TREATMENT OF REFRACTORY OR UNEXPLAINED CHRONIC COUGH WITH GEFAPIXANT, A P2X3 RECEPTOR ANTAGONIST, OVER 52 WEEKS IN TWO PHASE III CLINICAL TRIALS

TOPIC: Respiratory Care TYPE: Original Investigations PURPOSE: Gefapixant is a P2X3 receptor antagonist that demonstrated significant reduction in 24-hour cough frequency at 45 mg BID in two Phase III trials (COUGH-1 and COUGH-2) over treatment periods of up to 12 and 24 weeks in patients with refractory or unexplained chronic cough (RCC or UCC) (McGarvey et al. Eur Resp J. 2010;56 (suppl 64) 3800). Here, we present a pooled analysis of COUGH-1 and COUGH-2 over 52 weeks of treatment with gefapixant. METHODS: COUGH-1 and COUGH-2 were randomized, double-blind clinical trials in participants ≥18 years of age, with chronic cough ≥1 year, baseline cough severity visual analogue scale (VAS) score ≥40 mm, and a diagnosis of RCC or UCC (Irwin et al Chest. 2006 Jan;129(1 Suppl):1S-23S). Participants were randomized to placebo, gefapixant 15 mg BID, or gefapixant 45 mg BID for a total of 52 weeks. Efficacy through 52 weeks was measured using validated patient-reported outcomes (PROs) including the Leicester Cough Questionnaire (LCQ; total score from 3-21 points evaluating physical, psychological and social burden), the Cough Severity VAS (0-100 mm scale), and Cough Severity Diary (CSD; scores from 0-10 measuring cough frequency, intensity, and disruption due to cough). Logistic regression models evaluated change from baseline for the following responder definitions: LCQ total score increase of ≥1.3 points, ≥30 mm reduction in mean weekly cough severity VAS score, and ≥1.3-point reduction and ≥2.7-point reduction in mean weekly CSD total score. AEs were monitored throughout the study. RESULTS: The pooled dataset included 2,044 participants. Odds ratios for either dose of gefapixant vs. placebo for each responder endpoint favored gefapixant. Odds ratios (95% CI) for gefapixant 45 mg BID at 12, 24, and 52 weeks were: 1.42 (1.11, 1.83), 1.37 (1.06, 1.77), and 1.72 (1.31, 2.27) for the LCQ; 1.53 (1.21, 1.93), 1.70 (1.34, 2.16), and 1.47 (1.15, 1.89) for the VAS; 1.33 (1.05, 1.67), 1.47 (1.14, 1.90), and 1.62 (1.23, 2.15) for the CSD (≥1.3); and 1.49 (1.18, 1.89), 1.70 (1.33, 2.16) and 1.57 (1.21, 2.03) for the CSD (≥2.7), respectively. The most common AEs were those related to taste; taste-related AEs led to dose-related treatment discontinuation rates. Discontinuations due to taste-related AEs occurred in 14% of 45 mg BID participants. Serious AEs occurred in 6% in both the placebo and gefapixant 45 mg BID groups over 52 weeks. CONCLUSIONS: Gefapixant 45 mg BID resulted in efficacy over 52 weeks of treatment as assessed by several validated PRO measures. Discontinuations due to taste-related AEs were dose-related. The occurrence of serious AEs was similar in the gefapixant 45 mg BID and placebo groups. These results provide meaningful patient-relevant evidence in support of the long-term efficacy of gefapixant 45mg BID for the treatment of patients with chronic cough. CLINICAL IMPLICATIONS: In Phase 3 randomized clinical trials, gefapixant 45 mg BID demonstrated sustained improvement according to patient-reported outcomes and had an acceptable safety profile over 52 weeks of treatment for RCC or UCC. DISCLOSURES: Advisory Committee Member relationship with Merck Please note: $1001 - $5000 by Surinder Birring, source=Web Response, value=Consulting fee Consultant relationship with Merck Please note: 2017-2021 Added 04/28/2021 by Peter Dicpinigaitis, source=Web Response, value=Consulting fee Employee relationship with Merck & Co., Inc. Please note: 2015 to present Added 05/06/2021 by Carmen La Rosa, source=Web Response, value=Salary Employee relationship with Merck & Co., Inc. Please note: 12/2010 to now Added 04/30/2021 by Qing Li, source=Web Response, value=Salary No relevant relationships by Lorcan McGarvey, source=Web Response Advisory Committee Member relationship with Merck Please note: $5001 - $20000 by Alyn Morice, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Bellus Please note: $5001 - $20000 by Alyn Morice, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Bayer Please note: $5001 - $20000 by Alyn Morice, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Sanofi Please note: $5001 - $20000 by Alyn Morice, source=Web Response, value=Consulting fee Employee relationship with MSD Please note: 11/2016 to current Added 05/06/2021 by David Muccino, source=Web Response, value=Salary Employee relationship with Merck Sharp & Dohme Corp. Please note: May 1995 - present Added 04/30/2021 by Allison Nguyen, source=Web Response, value=Salary Advisory Committee Member relationship with GSK Please note: $1001 - $5000 by Ian Pavord, source=Web Response, value=Consulting fee Employee relationship with Merck & Co., Inc. Please note: 7 years Added 04/30/2021 by Jonathan Schelfhout, source=Web Response, value=Salary Scientific Medical Advisor relationship with Merck Please note: $1001 - $5000 by Jaclyn Smith, source=Web Response, value=Consulting fee Scientific Medical Advisor relationship with Vitalograph Ltd Please note: $5001 - $20000 by Jaclyn Smith, source=Web Response, value=Grant/Research Support Grant Funding relationship with Merck Please note: 2020-2022 Added 05/01/2021 by Jaclyn Smith, source=Web Response, value=Grant/Research Support No relevant relationships by Anjela Tzontcheva, source=Web Response