To the Editor:
Gefapixant is a P2X3 receptor antagonist that has demonstrated efficacy in COUGH-1 [A Study of Gefapixant (MK-7264) in Adult Participants with Chronic Cough (MK-7264-027)] and COUGH-2 [A Study of Gefapixant (MK-7264) in Adult Participants with Chronic Cough (MK-7264-030)], two phase III trials for the treatment of refractory chronic cough (RCC; a cough that persists despite treatment of cough-related conditions) and unexplained chronic cough (UCC; a cough that persists despite a full clinical evaluation that does not identify a comorbid condition associated with chronic cough) (1). Data demonstrating the durability of effect on RCC and UCC are important, as is the evaluation of outcome measures that reflect the patient perspective. No prior study has explored the durability of chronic cough treatment over time periods of up to 52 weeks. We present patient-reported outcome (PRO) data evaluating long-term benefit and safety over 52 weeks from COUGH-1 and COUGH-2.
Methods
The design, entry criteria, and procedures for COUGH-1 and COUGH-2 have been described previously (1, 2). The main study periods, during which the primary efficacy endpoint of 24-hour cough frequency (measured objectively) was evaluated, were 12 weeks (COUGH-1) and 24 weeks (COUGH-2). The main study periods were followed by blinded 40-week (COUGH-1) and 28-week (COUGH-2) extension periods for a total of 52 weeks; 24-hour cough frequency was not evaluated in the extension periods.
The present analysis evaluated a pooled dataset of both studies through 52 weeks of treatment. Although gefapixant 45 mg twice daily demonstrated statistically significant improvement versus placebo in primary and secondary endpoints during the main study periods, gefapixant 15 mg twice daily did not (1); therefore, the PRO and safety and tolerability results for the gefapixant 45 mg arm and placebo arm are presented here.
PROs were collected through 52 weeks as secondary endpoints and included the Leicester Cough Questionnaire (LCQ), cough severity visual analog scale (VAS), and Cough Severity Diary (CSD). The LCQ is a 19-item questionnaire assessing cough-specific health-related quality of life; a lower score (total LCQ score range, 3–21) indicates a lower quality of life, and a ⩾1.3-point increase from baseline in the LCQ total score was considered to be a clinically meaningful improvement (3). Participants assessed cough severity on a VAS from 0 to 100 mm; a ⩾30-mm reduction was considered clinically meaningful improvement (4). The CSD includes seven items (total CSD score range, 1–10); levels of clinically meaningful improvement were assessed as a ⩾1.3-point (first threshold) or ⩾2.7-point (second threshold) reduction from baseline (5). Efficacy was evaluated with least-squares means over time and responder analyses using definitions of clinically meaningful improvement at Weeks 12, 24, and 52 (analyzed using a logistic regression model) (1).
Adverse events (AEs) were assessed at each clinical visit (screening, baseline, randomization), then every 4 weeks until Week 24, then every 7 weeks thereafter. Data on all AEs reported in the trials have been described previously (1). Among these, taste-related AEs (dysgeusia, ageusia, hypogeusia, or related terms) were prespecified for analysis (1). Post hoc analyses of discontinuation due to a taste-related AE, time to discontinuation due to a taste-related AE, and time to resolution of taste-related AEs were conducted.
Results
The pooled trial population included 2,044 participants across three treatment arms. Of these, 1,631 continued in the extension periods and 1,534 completed 52 weeks of treatment. Participants were mostly female (75%) and White (80%), with mean cough duration of 11.3 years (1). In this analysis, focused on two treatment arms, 683 participants were treated with gefapixant 45 mg twice daily, and 675 participants were treated with placebo.
Least-squares mean PROs in both the placebo and gefapixant groups improved over 52 weeks, with numerically greater improvement observed with gefapixant 45 mg twice daily versus placebo (Figure 1). The odds for achieving a clinically meaningful response were improved for gefapixant 45 mg twice daily versus placebo at each time point for each PRO (Figure 1).
Figure 1.
Mean (SE) patient-reported outcome values over 52 weeks and odds ratios at Weeks 12, 24, and 52 for achieving clinically meaningful improvements in the LCQ total score, mean weekly cough severity VAS, and mean weekly CSD for gefapixant 45 mg twice daily versus placebo. BID = twice daily; CSD = Cough Severity Diary; LCQ = Leicester Cough Questionnaire; VAS = visual analog scale.
At 52 weeks, there was a higher proportion of participants who reported at least one taste-related AE in the gefapixant 45 mg twice daily arm (447 of 683; 65.4%) than in the placebo arm (47 of 675; 7.0%). There was also a higher proportion of participants who discontinued because of a taste-related AE in the gefapixant 45 mg twice daily arm (95 of 683; 13.9%) than in the placebo arm (2 of 675; 0.3%). Of the discontinuations resulting from taste-related AEs in the gefapixant 45 mg twice daily group, half occurred during the initial 4 weeks of treatment.
