Abstract 4359840: A First-In-Human Phase 1 Study of the Safety, Tolerability, and Pharmacodynamics of REGN7544, a Novel Natriuretic Peptide Receptor 1–Blocking Monoclonal Antibody

Background: The cardiac hormones atrial natriuretic peptide and brain natriuretic peptide activate natriuretic peptide receptor 1 (NPR1), leading to the generation of cyclic guanosine monophosphate. Subsequently, reduction of blood pressure (BP) occurs via vasodilation and decreasing intravascular volume. Research questions: 1) What are the safety, tolerability, and pharmacodynamics of REGN7544, an investigational first-in-class NPR1-blocking monoclonal antibody? 2) What are the physiological effects and therapeutic potential of NPR1 signaling blockade? Methods: This phase 1, randomized, double-blind, placebo-controlled trial included 10 dose cohorts of healthy adults (NCT05970718). Participants received REGN7544 or placebo in single doses of 3–1000 mg IV or 100–600 mg SC. Eighty adults (aged 18–55 years; 59% male) were dosed with REGN7544 (IV, n=42; SC, n=18) or placebo (n=20). The primary endpoint was the incidence and severity of treatment-emergent adverse events (TEAEs). Results: REGN7544 administration increased BP by approximately 5–10 mmHg above baseline as measured by ambulatory BP monitoring. The magnitude of the BP effect appeared to plateau at higher doses; however, its duration was apparently dose-dependent and persisted for ≥4 weeks. REGN7544 was associated with increases in N-terminal pro-brain natriuretic peptide and with decreases in hemoglobin concentration, both consistent with the expansion of plasma volume. As further evidence of volume expansion, exposure to REGN7544 was associated with increases in body weight and a decrease in natriuresis. The incidence of moderate-to-severe TEAEs for REGN7544-treated adults was comparable to placebo for each cohort. No serious adverse events related to REGN7544 were reported. Conclusions: REGN7544 was generally well-tolerated at doses up to 1000 mg IV and 600 mg SC. REGN7544 durably increased BP to a plateau (5–10 mmHg), with body weight and biomarker results suggesting increased plasma volume. These data support the development of REGN7544 for conditions characterized by hypovolemia and/or hypotension, such as postural orthostatic tachycardia syndrome and sepsis-associated hypotension.