Lixivaptan (DB06666): A Comprehensive Monograph on a Dual-Indication Vasopressin V2 Receptor Antagonist and a Case Study in Developmental Failure

Executive Summary

Lixivaptan (DrugBank ID: DB06666) is an orally active, non-peptide, small molecule that functions as a potent and selective antagonist of the vasopressin V2 (AVPR2) receptor. Its development history is characterized by a significant strategic pivot, representing two distinct and ultimately unsuccessful attempts to bring a pharmacologically active compound to market for two different indications.

The initial development program, spearheaded by companies including Cardiokine, Inc., targeted the treatment of euvolemic and hypervolemic hyponatremia. The therapeutic rationale was sound: by blocking the V2 receptor in the renal collecting ducts, Lixivaptan induces aquaresis—the electrolyte-sparing excretion of free water—thereby correcting the underlying water imbalance that causes low serum sodium in conditions like the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) and congestive heart failure. Despite successfully demonstrating an ability to raise serum sodium levels in a large Phase III program, the drug failed to gain regulatory approval. In 2012, the U.S. Food and Drug Administration (FDA) issued a Complete Response Letter, effectively rejecting the New Drug Application. The decision was based on an unfavorable risk-benefit assessment, citing a lack of demonstrated improvement in clinical outcomes and a concerning, albeit unexplained, mortality signal in heart failure patients.