{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T17:51:04Z","timestamp":1792173064449,"version":"4.4.0"},"reference-count":23,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T00:00:00Z","timestamp":1774828800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T00:00:00Z","timestamp":1774828800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100004336","name":"Novartis","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100004336","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Med"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Therapies targeting the natriuretic peptide system have the potential to reduce death or heart failure events in heart failure with reduced ejection fraction. Here we assess XXB750, a human monoclonal antibody activating natriuretic peptide receptor 1, in patients with heart failure. Patients with heart failure and a left ventricular ejection fraction\u2009&lt;50% were enrolled. Those patients who were on background angiotensin-converting enzyme inhibitor or angiotensin receptor blocker treatment were randomized to receive 60\u2009mg XXB750, 120\u2009mg XXB750 or placebo in a blinded fashion or sacubitril\/valsartan treatment in an open-label fashion. Those patients on background sacubitril\/valsartan treatment were randomized to either 60\u2009mg XXB750, 120\u2009mg XXB750 or placebo treatment in a blinded fashion. The primary endpoint was the change in NT-proBNP levels at 16\u2009weeks after treatment initiation, and safety was also assessed. We randomized 136 participants (70% male, 30% female) to 60\u2009mg XXB750 (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200926), 120\u2009mg XXB750 (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200955), matching placebo (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200929) or sacubitril\/valsartan (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200925). At 16\u2009weeks, NT-proBNP levels rose (ratio of change from baseline 1.34, 95% confidence interval (CI) 1.07\u20131.66) and cyclic guanosine monophosphate (cGMP) levels declined (ratio of change from baseline 0.77, 95% CI 0.65\u20130.91) in the pooled XXB750 arms, whereas NT-proBNP levels declined from baseline (ratio of change from baseline 0.70, 95% CI 0.45\u20131.10), and cGMP levels rose (ratio of change from baseline 1.38, 95% CI 1.13\u20131.69) in the sacubitril\/valsartan arm. Death or worsening heart failure events occurred more frequently in those receiving XXB750 (25%) compared with those receiving sacubitril\/valsartan (8%), or placebo (0%). Because of the excess heart failure events in participants receiving XXB750, the data monitoring committee recommended stopping the trial prematurely. In contrast to the expected mechanism of drug action, XXB750 treatment led to increased NT-proBNP levels, lowered cGMP levels and more worsening heart failure events, suggesting that XXB750 may paradoxically behave as a functional antagonist of endogenous natriuretic peptides in patients with heart failure. Clinicaltrials.gov registration:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT06142383\" ext-link-type=\"uri\">NCT06142383<\/jats:ext-link>\n                    .\n                  <\/jats:p>","DOI":"10.1038\/s41591-026-04313-w","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T17:02:09Z","timestamp":1774890129000},"page":"1694-1700","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The NPR1 agonist antibody XXB750 in heart failure: a phase 2 randomized trial"],"prefix":"10.1038","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3698-9597","authenticated-orcid":false,"given":"Scott D.","family":"Solomon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6317-3975","authenticated-orcid":false,"given":"John J. V.","family":"McMurray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. Michael","family":"Felker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James L.","family":"Januzzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1903-0018","authenticated-orcid":false,"given":"Carolyn S. P.","family":"Lam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5417-4415","authenticated-orcid":false,"given":"Adriaan A.","family":"Voors","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Claggett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7675-7120","authenticated-orcid":false,"given":"Thomas