Key Points
- XXB750, a monoclonal antibody targeting the natriuretic peptide receptor 1 (NPR1), was designed to enhance natriuretic peptide signaling in heart failure.
- In a phase 2 randomized trial, XXB750 paradoxically increased NT-proBNP and reduced cGMP levels.
- Patients receiving XXB750 experienced significantly higher rates of worsening heart failure events compared with placebo and sacubitril/valsartan.
- The trial was terminated early due to safety concerns.
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 published in Nature Medicine
XXB750 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.
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.
Contrary to expectations, XXB750 was associated with worsening heart failure biomarkers. NT-proBNP increased (ratio 1.34, 95% CI 1.07–1.66) and cGMP decreased (ratio 0.77, 95% CI 0.65–0.91), while sacubitril/valsartan demonstrated the anticipated improvements in both markers.
These biomarker changes were accompanied by worse clinical outcomes. 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.
Notably, 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.
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.
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.