Abstract 13840: Safety Outcomes From a First-in-Human Study of a Novel Investigational Monoclonal Antibody, REGN5381, an Agonist to the Natriuretic Peptide Receptor 1

Abstract

Introduction: Natriuretic peptides (NPs) regulate vascular volume and tone via the membrane-bound guanylate cyclase, natriuretic peptide receptor 1 (NPR1). Activation of this pathway is known to lower systemic and venous blood pressure (BP) and effect natriuresis and diuresis. Previous recombinant NP infusions for heart failure were limited by their duration of effects. REGN5381, a novel investigational NPR1 agonist monoclonal antibody, showed sustained hemodynamic effects in animal models. Here, we report safety and pharmacodynamic (PD) outcomes from a phase 1, first-in-human study of REGN5381. Hypothesis: REGN5381 is sufficienty well tolerated in healthy humans to warrant continued clinical investigation. Aim: To assess the safety, tolerability, and REGN5381 PD in normotensive humans. Methods: This double-blind, single-ascending dose study (NCT04506645), randomized healthy adults aged 18-55 years (6:2) to receive a single intravenous dose of REGN5381 or placebo. Participants received a fixed-sodium and fluid diet and remained 4 days in the clinic for non-invasive hemodynamics monitoring and safety assessment. Results: A total of 48 participants were enrolled; 12 were randomized to placebo and 6 to each of 6 REGN5381 dose levels (total n=36). Eight (66.7%) participants in the placebo and 24 (66.7%) in the total REGN5381 group reported ≥1 treatment-emergent adverse event (TEAE), with no obvious relationship to dose level. Four (33.3%) participants in the placebo and 15 (41.7%) in the total REGN5381 group reported ≥1 study drug related TEAE, with no obvious relationship to dose level. Common TEAEs (experienced by >10% of participants in the total group) were postural dizziness (placebo: 2 [16.7]%; total REGN5381: 6 [16.7]%) and headache (placebo: 5 [41.7%]; total REGN5381: 4 [11.1%]). Pyuria and orthostatic hypotension were reported in 4 (11.1%) participants in the total group, but none in the placebo group. No serious or severe TEAEs or deaths were reported in any dose groups. Participants treated with the highest dose saw a 7-11 mmHg reduction of systolic BP that was sustained over 72 hours (the full duration of inpatient monitoring). Conclusion: A single dose of REGN5381 is generally well-tolerated and provides sustained hemodynamic effects.