REGN7544, an investigational first-in-class, fully human natriuretic peptide receptor 1-blocking monoclonal antibody for hypovolemic and hypotensive disorders
Year: 2026
Type: conference-paper
Study design: Clinical Trial
Abstract: Natriuretic peptide receptor 1 (NPR1) is a transmembrane guanylyl cyclase activated by atrial and brain natriuretic peptides to regulate blood pressure through vasodilation and reduced intravascular volume. REGN7544 is a first-in-class monoclonal antibody that blocks NPR1 signaling with subnanomolar affinity and noncompetitive inhibition. Structural modeling from a 3.15 Å cryo-EM complex indicates that antibody binding prevents the receptor from adopting its active conformation. In NPR1-humanized mice, single doses produced dose-dependent systolic blood pressure (SBP) increases, with higher doses maintaining 10–15 mmHg elevations for up to 28 days and correcting severe hypotension in ANP-overexpressing mice by 30–40mmHg. Cynomolgus monkeys showed similarly durable, dose-dependent increases in blood pressure accompanied by transient elevations in natriuretic peptide biomarkers and reductions in hematocrit, consistent with plasma-volume expansion. Standard antihypertensives reversed the BP increases, indicating no need for a dedicated reversal strategy. In a Phase 1 randomized, placebo-controlled study in healthy adults (N=80), REGN7544 administered intravenously (3–1000 mg) or subcutaneously (100–600 mg) was generally well tolerated, with TEAE incidence comparable to placebo and no drug-related serious adverse events. REGN7544 increased BP by approximately 5–10 mmHg, with a plateau in magnitude but dose-dependent duration of ≥4 weeks. Plasma cGMP decreased by ~40% for several weeks. NT-proBNP elevations and hemoglobin reductions further supported plasma-volume expansion as the pharmacodynamic mechanism. Collectively, these data support REGN7544 as a potential long-acting therapy for disorders characterized by hypovolemia or hypotension, including postural orthostatic tachycardia syndrome and sepsis-associated hypotension.
Authors: Kishor Devalaraja-Narashimha, Mohsin Ahmed, Jee Hae Kim, Matthew C. Franklin, Katie Tuckwell, Meng Xu, Ximei Jin, Dongqin Zhang, Justin Torello, Xia Mao, Akshay Shekhar, Xiping Cheng, Emily Redington, Raji Swamy, Andre Jo-Hao Ho, Elena Garnova, Ashique Rafique, Pamela Krueger, Hao Pan, Mao Wang, Tammy Huang, Dipti Pawaskar, Mazhar Thakur, Andrew J. Murphy, George D. Yancopoulos, Gary Herman, Chris Wynne, Benjamin A. Olenchock, William Olson, Ethan Marin, Lori Morton
Institutions: Regeneron (United States), New Zealand Clinical Research
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Funder: Regeneron Pharmaceuticals
OpenAlex ID: W7163216055