P2X3 receptor antagonist shows promise for treatment of refractory chronic cough
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A novel P2X3 receptor antagonist, in multiple doses up to 750 mg, was well tolerated, and higher doses significantly reduced cough count and severity compared with placebo in patients with refractory chronic cough.
The potent selective P2X3 receptor antagonist (BAY 1817080, Bayer AG) inhibited vagus nerve depolarization in preclinical models.
“An estimated 10% of the population has a chronic cough, which is often misdiagnosed as respiratory tract infections, asthma or COPD,” Alyn Morice, MD, FRCP, head of respiratory medicine and the Center for Cardiovascular and Metabolic Research at Hull York Medical School, University of Hull at East Yorkshire, United Kingdom, told Healio.
There are currently no approved pharmacological treatments for refractory chronic cough.
Researchers conducted a double-blind, placebo-controlled, randomized, two-way-crossover study to evaluate the safety and efficacy of oral BAY 1817080 10 mg, 50 mg, 200 mg and 750 mg twice daily for 7 days each. The researchers randomly assigned 40 adult nonsmokers (78% women; median age, 63 years; 98% white) with refractory chronic cough for at least 1 year who were unresponsive to 8 or more weeks of targeted treatment for identified underlying triggers, or had no underlying triggers.
Morice and colleagues reported the second component of the phase 1/2a study of this novel treatment. The data were scheduled for presentation at the American Thoracic Society International Conference.
The primary endpoint was the frequency and severity of adverse events.
Mild adverse events were reported in 49% of patients randomly assigned to BAY 1817080 compared with 65% of patients assigned placebo. Taste-related adverse events, which also occurred in chronic cough studies of another P2X3 receptor antagonist, gefapixant (Merck), occurred in 5% of patients assigned the 10 mg dose, 10% assigned 50 mg, 15% assigned 200 mg and 21% assigned 750 mg compared with 3% of those assigned placebo. Headache occurred in 3% to 13% of patients assigned BAY 1817080 compared with 15% of those assigned placebo, and fatigue occurred in 3% to 5% assigned BAY 1817080 compared with 10% assigned placebo. One patient in the placebo group developed obstructive pancreatitis due to cholelithiasis, according to the study abstract.
Higher doses of BAY 1817080 decreased 24-hour cough counts, the researchers reported. The mean relative decrease in 24-hour cough count vs. placebo was 15% with the 50 mg dose (90% CI, –0.4 to 27.6; P = .054), 23% with the 200 mg dose (90% CI, 8.9-34.4; P = .004) and 25% with the 750 mg dose (90% CI, 11.5-36.5; P = .002). In the placebo group, 24-hour cough count decreased by 17% (90% CI, 3.3-29.1; P = .025).
Patient-reported cough severity significantly improved with higher doses of BAY 1817080 (VAS score change vs. placebo: 50 mg, 6.7 [90% CI, 1.7-11.7]; 200 mg, 9.3 [90% CI, 4.1-14.4]; 750 mg, 14.5 [90% CI, 9.4-19.6]), according to the abstract.
The researchers concluded that BAY 1817080 may be a possible new treatment for refractory chronic cough.
“BAY 1817080 is the second P2X3 antagonist to demonstrate efficacy in the disease of chronic cough. It thus proves the concept that inhibition of P2X3 is a valuable treatment of this common, but poorly recognized disease,” Morice told Healio.
In March, Healio reported new data published in The Lancet Respiratory Medicine that showed a 50 mg dose of the P2X3 receptor antagonist gefapixant significantly reduced cough frequency in patients with chronic cough when compared with placebo.