REGN5381, an agonist antibody to guanylate cyclase receptor NPR1 regulates vascular tone in preclinical and clinical studies, and preserves renal function in models of Chronic Kidney Disease
Year: 2026
Type: conference-paper
Abstract: Heart failure, Hypertension and Chronic Kidney Disease remain major contributors to morbidity and mortality, and often overlap within individuals. Novel approaches to modulate vascular tone and renovascular homeostasis may address unmet medical need in all three conditions. Natriuretic peptides signal through natriuretic peptide receptor 1 (NPR1), a membrane-bound guanylyl cyclase, to promote vasodilation and relieve venous congestion, but recombinant peptide infusions have been limited by short duration of effect. In a human genetic analysis of more than 700,000 individuals, lifelong exposure to coding variants in NPR1 was associated with changes in blood pressure and heart failure risk, supporting therapeutic NPR1 modulation. REGN5381 is an investigational monoclonal agonist antibody that allosterically activates NPR1 by inducing an active-like receptor conformation. In preclinical studies, REGN5381 produced haemodynamic effects that preferentially target the venous vasculature, reducing venous pressure and systolic blood pressure in normotensive and hypertensive models. In healthy volunteers, a single intravenous dose produced expected haemodynamic changes consistent with lower venous pressures, with general tolerability and no serious treatment-emergent adverse events reported across dose groups; blood pressure reductions persisted for several days in mildly hypertensive adults. Beyond haemodynamics, NPR1 agonism with REGN5381 improved renal outcomes across multiple preclinical chronic kidney disease models, including reductions in urinary albumin and injury biomarkers; combination with enalapril further improved biomarkers, histopathology, and suppression of fibrotic and inflammatory gene programs. Together, these findings support NPR1 agonism as an approach to selectively lower venous pressures, preserve renal function and potentially address cardiorenal diseases.
Authors: Kishor Devalaraja-Narashimha, Aaron Kithcart, Michael Dunn, Jee Hae Kim, Andre Ho, Matthew Franklin, Annabel Hernandez, Akshay Shekhar, Ethan Marin, Jan de Hoon, Wouter Botermans, Jonathan Meyer, Ximei Jin, Dongqin Zhang, Justin Torello, Xia Mao, Nosirudeen Quadri, Kristi Powers, Wanda Sharif, Anita Jackson, Yifan Luo, John O'Brien, Encarnacion Flores-Hernandez, Theodore Kaplan, Chien Liu, Gabor Halasz, Simisola Afolayan, Daniel Jasewicz, Vishal Kamat, Elena Garnova, Nina Liu, Michael Rosconi, Hao Pan, Satyajit Karnik, Michael Burczynski, Xiping Cheng, Dipti Pawaskar, Wenjun Zheng, Ashique Rafique, Jonas Nielsen, Tanima De, Niek Verweij, Anita Pandit, Adam Locke, Naga Chalasani, Olle Mellander, Tae-Hwi Schwantes-An, Aris Baras, Luca Lotta, Bret Musser, Jason Mastaitis, Andrew Rankin, Srihari Gopal, Tammy Huang, Gary Herman, William Olson, Andrew Murphy, George Yancopoulos, Benjamin Olenchock, Lori Morton
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Funder: Regeneron Pharmaceuticals
OpenAlex ID: W7163203843