Nature Medicine<\/em><\/a><\/p>\n\n\n\nXXB750 was designed to directly stimulate the natriuretic peptide pathway, a key compensatory mechanism in heart failure that promotes natriuresis, vasodilation, and reduced cardiac filling pressures. Unlike neprilysin inhibition, which augments endogenous natriuretic peptides, XXB750 provides sustained receptor activation through a long-acting monoclonal antibody.<\/p>\n\n\n\n
In this randomized trial, 136 patients with heart failure and LVEF <50% on background guideline-directed therapy were assigned to XXB750 (60 mg or 120 mg), placebo, or open-label sacubitril\/valsartan. The primary endpoint was change in NT-proBNP at 16 weeks, with additional evaluation of cGMP and clinical outcomes. The trial was stopped following a recommendation of the data safety monitoring board on 6 August 2024 because of evidence of harm in patients receiving XXB750. The trial was stopped following a recommendation of the data safety monitoring board on 6 August 2024 because of evidence of harm in patients receiving XXB750.<\/p>\n\n\n\n
Contrary to expectations, XXB750 was associated with worsening heart failure biomarkers<\/strong>.<\/em> NT-proBNP increased (ratio 1.34, 95% CI 1.07\u20131.66) and cGMP decreased (ratio 0.77, 95% CI 0.65\u20130.91), while sacubitril\/valsartan demonstrated the anticipated improvements in both markers.<\/p>\n\n\n\nThese biomarker changes were accompanied by worse clinical outcomes<\/em><\/strong>. <\/em>Death or worsening heart failure events occurred in 25% of patients receiving XXB750, compared with 8% in the sacubitril\/valsartan group and 0% in the placebo group.<\/p>\n\n\n\nNotably, the adverse effects of XXB750 were most pronounced among patients receiving background sacubitril\/valsartan, who exhibited greater increases in NT-proBNP, greater reductions in cGMP, and higher rates of worsening heart failure events.<\/p>\n\n\n\n
Mechanistically, investigators suggested that sustained NPR1 activation by a monoclonal antibody may lead to receptor desensitization or functional antagonism of endogenous natriuretic peptide signaling, particularly in patients with already elevated baseline pathway activation.<\/p>\n\n\n\n
These findings highlight important differences between direct receptor agonism and indirect pathway augmentation, and raise caution for future development of therapies targeting the natriuretic peptide system in heart failure.<\/p>\n","protected":false},"excerpt":{"rendered":"
Key Points In an Investigative Horizons session at the American College of Cardiology 2026 Scientific Sessions, Dr. Scott Solomon from Mass General Brigham Boston, MA, presented results from a phase 2 randomized trial evaluating XXB750, a monoclonal antibody agonist of the natriuretic peptide receptor 1 (NPR1), in patients with heart failure. The study was simultaneously […]<\/p>\n","protected":false},"author":40615,"featured_media":7279,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"aside","meta":{"footnotes":""},"categories":[1074,8],"tags":[1075,45,47,185],"ppma_author":[1069],"class_list":{"0":"post-139781","1":"post","2":"type-post","3":"status-publish","4":"format-aside","5":"has-post-thumbnail","7":"category-acc-2026","8":"category-news","9":"tag-acc-2026","10":"tag-conference","11":"tag-featured","12":"tag-news","13":"post_format-post-format-aside","14":"author-hassan-adam-alhassan-md"},"authors":[{"term_id":1069,"user_id":40615,"is_guest":0,"slug":"hassan-adam-alhassan-md","display_name":"Hassan Adam Alhassan MD","avatar_url":"https:\/\/secure.gravatar.com\/avatar\/8cc8318e58bf0ad1548b042cbb04e2e62466d8fe5780d7b1f138246f2c21b2b5?s=96&r=g","author_category":"1","first_name":"Hassan","last_name":"Adam Alhassan","user_url":"","job_title":"Clinical Fellow Electrophysiology BIDMC","description":""}],"_links":{"self":[{"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/posts\/139781","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/users\/40615"}],"replies":[{"embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=139781"}],"version-history":[{"count":1,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/posts\/139781\/revisions"}],"predecessor-version":[{"id":139782,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/posts\/139781\/revisions\/139782"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/media\/7279"}],"wp:attachment":[{"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=139781"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=139781"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=139781"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=139781"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}