Pipeline Insights

On the path of P2X3 to address nerve hypersensitivity

Potential new treatment option for a variety of chronic diseases: How targeting a mediator of excessive nerve fiber signaling could improve the quality of life for patients suffering from refractory chronic cough, endometriosis, neuropathic pain or overactive bladder.

What began as a research project trying to find a better treatment for one condition, has transformed into a multi-indication program that now has the potential to provide a meaningful therapeutic option for a series of similar yet very different diseases, including refractory chronic cough, endometriosis, neuropathic pain and overactive bladder. Although not life-threatening, all these diseases have a debilitating effect on the life of a very large number of patients. P2X3 is assumed to play a key role in causing nerve hypersensitivity and neurogenic inflammation. 

 

The underlying mechanism

Expressed on sensory nerve fibers, P2X3 is one of many receptors activating afferent nerve signaling, meaning axonal projections that arrive at certain regions of the brain in response to internal and external stimuli. Under normal circumstances, activity of P2X3 signaling is modest, whereas under conditions of chronic inflammation, signaling activity through P2X3 is significantly enhanced. Dr. Oliver Martin Fischer, Principal Scientist and pharmacology expert at Bayer explains: “We believe that under certain disease conditions these nerve fibers become hypersensitive, until they are even activated without external stimuli – meaning something has gone wrong.” Over time, the body’s ability to cease the receptor hyperactivity for pain perception or reflexes is impaired, resulting in hypersensitivity to pain or chronic coughing, for example. 

 

Bringing the innovation to life

Bayer is now exploring ways to block the P2X3 receptor causing painful symptoms. “We are developing a P2X3 antagonist called eliapixant to interfere with the channels which pass on the signals,” says Fischer. “The aim is to eliminate exaggerated nerve signals and decrease nerve hypersensitivity responsible for refractory chronic cough or endometriosis pain. Ultimately, this would offer huge relief for patients.” 

Eliapixant is an investigational selective P2X3 receptor antagonist that was derived from Bayer’s former strategic research alliance on endometriosis with Evotec, a global drug discovery and development company.  Since the start of phase I clinical trials, Bayer is solely responsible for further development.

 

Project outlook

Based on an in-depth biochemical understanding of the role of P2X3 in chronic inflammation, Bayer decided to explore a novel path for its clinical development strategy: pursuing not one but multiple possible indications where neuronal hypersensitivity plays a role, in parallel early on. Several clinical trials with eliapixant are currently ongoing:  In September 2021, Bayer reported the positive outcome of a Phase IIb dose-finding study in patients with refractory chronic cough. A Phase IIb study in the indication endometriosis pain is ongoing, as are two Phase IIa studies evaluating eliapixant in overactive bladder and diabetic neuropathic pain. 

Also, further indications could potentially be targeted in the future.

Fischer concludes, “Early clinical data are encouraging. We are excited to see whether our P2X3 antagonist can continue to translate the promising research to the clinic and bring much-needed relief to suffering patients.”

 

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