P2X3 antagonists – potential treatments for endometriosis and chronic cough

How targeting mediators of excessive nerve signaling could improve the quality of life for patients enduring long-term chronic conditions.

Worldwide, around 10% of all women of childbearing age suffer from endometriosis and around 10% of the global population suffers from chronic cough, of which 10% of cases fall under the category refractory and/or unexplained (RUCC). Both conditions, endometriosis and RUCC, have a devastating impact on patients’ lives, yet neither has an approved long-term treatment option. What else could these two seemingly unrelated diseases possibly have in common?

Dysregulated afferent nerve fiber signaling by P2X3 receptors is believed to play a crucial role in the development and progression of both endometriosis and RUCC. P2X3 receptors are natural mediators of pain as well as inducers of neurogenic inflammation and are known to play a role in the cough reflex. Our global, cross-functional team is looking into mechanisms to inhibit the dysregulated nerve signaling via a P2X3 antagonist, a substance which interferes with or inhibits the physiological action of another. The antagonist, derived from the Bayer-Evotec multi-target alliance, may hold the potential for new, promising long-term treatment options for both patient groups and beyond.

Expert view

Dr. Oliver Martin Fischer, Principal Scientist and pharmacology expert in Gynecological Therapy Research, has worked for Bayer for 13 years. He reveals, “The chance to significantly improve the lives of millions of people through our work both inspires and motivates me. It’s exciting. For the P2X3 project, we joined forces with Evotec in a research alliance. Their research expertise in the area of pain and our strong background in gynecological treatments made it a perfect partnership. After several years of joint research into the P2X3 pathway in the initial indication endometriosis, our investigations evolved into additional, seemingly unrelated indications, like RUCC, underlining the exciting potential of this target.”

Bringing the innovation to life

The P2X3 receptor is mainly expressed on sensory nerve fibers and is involved in afferent nerve signaling in response to internal and external stimuli. “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,” says Fischer. “Over time, the body’s usual ability to cease the receptor’s hyperactivity for pain perception or reflexes is impaired, resulting in hypersensitivity to pain or uncontrollable bodily responses, like chronic coughing.”

Bayer is now exploring ways to block this receptor, to reduce the nerve fiber stimulations causing painful symptoms. Fischer explains, “we are developing compounds – small molecules that attach to P2X3 receptors– to interfere with the channels which pass on the signals. The aim is to eliminate the chance of exaggerated signals responsible for endometriosis pain or RUCC as a long-term treatment option. This would offer huge relief for patients.”

Disease indication endometriosis
Fischer’s advanced research makes him fully aware of how endometriosis patients suffer: “The excruciating pain, unpredictability of symptoms and prospect of infertility all devastate these women’s professional, social and personal lives, causing great emotional distress or depression. Pain levels are difficult to quantify objectively, so patients can endure symptoms for years before receiving a diagnosis.” There are no biomarkers for the disease, so once pain becomes too severe, an invasive laparoscopy is performed to find and excise possible lesions. As lesions can be spread throughout the entire abdominal region, difficult surgeries often take hours – and eliminating all lesions with one surgery is very challenging. As a consequence, patients have three abdominal surgeries per lifetime on average. “This motivates our focus on potential for new pathways for the disease, away from surgery”, says Fischer.

Classic medication, in the form of hormonal agents, such as oral contraceptives, is considered appropriate for initial phases. As the disease becomes more aggressive, GnRH antagonists are considered, which effectively force patients into artificial menopause. “Debilitating side effects like hot flashes, and risks, including bone density loss, make many women reluctant to take anti-hormonal therapies – creating a real need for alternative, non-hormonal approaches,” explains Fischer.

Disease indication chronic cough
Patients with chronic cough suffer continuously, as they cough between 10 and 100 times per hour for eight weeks or longer. Regular activities like¬ phone calls, meetings and theater visits become embarrassing or stressful. But the coughing continues – for months or even years. Lack of sleep from overnight bouts of hacking makes each day increasingly exhausting.

Fischer reveals, “Diagnosis for the 1-5% of patients stricken with RUCC worldwide can take months or years as, in order to label a refractory cough as ‘unexplained,’ all other possible causes must first be explored and ruled out.” Currently, there are only limited treatment options available to manage this condition. The call for a new approach is therefore urgent.

Project outlook

Since the start of phase I clinical trials, Bayer is now solely responsible for further clinical development of the P2X3 antagonists. Several early clinical trials in the P2X3 antagonist program are currently ongoing, with two trials in the indication RUCC having reached proof-of-concept phase. Here, the aim is to investigate the safety, tolerability and efficacy in groups comprising about 40 patients.

Based on its mode of action, further indications could potentially be targeted. Fischer concludes, “we will be excited to see whether our P2X3 antagonist can translate the promising preclinical results to the clinic and bring much-needed relief to suffering patients.”