Abstract 4364215: Impact of REGN5381, a Monoclonal Antibody Agonist to Natriuretic Peptide Receptor 1, on Pulmonary Capillary Wedge Pressure in Patients With Heart Failure With Preserved Ejection Fraction

Introduction: Activation of natriuretic peptide receptor 1 (NPR1) regulates vascular tone, lowers venous pressures, and effects natriuresis and diuresis, which may have therapeutic benefit in heart failure with preserved ejection fraction (HFpEF). REGN5381, an investigational monoclonal antibody agonist of NPR1, has the potential to overcome the limitations of previous recombinant natriuretic peptide (NP) infusions that were limited by their short half-life. Research question: What are the safety, tolerability, and hemodynamic effects of REGN5381 in patients with HFpEF (NCT05353166)? Methods: Patients aged 18–75 years, with New York Heart Association class II/III heart failure with left ventricular ejection fraction ≥50% and N-terminal pro B-type natriuretic peptide (NT-proBNP) >300 pg/mL, were randomized 1:1 to a single intravenous injection of REGN5381 (30 mg, 100 mg, 300 mg) or placebo. Key hemodynamic inclusion criteria were pulmonary capillary wedge pressure (PCWP) ≥15 mmHg and right atrial pressure >5 mmHg upon right heart catheterization on Day 1. Safety and tolerability were assessed, including change from baseline in PCWP, systemic blood pressure (BP), and biomarkers. Results: Thirty-six patients received REGN5381 30 mg (n=3), 100 mg (n=3), 300 mg (n=12), or placebo (n=18). Mean (SD) change from baseline 6 h post-infusion in PCWP for 100 mg and 300 mg was −9.3 (1.4) and −7.7 (2.1), respectively, and −3.3 (2.4) for placebo (Fig. 1). Baseline mean (SD) systolic BP was 141.1 (20.3), 128.3 (12.6), and 134.8 (8.8) mmHg in the placebo, 100 mg, and 300 mg dose groups, respectively, with changes from baseline 6 h post-infusion of −0.6 (11.2), −5.7 (6.4), and −8.5 (13.7) mmHg, respectively. No effect of REGN5381 on cardiac output, no effect on systemic BP beyond 24 h, and no effects on renal function or biomarkers including NP, were observed. Most reported treatment-emergent adverse events (TEAEs) were mild (Table). One patient (8.3%) had a serious TEAE (respiratory tract procedural complication and hemoptysis), and 2 (16.7%) had mild treatment-related TEAEs (increased liver enzymes and dizziness) in the 300 mg dose group. No deaths were reported. Conclusions: REGN5381 was generally well-tolerated and improved PCWP with no persistent drops in systemic BP or cardiac output in patients with HFpEF. A reduction in PCWP with REGN5381 suggests efficacy in cardiopulmonary decongestion. These data support future clinical studies of REGN5381 in patients with HFpEF.