Key result
Novel NPR1 agonist REGN5381 reduces venous pressures in healthy human volunteers.
Why the study?
Does REGN5381 lower venous pressures in animal models and healthy human volunteers?
Does REGN5381 lower venous pressures in animal models and healthy human volunteers?
REGN5381, a novel monoclonal agonist antibody targeting NPR1, selectively lowers venous pressures in animal models and healthy volunteers, presenting a potential new therapeutic approach for heart failure.
Heart failure is a leading cause of morbidity and mortality1,2. Elevated intracardiac pressures and myocyte stretch in heart failure trigger the release of counter-regulatory natriuretic peptides, which act through their receptor (NPR1) to affect vasodilation, diuresis and natriuresis, lowering venous pressures and relieving venous congestion3–8. Recombinant natriuretic peptide infusions were developed to treat heart failure but have been limited by a short duration of effect9,10. Here we report that in a human genetic analysis of over 700,000 individuals, lifelong exposure to coding variants of the NPR1 gene is associated with changes in blood pressure and risk of heart failure. We describe the development of REGN5381, an investigational monoclonal agonist antibody that targets the membrane-bound guanylate cyclase receptor NPR1. REGN5381, an allosteric agonist of NPR1, induces an active-like receptor conformation that results in haemodynamic effects preferentially on venous vasculature, including reductions in systolic blood pressure and venous pressure in animal models. In healthy human volunteers, REGN5381 produced the expected haemodynamic effects, reflecting reductions in venous pressures, without obvious changes in diuresis and natriuresis. These data support the development of REGN5381 for long-lasting and selective lowering of venous pressures that drive symptomatology in patients with heart failure. Durable agonism of NPR1 achieved with a novel investigational monoclonal antibody could mirror the positive hemodynamic changes in blood pressure and heart failure identified in humans with lifelong exposure to NPR1 coding variants.
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Dunn et al. (2024) studied Heart failure / Healthy volunteers (n=700,000). REGN5381 was evaluated on Haemodynamic effects (venous pressures, diuresis, natriuresis). The novel monoclonal agonist antibody REGN5381 reduced venous pressures in healthy human volunteers, mirroring the hemodynamic changes identified in humans with NPR1 coding variants.
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