XXB750 treatment paradoxically increased NT-proBNP levels (ratio of change 1.34; 95% CI 1.07-1.66) and led to more death or worsening heart failure events (25%) vs sacubitril/valsartan (8%).
RCT (n=136)
Blinded and Open-label
Randomized
Does the NPR1 agonist antibody XXB750 improve NT-proBNP levels and clinical outcomes in patients with heart failure and reduced ejection fraction?
The NPR1 agonist XXB750 paradoxically acted as a functional antagonist in heart failure patients, increasing NT-proBNP and worsening clinical outcomes, highlighting the complex pharmacodynamics of the natriuretic peptide system in HF.
Absolute Event Rate: 1.34% vs 0.7%
Abstract 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 <50% were enrolled. Those patients who were on background angiotensin-converting enzyme inhibitor or angiotensin receptor blocker treatment were randomized to receive 60 mg XXB750, 120 mg 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 mg XXB750, 120 mg XXB750 or placebo treatment in a blinded fashion. The primary endpoint was the change in NT-proBNP levels at 16 weeks after treatment initiation, and safety was also assessed. We randomized 136 participants (70% male, 30% female) to 60 mg XXB750 ( n = 26), 120 mg XXB750 ( n = 55), matching placebo ( n = 29) or sacubitril/valsartan ( n = 25). At 16 weeks, NT-proBNP levels rose (ratio of change from baseline 1.34, 95% confidence interval (CI) 1.07–1.66) and cyclic guanosine monophosphate (cGMP) levels declined (ratio of change from baseline 0.77, 95% CI 0.65–0.91) in the pooled XXB750 arms, whereas NT-proBNP levels declined from baseline (ratio of change from baseline 0.70, 95% CI 0.45–1.10), and cGMP levels rose (ratio of change from baseline 1.38, 95% CI 1.13–1.69) 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: NCT06142383 .
“The NPR1 agonist antibody XXB750 in heart failure: a phase 2 randomized trial In patients with heart failure and LVEF <50%, treatment with XXB750 was associated with: •an increase in NT-proBNP, •a decrease in cGMP, •and a higher rate of death or worsening heart failure events.”
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Solomon et al. (Mon,) conducted a rct in Heart failure with reduced ejection fraction (n=136). XXB750 vs. Placebo or sacubitril/valsartan was evaluated on Change in NT-proBNP levels at 16 weeks after treatment initiation (95% CI 1.07-1.66). XXB750 treatment paradoxically increased NT-proBNP levels (ratio of change 1.34; 95% CI 1.07-1.66) and led to more death or worsening heart failure events (25%) vs sacubitril/valsartan (8%).