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.
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 5.4 mmol lIndividuals who met eligibility criteria who were on background ACEi or ARB were randomly allocated to receive blinded subcutaneous XXB750 60-mg doses, XXB750 titrated to a maximum dose of 120 mg, matching subcutaneous placebo or open-label oral sacubitril/valsartan. Those who were on background sacubitril/valsartan were randomly allocated to either blinded XXB750 60-mg doses, XXB750 titrated to a maximum dose of 120 mg or matching placebo . Randomization was stratified by region and ACEi or ARB versus sacubitril/valsartan background therapy to ensure that the XXB750 or placebo arms had approximately two thirds of patients on background sacubitril/valsartan therapy. Participants randomized to XXB750, or its matching placebo, received one subcutaneous injection every 4 weeks, with a total of four injections during the 16-week treatment period, whereas participants randomized to open-label sacubitril/valsartan were titrated, where possible, to a target dose of 97/103 mg twice daily for 16 weeks. Once the participants entered the trial, every effort was made to avoid modifications of any background HF therapy components, unless essential. All study treatments were discontinued at week 16, after which participants entered the safety follow-up period and were managed at the discretion of the investigator. The original plan was to randomize 720 participants and include an XXB750 group with a target dose of 240 mg in an adaptive design. A staggered enrollment was planned, initially excluding the planned highest 240-mg target dose of XXB750 until the safety of the 60 mg and 120 mg target dose results were confirmed by the DMC. However, enrollment was stopped early after 135 participants had received randomly allocated treatment owing to an excess of adverse events in the XXB750 groups, and no patients were randomized to the planned 240-mg group.The primary objective of the study was to evaluate the efficacy and dose–response relationship of the three XXB750 target dose levels compared with placebo in reducing NT-proBNP, reflecting a reduction in left ventricular wall stress from baseline to week 16. Secondary objectives included evaluating the effect on NT-proBNP from adding the two highest doses of XXB750 to background ACEi or ARB treatment, compared with switching to sacubitril/valsartan. Safety assessments included adverse events, serious adverse events and adverse events of special interest, including serious hypotension, presyncope or syncope, hypersensitivity reactions, injection site reactions and severe tachycardia or bradycardia.An external DMC independent of the sponsor was appointed to monitor the study conduct, review safety regularly and determine if it was safe to continue the study according to the protocol. During a regular meeting on 6 August 2024, the DMC reviewed cumulative safety data from the study, identified a marked increase in the frequency of worsening HF events in participants receiving XXB750 versus those on placebo or on sacubitril/valsartan and recommended the termination of the trial. All participants who had been randomized to receive XXB750 or placebo were followed up for 12 weeks after they received the last dose, which was in accordance with the originally planned follow-up duration as per protocol.It was originally planned to randomly allocate a total of 720 participants in the ratio of 2:2:3:3:2 to placebo, 60 mg of XXB750, 120 mg of XXB750, 240 mg of XXB750 or sacubitril/valsartan, respectively. Assuming a common standard deviation of 0.67 for log NT-proBNP change from baseline and a two-sided 5% significance level, a sample size of 600 participants would have provided a power of 90% if the underlying true maximum NT-proBNP reduction with XXB750 versus placebo was 23%. Owing to the early study termination, the primary estimand and statistical modeling for the dose–response relationship were no longer applicable. The primary endpoint of change in NT-proBNP was summarized descriptively as geometric means and 95% CI for each treatment group administered in the trial and by pooling the two XXB750 groups. We provided exploratory least-square mean difference in change versus placebo at 16 weeks in sensitivity analyses using analysis of covariance with log-transformed baseline biomarker values and treatment terms as covariates. Separate assessments were made on the basis of the background treatment group .The data from this clinical trial are not publicly available. Novartis is committed to sharing access to patient-level data and supporting clinical documents with qualified external researchers. These requests are reviewed on an ongoing basis and approved expeditiously on the basis of scientific merit based on the policies described at the website below. All data provided are anonymized to respect the privacy of patients who have participated in the trial, in line with applicable laws and regulations. The data can be requested fromSangaralingham, S. J., Kuhn, M., Cannone, V., Chen, H. H. & Burnett, J. C. Natriuretic peptide pathways in heart failure: further therapeutic possibilities.Vardeny, O., Miller, R. & Solomon, S. D. Combined neprilysin and renin-angiotensin system inhibition for the treatment of heart failure.Nishikimi, T. & Nakagawa, Y. Does impaired processing of pro-B-type natriuretic peptide cause decreased plasma BNP levels in obese heart failure patients?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.Butler, J. et al. Vericiguat in patients with chronic heart failure and reduced ejection fraction : a double-blind, placebo-controlled, randomised, phase 3 trial.Udelson, J. E. et al. Phase 2, randomized, double-blind, placebo-controlled study of CRD-740, a PDE9 inhibitor, in chronic heart failure.Nougué, H. et al. Effects of sacubitril/valsartan on neprilysin targets and the metabolism of natriuretic peptides in chronic heart failure: a mechanistic clinical study.Bryan, P. M. & Potter, L. R. The atrial natriuretic peptide receptor is dephosphorylated by distinct microcystin-sensitive and magnesium-dependent protein phosphatases.Schröter, J. et al. Homologous desensitization of guanylyl cyclase A, the receptor for atrial natriuretic peptide, is associated with a complex phosphorylation pattern.Khurana, M. L., Mani, I., Kumar, P., Ramasamy, C. & Pandey, K. N. Ligand-dependent downregulation of guanylyl cyclase/natriuretic peptide receptor-A: role of miR-128 and miR-195.The Cardiovascular Division, Mass General Brigham, Harvard Medical School, Boston, MA, USA The study was designed by the steering committee and the sponsor. S.D.S. drafted the paper. S.D.S. and B.C. performed an independent data analysis, which was also performed by the sponsor. All authors contributed to the data interpretation and writing of the final version of the paper, and all authors were responsible for the decision to submit the paper.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–National Heart Lung and Blood Institute , 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. . 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 ; 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 . The employer of A.A.V. has received consultancy fees and/or research support from Anacardio , AstraZeneca , Bayer AG , Boehringer Ingelheim , Cardurion , Corteria , Eli Lilly , Merck , Novartis , Novo Nordisk , QTsense , Rycarma and Salubris . 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.thanks Justin Ezekowitz, Yogesh Reddy and the other, anonymous, reviewer for their contribution to the peer review of this work. Primary Handling Editor: Michael Basson, in collaboration with the Extended Data Fig. 1 Distribution of NT-proBNP or cyclic GMP ratio change at Week 16 by treatment group. Violin plots display the distribution of the ratio change in NT-proBNP or cGMP from baseline to Week 16 for each treatment group. The width of each violin represents the relative data density at a given value , with wider regions indicating a higher concentration of observations. The central box indicates the interquartile range , and the white dot within the box denotes the median value. The outer limits of the whiskers are determined by the most distant points from the edges of the IQR box that are within 1.5 times the width of the box. The x-axis is shown on a logarithmic scale, where a value of 1 represents no change from baseline; values 1 indicate increases in NT-proBNP or cGMP.This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit
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