":"Circulation"},{"key":"2025010614204936300_bib15","doi-asserted-by":"publisher","first-page":"1143","DOI":"10.1172\/JCI102534","article-title":"Evaluation of renal resistances, with special reference to changes in essential hypertension","volume":"30","author":"G\u00f3mez","year":"1951","journal-title":"J Clin Invest"},{"key":"2025010614204936300_bib16","doi-asserted-by":"publisher","first-page":"F967","DOI":"10.1152\/ajprenal.00415.2016","article-title":"The Gomez equations and renal hemodynamic function in kidney disease research","volume":"311","author":"Bjornstad","year":"2016","journal-title":"Am J Physiol Renal Physiol"},{"key":"2025010614204936300_bib17","doi-asserted-by":"publisher","first-page":"994","DOI":"10.1161\/CIRCHEARTFAILURE.114.001536","article-title":"Renal hemodynamic effects of serelaxin in patients with chronic heart failure: a randomized, placebo-controlled study","volume":"7","author":"Voors","year":"2014","journal-title":"Circ Heart Fail"},{"key":"2025010614204936300_bib18","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1093\/eurheartj\/eht386","article-title":"Renal impairment, worsening renal function, and outcome in patients with heart failure: an updated meta-analysis","volume":"35","author":"Damman","year":"2014","journal-title":"Eur Heart J"},{"key":"2025010614204936300_bib19","doi-asserted-by":"publisher","first-page":"1746","DOI":"10.1681\/ASN.2019010008","article-title":"Evaluating glomerular filtration rate slope as a surrogate end point for ESKD in clinical trials: an individual participant meta-analysis of observational data","volume":"30","author":"Grams","year":"2019","journal-title":"J Am Soc Nephrol"},{"key":"2025010614204936300_bib20","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1007\/s40256-014-0069-0","article-title":"Serelaxin: a novel therapy for acute heart failure with a range of hemodynamic and non-hemodynamic actions","volume":"14","author":"D\u00edez","year":"2014","journal-title":"Am J Cardiovasc Drugs"},{"key":"2025010614204936300_bib21","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.cardfail.2010.08.011","article-title":"The positive inotropic effect of relaxin-2 in human atrial myocardium is preserved in end-stage heart failure: role of Gi-phosphoinositide-3 kinase signaling","volume":"17","author":"Dschietzig","year":"2011","journal-title":"J Card Fail"},{"key":"2025010614204936300_bib22","first-page":"405","article-title":"Relaxin family peptides and their receptors","volume":"93","author":"Bathgate","year":"2013","journal-title":"Ann NY Acad Sci"},{"key":"2025010614204936300_bib23","doi-asserted-by":"publisher","first-page":"18545","DOI":"10.1038\/s41598-019-53867-y","article-title":"Relaxin reverses maladaptive remodeling of the aged heart through Wnt-signaling","volume":"9","author":"Martin","year":"2019","journal-title":"Sci Rep"},{"key":"2025010614204936300_bib24","doi-asserted-by":"publisher","first-page":"8897","DOI":"10.1038\/s41598-022-12930-x","article-title":"Chronic treatment with serelaxin mitigates adverse remodeling in a murine model of ischemic heart failure and modulates bioactive sphingolipid signaling","volume":"12","author":"Devarakonda","year":"2022","journal-title":"Sci Rep"},{"key":"2025010614204936300_bib25","doi-asserted-by":"publisher","first-page":"3905","DOI":"10.7150\/thno.38640","article-title":"Serelaxin alleviates cardiac fibrosis through inhibiting endothelial-to-mesenchymal transition via RXFP1","volume":"10","author":"Wilhelmi","year":"2020","journal-title":"Theranostics"},{"key":"2025010614204936300_bib26","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.1016\/j.bbrc.2017.09.110","article-title":"Relaxin alleviates TGF\u03b21-induced cardiac fibrosis via inhibition of Stat3-dependent autophagy","volume":"493","author":"Yuan","year":"2017","journal-title":"Biochem Biophys Res Commun"}],"container-title":["Nephrology Dialysis Transplantation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ndt\/advance-article-pdf\/doi\/10.1093\/ndt\/gfae112\/58248901\/gfae112.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ndt\/article-pdf\/40\/1\/109\/58248901\/gfae112.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ndt\/article-pdf\/40\/1\/109\/58248901\/gfae112.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,6]],"date-time":"2025-01-06T14:21:10Z","timestamp":1736173270000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ndt\/article\/40\/1\/109\/7680605"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,23]]},"references-count":26,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,5,23]]},"published-print":{"date-parts":[[2024,12,20]]}},"URL":"https:\/\/doi.org\/10.1093\/ndt\/gfae112","relation":{},"ISSN":["0931-0509","1460-2385"],"issn-type":[{"value":"0931-0509","type":"print"},{"value":"1460-2385","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,1]]},"published":{"date-parts":[[2024,5,23]]}}}