Gefapixant: A Comprehensive Monograph on a First-in-Class P2X3 Antagonist for Chronic Cough

I. Executive Summary

Gefapixant, marketed under the brand name Lyfnua, is a first-in-class, orally administered, selective P2X3 receptor antagonist developed for the treatment of refractory or unexplained chronic cough (RCC/UCC).[1] This condition, characterized by a persistent and debilitating cough, has long represented a significant unmet medical need with no specifically approved therapies in many parts of the world. Gefapixant introduces a novel therapeutic approach, moving beyond non-specific central suppression to the targeted modulation of peripheral neural pathways.

The drug's mechanism of action involves blocking adenosine triphosphate (ATP)-gated P2X3 ion channels located on sensory C fibers in the airway lining.[1] By interrupting this signaling pathway, which is believed to drive the neuronal hypersensitivity underlying chronic cough, Gefapixant aims to reduce the exaggerated cough reflex.[2] This targeted approach represents a significant evolution in the pharmacological management of cough.

The clinical development program was anchored by two large, pivotal Phase 3 trials, COUGH-1 and COUGH-2. In these studies, the 45 mg twice-daily (BID) dose of Gefapixant met its primary endpoint, demonstrating a statistically significant reduction in 24-hour cough frequency compared to placebo.[6] However, the therapeutic gain over a substantial placebo response was modest, a critical point that would later dominate regulatory discussions.[9]