Eliapixant is a selective P2X3 receptor antagonist for the treatment of\xa0disorders\xa0associated with\xa0hypersensitive\xa0nerve fibers

Adam J Davenport,Nikisha Carty,Ioana Neagoe,Mark J Gemkow,Nico Bräuer,Thomas M Zollner,Jens Nagel,Stephen D Hess,Susan Boyce,Alexis Laux-Biehlmann,Frederic Machet,Andrea Rotgeri,Oliver M Fischer,Markus Koch,Anne-Marie Coelho

doi:10.1038/s41598-021-99177-0

Abstract

ATP-dependent P2X3 receptors play a crucial role in the sensitization of nerve fibers and pathological pain pathways. They are also involved in pathways triggering cough and may contribute to the pathophysiology of endometriosis and overactive bladder. However, despite the strong therapeutic rationale for targeting P2X3 receptors, preliminary antagonists have been hampered by off-target effects, including severe taste disturbances associated with blocking the P2X2/3 receptor heterotrimer. Here we present a P2X3 receptor antagonist, eliapixant (BAY 1817080), which is both highly potent and selective for P2X3 over other P2X subtypes in vitro, including P2X2/3. We show that eliapixant reduces inflammatory pain in relevant animal models. We also provide the first in vivo experimental evidence that P2X3 antagonism reduces neurogenic inflammation, a phenomenon hypothesised to contribute to several diseases, including endometriosis. To test whether eliapixant could help treat endometriosis, we confirmed P2X3 expression on nerve fibers innervating human endometriotic lesions. We then demonstrate that eliapixant reduces vaginal hyperalgesia in an animal model of endometriosis-associated dyspareunia, even beyond treatment cessation. Our findings indicate that P2X3 antagonism could alleviate pain, including non-menstrual pelvic pain, and modify the underlying disease pathophysiology in women with endometriosis. Eliapixant is currently under clinical development for the treatment of disorders associated with hypersensitive nerve fibers.

Highlights

P2X3 receptors are adenosine triphosphate (ATP)-activated ion channels expressed on peripheral sensory neurons and are well-recognized players in the generation of pathological p ain[1,2]
We have developed a selective P2X3 receptor antagonist, eliapixant (BAY 1817080; structure shown in Supplementary Fig. S1), which is currently undergoing clinical testing in phase IIb trials for refractory and/or unexplained chronic cough (RUCC), phase IIa trials for overactive bladder (OAB), phase IIa trials for diabetic neuropathic pain, and phase IIb trials for endometriosis (Supplementary Table S1)
Using recombinant 1321N1 cell lines and a fluorescence imaging plate reader (FLIPR)-based calcium flux assay, we showed that eliapixant was ~ 20-fold more potent against the human (h) P2X3 homotrimer receptor than the hP2X2/3 heterotrimer receptor

Summary

Introduction

P2X3 receptors are adenosine triphosphate (ATP)-activated ion channels expressed on peripheral sensory neurons and are well-recognized players in the generation of pathological p ain[1,2]. In rat models of endometriosis, the levels of endogenous ATP and expression of P2X3 receptors were increased in both endometriotic lesions and dorsal root ganglion (DRG) tissue, and delivery of a P2X3 receptor antagonist reduced peripheral hyperalgesia in this s etting[17,37,42]. It remains unclear if the beneficial effects of P2X3 receptor antagonism on peripheral pain translate to visceral pain (i.e., the disease-relevant pain pathway in women with endometriosis). This strategy offers advantages over current hormone-based treatments for endometriosis (e.g., gonadotropinreleasing hormone agonists/antagonists43), as it would allow for long-term treatment, does not interfere with the menstrual cycle, and, importantly, could target non-menstrual pelvic pain

Methods

Results

Conclusion