Agonist Antibody to Natriuretic Peptide Receptor 1 for CKD

Background: Chronic kidney disease (CKD) affects >800 million people globally. Despite medical advances, unmet need persists and patients continue to experience declining kidney function. Data suggest that activating natriuretic peptide receptor 1 (NPR1) can slow CKD progression by modulating hemodynamics and maintaining podocyte health. Methods: We examined the impact of REGN5381, an investigational NPR1 agonist antibody developed by VelocImmune® technology, independently / in conjunction with standard-of-care medications in different CKD models including collagen type IV alpha (COL4A) 3 and COL4A4 knock-out models of Alport Syndrome (AS), and the remnant kidney model (RKM). Results: Combined with enalapril, REGN5381 provided a robust survival benefit and slowed glomerular filtration rate decline in 2 AS mouse models. The survival benefit was associated with reduced albuminuria and blood pressure, increased urinary cyclic GMP, improvement in serum markers of kidney injury, biomarkers of kidney and cardiac function, and kidney histopathology. Kidney molecular expression analysis indicated a restoration of gene signatures related to fibrosis and inflammation. The addition of empagliflozin to REGN5381 plus enalapril further improved survival and reduced albuminuria. In the RKM model of CKD, REGN5381 reduced albuminuria, and improved kidney histopathology and cardiac ejection fraction, indicating that the benefits of REGN5381 are not limited to AS. Conclusion: NPR1 agonism with REGN5381 benefited the kidney and heart in multiple CKD models, presenting a potential novel therapeutic strategy to treat CKD. Funding: Commercial Support - Regeneron Pharmaceuticals, Inc.