G.","family":"Nuehrenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adel R.","family":"Rizkala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelia","family":"Koch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyue","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin P.","family":"Lefkowitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,30]]},"reference":[{"key":"4313_CR1","doi-asserted-by":"publisher","first-page":"3416","DOI":"10.1093\/cvr\/cvac125","volume":"118","author":"SJ Sangaralingham","year":"2023","unstructured":"Sangaralingham, S. J., Kuhn, M., Cannone, V., Chen, H. H. & Burnett, J. C. Natriuretic peptide pathways in heart failure: further therapeutic possibilities. Cardiovasc. Res. 118, 3416\u20133433 (2023).","journal-title":"Cardiovasc. Res."},{"key":"4313_CR2","doi-asserted-by":"crossref","unstructured":"O\u2019Connor, C. M. et al. Effect of nesiritide in patients with acute decompensated heart failure. N. Engl. J. Med. 365, 32\u201343 (2011).","DOI":"10.1056\/NEJMx110061"},{"key":"4313_CR3","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1056\/NEJMoa1409077","volume":"371","author":"JJ McMurray","year":"2014","unstructured":"McMurray, J. J. et al. Angiotensin\u2013neprilysin inhibition versus enalapril in heart failure. N. Engl. J. Med. 371, 993\u20131004 (2014).","journal-title":"N. Engl. J. Med."},{"key":"4313_CR4","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/j.jchf.2020.09.013","volume":"9","author":"SP Murphy","year":"2021","unstructured":"Murphy, S. P. et al. Atrial natriuretic peptide and treatment with sacubitril\/valsartan in heart failure with reduced ejection fraction. JACC Heart Fail. 9, 127\u2013136 (2021).","journal-title":"JACC Heart Fail."},{"key":"4313_CR5","doi-asserted-by":"publisher","first-page":"1264","DOI":"10.1016\/j.jacc.2019.01.018","volume":"73","author":"PL Myhre","year":"2019","unstructured":"Myhre, P. L. et al. B-type natriuretic peptide during treatment with sacubitril\/valsartan: the PARADIGM-HF trial. J. Am. Coll. Cardiol. 73, 1264\u20131272 (2019).","journal-title":"J. Am. Coll. Cardiol."},{"key":"4313_CR6","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1016\/j.jchf.2014.09.001","volume":"2","author":"O Vardeny","year":"2014","unstructured":"Vardeny, O., Miller, R. & Solomon, S. D. Combined neprilysin and renin-angiotensin system inhibition for the treatment of heart failure. JACC Heart Fail. 2, 663\u2013670 (2014).","journal-title":"JACC Heart Fail."},{"key":"4313_CR7","doi-asserted-by":"publisher","first-page":"135","DOI":"10.21037\/atm.2019.12.81","volume":"8","author":"LK Lewis","year":"2020","unstructured":"Lewis, L. K. et al. ProBNP processing is decreased by obesity in patients with heart failure. Ann. Transl. Med. 8, 135 (2020).","journal-title":"Ann. Transl. Med."},{"key":"4313_CR8","doi-asserted-by":"publisher","first-page":"S221","DOI":"10.21037\/atm.2019.08.56","volume":"7","author":"T Nishikimi","year":"2019","unstructured":"Nishikimi, T. & Nakagawa, Y. Does impaired processing of pro-B-type (or brain) natriuretic peptide cause decreased plasma BNP levels in obese heart failure patients? Ann. Transl. Med. 7, S221 (2019).","journal-title":"Ann. Transl. 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First-in-human study of MANP: a novel ANP (atrial natriuretic peptide) analog in human hypertension. Hypertension 78, 1859\u20131867 (2021).","journal-title":"Hypertension"},{"key":"4313_CR12","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1038\/s41586-024-07903-1","volume":"633","author":"ME Dunn","year":"2024","unstructured":"Dunn, M. E. et al. Agonist antibody to guanylate cyclase receptor NPR1 regulates vascular tone. Nature 633, 654\u2013661 (2024).","journal-title":"Nature"},{"key":"4313_CR13","doi-asserted-by":"publisher","first-page":"1544","DOI":"10.1161\/CIRCULATIONAHA.124.072636","volume":"151","author":"Y He","year":"2025","unstructured":"He, Y. et al. Blood pressure lowering effects of a novel long-acting NPR1 agonist, XXB750, in healthy participants: a randomized, first-in-human clinical study. Circulation 151, 1544\u20131546 (2025).","journal-title":"Circulation"},{"key":"4313_CR14","doi-asserted-by":"publisher","first-page":"1956","DOI":"10.1056\/NEJMoa1601895","volume":"376","author":"M Packer","year":"2017","unstructured":"Packer, M. et al. Effect of ularitide on cardiovascular mortality in acute heart failure. N. Engl. J. Med. 376, 1956\u20131964 (2017).","journal-title":"N. Engl. J. Med."