As previously reported, among 447 participants with taste-related AEs in the gefapixant 45 mg twice daily group, 429 (96%) had documented resolution as of database lock (1); 63% had resolution after discontinuation, whereas 25% had resolution on or before the day of the last dose (Figure 2). There were 18 (4%) participants who did not have documented resolution as of database lock. An analysis of follow-up information obtained as of December 2021 (after database lock) showed that only 7 of 683 gefapixant participants had unresolved taste-related AEs, which was nearly identical to the number of placebo participants with unresolved taste-related AEs (n = 6 of 675 participants).
Figure 2.
Resolution of taste-related AEs reported by 447 participants in the gefapixant 45 mg twice daily group. AE = adverse event.
Discussion
The results of this analysis demonstrate that a greater proportion of participants receiving gefapixant 45 mg twice daily than those who received placebo achieved clinically meaningful improvements in PROs that were maintained over 52 weeks of treatment. In the gefapixant 45 mg twice daily arm, the most common AEs were related to taste, as seen in previous gefapixant studies (6, 7) and consistent with preclinical evidence indicating that expression of either P2X3 homotrimers or P2X2/3 heterotrimers or both on gustatory nerves is essential for taste responses in mice (6–8).
In the vast majority (99%) of participants, taste-related AEs resolved, and this percentage was the same in the gefapixant and placebo arms. Although most of these AEs resolved after the last day of treatment, one-fourth of participants had resolution while still receiving gefapixant. As previously observed, taste-related AEs were not considered serious or a cause of hospitalization, meaning that even the taste-related AEs that led to discontinuation can be considered an issue of tolerability rather than safety.
Consistent with previous trials of chronic cough treatments, and as seen with both objective cough frequency and PROs in the main study periods, a robust placebo response was observed through Week 52; this may be consistent with the identified role of the central nervous system component of the cough reflex arc (9). Nonetheless, these studies demonstrate efficacy with gefapixant and are the largest and longest prospective clinical trials in RCC or UCC to date. These data indicate that gefapixant may be an important, durable treatment for RCC and UCC, which are long-lasting conditions with a significant unmet need for safe and effective treatments.
Acknowledgments
Acknowledgment
Medical writing support was provided by Anish Mehta of Merck & Co., Inc., Rahway, NJ. The authors thank Jennifer Pawlowski, M.S., of Merck & Co., Inc., Rahway, NJ, for editorial and administrative support. Additional editorial support was provided by Jenna Lewis, M.A., E.L.S., of MedThink SciCom, Cary, NC, and funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ.
Footnotes
Supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ. S.S.B. receives research support from the National Institute for Health Research Wellcome King’s Clinical Research Facility, National Institute for Health Research Biomedical Research Centre at South London and Maudsley NHS Foundation Trust, King’s College London. J.A.S. is funded by the National Institute for Health Research Manchester Biomedical Research Centre and a Wellcome Investigator Award and is a National Institute for Health Research senior investigator. L.P.M. receives research support from the Northern Ireland Clinical Research Network and by the National Institute for Health Research Clinical Research Facilities and Clinical Research Network staff.
Data availability: The data-sharing policy, including restrictions, of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, is available at https://engagezone.msd.com/ds_documentation.php. Requests for access to the clinical study data can be submitted through the Engage Zone site or via e-mail to dataaccess@merck.com.
Author Contributions: S.S.B., P.V.D., J.A.S., A.H.M., L.P.M., I.D.P., J.S., B.I., S.A.G., and D.R.M. contributed to the conception, design, or planning of the study. S.S.B., J.A.S., A.H.M., L.P.M., S.A.G., and D.R.M. contributed to data acquisition. P.V.D., J.A.S., A.H.M., I.D.P., Q.L., G.P., D.R.M., and C.L.R. contributed to the analysis of the data. S.S.B., J.A.S., A.H.M., L.P.M., I.D.P., A.M.N., J.S., Q.L., G.P., D.R.M., and C.L.R. contributed to interpretation of the results. J.A.S., A.H.M., L.P.M., I.D.P., J.S., and D.R.M. contributed to drafting of the manuscript. S.S.B., P.V.D., J.A.S., A.H.M., L.P.M., I.D.P., A.M.N., J.S., Q.L., B.I., S.A.G., G.P., D.R.M., and C.L.R. contributed to critically reviewing or revising the manuscript. All authors had access to the data, were responsible for the decision to submit the manuscript, and agree to be accountable for all aspects of the work.
Originally Published in Press as DOI: 10.1164/rccm.202211-2128LE on March 30, 2023
Author disclosures are available with the text of this letter at www.atsjournals.org.
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