Gefapixant, a P2X3 receptor antagonist, for the treatment of refractory or unexplained chronic cough in a phase 2b randomised controlled trial

Background: Gefapixant is a P2X3 receptor antagonist in development for treatment of refractory (RCC) and unexplained chronic cough (UCC). Methods: We conducted a 12-week, Phase 2b, randomized, double-blind, placebo-controlled study in patients with RCC or UCC (u003e1 year) with no radiographic chest abnormality and ≥40 mm on the Cough Severity Visual Analog Scale [VAS]. Patients were randomized to receive placebo or gefapixant (7·5 mg BID, 20 mg BID, or 50 mg BID). The primary efficacy endpoint was placebo-adjusted change from baseline in Awake Cough Frequency (coughs/hour) after 12 weeks of treatment. Adverse events (AE) were monitored throughout the study. Findings: 253 patients were randomized to placebo (n=63), gefapixant 7·5 mg (n=64), 20 mg (n=63), or 50 mg (n=63). Mean (SD) age was 60 (10·0) years and 76% of patients were women. At 12 weeks, Geometric Mean Awake Cough Frequency was 18·2, 14·5, 12·0, 11·3 coughs/hr with placebo and gefapixant 7·5 mg, 20 mg, and 50 mg, respectively; % change vs. placebo (95% CI) was -37% (-53·3,-14·9) with gefapixant 50 mg (p=0·003), -22·2% (-42,4·3) with 20 mg (p=0·093), and -22·0% (-41·8,4·6) with 7·5 mg (p=0·097). Dysgeusia was the most common AE, occurring in 5%, 10%, 33%, and 48% of placebo and gefapixant 7·5-mg, 20-mg, and 50-mg patients, respectively. Interpretation: Targeting P2X3 with gefapixant at a dose of 50 mg BID significantly reduces cough frequency in patients with RCC and UCC after 12 weeks of treatment compared with placebo. Gefapixant was generally well tolerated with dysgeusia being the most frequent AE. Funding: This study was funded by Afferent Pharmaceuticals, which has been acquired by Merck u0026 Co., Inc., Kenilworth, NJ, USA. Clinical Trials Registry: NCT02612610   Research in Context Evidence before this study Literature search: Pubmed search, Oct 2015 terms: P2X3, Chronic Cough Chronic cough affects 4-10% of the general population, a proportion of whom have cough that does not resolve upon treatment of underlying conditions or for whom underlying conditions cannot be found. Hyper-excitability of neuronal pathways mediating cough may be a therapeutic target for patients with refractory or unexplained condition. A previous study of gefapixant, a P2X3 receptor antagonist at a supratherapeutic dose of 600 mg demonstrated significant reduction in cough frequency in patients with refractory chronic cough. Added value of this study We report the results from the largest trial to date in chronic cough subjects. This trial evaluated lower doses of gefapixant within a therapeutic dose range and over a longer (12 week)treatment period. Implications of all the available evidence These results confirm the therapeutic potential of targeting P2X3 receptors for clinically meaningful reduction of chronic cough. The evidence from this trial supports further development of gefapixant. Future Research Phase 3 studies evaluating gefapixant are ongoing and will confirm efficacy and tolerability of this novel mechanism.