},{"key":"4313_CR15","doi-asserted-by":"publisher","first-page":"1883","DOI":"10.1056\/NEJMoa1915928","volume":"382","author":"PW Armstrong","year":"2020","unstructured":"Armstrong, P. W. et al. Vericiguat in patients with heart failure and reduced ejection fraction. N. Engl. J. Med. 382, 1883\u20131893 (2020).","journal-title":"N. Engl. J. Med."},{"key":"4313_CR16","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.1016\/S0140-6736(25)01665-4","volume":"406","author":"J Butler","year":"2025","unstructured":"Butler, J. et al. Vericiguat in patients with chronic heart failure and reduced ejection fraction (VICTOR): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet 406, 1341\u20131350 (2025).","journal-title":"Lancet"},{"key":"4313_CR17","doi-asserted-by":"publisher","first-page":"102706","DOI":"10.1016\/j.jchf.2025.102706","volume":"14","author":"JE Udelson","year":"2026","unstructured":"Udelson, J. E. et al. Phase 2, randomized, double-blind, placebo-controlled study of CRD-740, a PDE9 inhibitor, in chronic heart failure. JACC Heart Fail. 14, 102706 (2026).","journal-title":"JACC Heart Fail."},{"key":"4313_CR18","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1002\/ejhf.1342","volume":"21","author":"H Nougu\u00e9","year":"2019","unstructured":"Nougu\u00e9, H. et al. Effects of sacubitril\/valsartan on neprilysin targets and the metabolism of natriuretic peptides in chronic heart failure: a mechanistic clinical study. Eur. J. Heart Fail. 21, 598\u2013605 (2019).","journal-title":"Eur. J. Heart Fail."},{"key":"4313_CR19","doi-asserted-by":"publisher","first-page":"e44","DOI":"10.1161\/CIRCRESAHA.122.320882","volume":"130","author":"T Michel","year":"2022","unstructured":"Michel, T. et al. proANP metabolism provides new insights into sacubitril\/valsartan mode of action. Circ. Res. 130, e44\u2013e57 (2022).","journal-title":"Circ. Res."},{"key":"4313_CR20","first-page":"10351","volume":"S0735-1097","author":"WB White","year":"2026","unstructured":"White, W. B. et al. Natriuretic peptide receptor-1 agonist for resistant hypertension: a randomized phase 2 trial. J. Am. Coll. Cardiol. S0735-1097, 10351\u201310353 (2026).","journal-title":"J. Am. Coll. Cardiol."},{"key":"4313_CR21","doi-asserted-by":"publisher","first-page":"16041","DOI":"10.1074\/jbc.M110626200","volume":"277","author":"PM Bryan","year":"2002","unstructured":"Bryan, P. M. & Potter, L. R. 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Ligand-dependent downregulation of guanylyl cyclase\/natriuretic peptide receptor-A: role of miR-128 and miR-195. Int. J. Mol. Sci. 23, 13381 (2022).","journal-title":"Int. J. Mol. Sci."}],"container-title":["Nature Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41591-026-04313-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-026-04313-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-026-04313-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T14:02:37Z","timestamp":1779285757000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41591-026-04313-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,30]]},"references-count":23,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["4313"],"URL":"https:\/\/doi.org\/10.1038\/s41591-026-04313-w","relation":{},"ISSN":["1078-8956","1546-170X"],"issn-type":[{"value":"1078-8956","type":"print"},{"value":"1546-170X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,30]]},"assertion":[{"value":"19 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 February 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 March 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"S.D.S. has received research grants from Alexion, Alnylam, Applied Therapeutics, AstraZeneca, Bellerophon, Bayer, BMS, Boston Scientific, Cytokinetics, Edgewise, Bridgebio, Gossamer, GSK, Ionis, Intellia, Lilly, NIH\/NHLBI, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Tenaya, Theracos and US2.AI and has consulted for Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, Askbio, AstraZeneca, Bayer, BMS, Bridgebio, Cardior, Cardurion, Corvia, Cytokinetics, Intellia, GSK, Lilly, Novartis, Novo Nordisk, Roche, Theracos, Quantum Genomics, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, Valo, Synhale and Recordati. J.J.V.M. reports payments to Glasgow University for clinical trials and other research projects from the British Heart Foundation, National Institute for Health\u2013National Heart Lung and Blood Institute (NIH\u2013NHLBI), Alnylam Pharmaceuticals, AstraZeneca, Bayer, Cardurion, Cytokinetics, Novartis and Roche. He reports personal consultancy fees from Alnylam Pharmaceuticals, AnaCardio, AstraZeneca, Cardurion, Cytokinetics, Novartis, River BioMedics, Biohaven Pharmaceuticals, Protherics Medicine Developments Ltd., DalCor Pharmaceuticals, Curie Bio Operations LLC, Adium Pharmaceuticals, Kirkland and Ellis Int. Ltd., Tangram Therapeutics, Alphasights Ltd., APTA Therapeutics, Zoll Pharmaceuticals, Eli Lilly, and Regeneron. He reports personal lecture fees from Alkem Metabolics, AstraZeneca, Canadian Medical and Surgical Knowledge, Centrix Healthcare, Emcure Pharmaceuticals, Eris Lifesciences, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, J.B. Chemicals and Pharmaceuticals, Lupin Pharmaceuticals, Medscape\/Heart.Org., ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, Translational Medicine Academy, MCI India, Hilton Pharmaceuticals, IMEDIC Pharmaceuticals Micro Labs Ltd., At the Limits Ltd., ARMGO Pharmaceuticals, MSN Lab Ltd., and Omicuris Pvt Ltd. He is on the data safety monitoring board for WCG Clinical Services. He is director of Global Clinical Trial Partners Ltd. (which provides clinical trial services such as endpoint committees and educational programmes). J.L.J. has received research grants from Abbott Diagnostics, Applied Therapeutics, AstraZeneca, BridgeBio Pharma, BMS and Novartis; has acted as a consultant, advisor or speaker for Abbott Diagnostics, Beckman-Coulter, CeleCor, Jana Care, Janssen, Novartis, Prevencio, Quidel and Roche Diagnostics; has served on clinical endpoint committees\/data safety monitoring boards for Abbott, AbbVie, Amgen, CVRx, Medtronic, Pfizer and Roche Diagnostics; and has equity in Fibrosys, Imbria Pharma, Jana Care and Prevencio. C.S.P.L. has received research grants from the National Medical Research Council of Singapore, Novo Nordisk and Roche Diagnostic; has served in advisory, consulting and trial leadership roles for Alnylam Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Corteria, CPC Clinical Research, Cytokinetics, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Janssen Research and Development LLC, Medscape\/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Pfizer, Radcliffe Group Ltd., Roche and U (\n                      \n                      ); has patent no. PCT\/SG2016\/050217 pending and US patent nos 10,631,828 B1; US 10,702,247 B2; US 11,301,996 B2; US 11,446,009 B2; US 11,931,207 B2; US 12,001,939; and US 12,400,762 B2; and is a co-founder and non-executive director of U (\n                      \n                      ). The employer of A.A.V. has received consultancy fees and\/or research support from Anacardio (consultancy), AstraZeneca (consultancy), Bayer AG (consultancy and research support), Boehringer Ingelheim (consultancy and research support), Cardurion (consultancy), Corteria (consultancy), Eli Lilly (consultancy), Merck (consultancy), Novartis (consultancy), Novo Nordisk (consultancy and research support), QTsense (consultancy), Rycarma (consultancy) and Salubris (consultancy). B.C. has personal consulting fees from Alnylam, Bristol Myers Squibb, Cardior, Cardurion, Corvia, CVRx, Eli Lilly, Intellia, Rocket, Valo and has served on a data safety monitoring board for Novo Nordisk. T.G.N., A.R.R., C.K. and W.Z. are employees of Novartis. M.P.L. is a former employee of Novartis. G.M.F. has received research grants from NIH, Bayer, BMS, Novartis, Merck, Cytokinetics, Otsuka and CSL-Behring; he has acted as a consultant to Novartis, BMS, Cytokinetics, Boehringer-Ingelheim, Myovant, River2Renal and Whiteswell, and has served on clinical endpoint committees\/data safety monitoring boards for Merck, Rocket Pharma and V-Wave.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}