Gefapixant yields modest improvements in refractory, unexplained chronic cough vs. placebo
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Gefapixant only showed small effects vs. placebo on objective cough frequency, cough severity and quality of life among adults with refractory or unexplained chronic cough, according to results of a systematic review and meta-analysis.
These results, published in JAMA in conjunction with a presentation at the European Respiratory Society International Congress, must be interpreted considering the improvements seen in the placebo cohort, according to Imran Satia, MD, PhD, assistant professor in the department of medicine of the division of respirology at McMaster University.
“It must be remembered that patients who took gefapixant (MK-7264, Merck) and were able to tolerate the medication experienced a large improvement in daily cough frequency, but patients who received placebo also experienced large benefits,” Satia told Healio. “As a result, the difference compared to placebo was modest.”
Early phase 2 studies previously showed that gefapixant, a P2X3 receptor antagonist, significantly reduced the frequency of daily cough and improved patient-reported symptoms.
“However, earlier studies were at higher doses, and almost all patients developed taste disturbances, such as loss of tase, altered taste or reduced taste,” Satia said. “Therefore, in subsequent larger and longer clinical trials, lower doses were used to make side effects more tolerable but still improve objective and subjective measurements of cough. We wanted to conduct this research to understand the relationship between how effective and tolerable gefapixant performs at these much lower doses, particularly twice daily 45 mg, which is likely the dose to be used in clinical practice.”
Cough outcomes, adverse events
To evaluate the efficacy and safety of gefapixant for adults with refractory or unexplained chronic cough, Satia and colleagues reviewed MEDLINE, Embase, Cochrane Central Register of Controlled Trials and Web of Science to identify nine randomized controlled trials published between November 2014 and July 2023 and comprised of 2,980 patients (mean age, 58.5 years; 75.7% women; median cough duration, 11.6 years). Eight of the trials compared gefapixant with placebo, whereas one of the trials evaluated different doses of the drug.
Researchers evaluated several outcomes — including cough frequency, cough severity, cough-specific quality of life and adverse events — using random-effects dose-response meta-analysis or pairwise meta-analysis. They also used the Grading of Recommendations, Assessment, Development and Evaluation approach to rate the certainty of whether patients would deem the determined effects as important, defined as greater than the minimal important difference (MID) or small, defined as less than the MID.
Data from six of the trials (n = 2,472) on 24-hour cough frequency showed that 45 mg gefapixant twice daily showed a small effect, with a 16% (95% CI, 9.4%-22%) reduction compared with placebo and a 4.7% (95% CI, 0.6%-8.7%) risk difference in achieving at least the MID, indicating moderate certainty. A 60 mg twice daily dose showed an important reduction with moderate certainty (20.7% reduction; 95% CI, 12.5%-28.3%).
Using data from three trials (n = 2,145), researchers found 45 mg twice daily gefapixant had a small effect on awake cough frequency (17.6% reduction; 95% CI, 10.6%-23.7%) at moderate certainty (risk difference for achieving at least the MID, 6.9%; 95% CI, 3.3%-10.5%), with important improvements again seen at the 60 mg dose (22.8% reduction, 95% CI, 14%-30.7%) with moderate certainty.
Researchers noted no relationships between treatment and sleep cough frequency.
Among four trials (n = 2,292) that assessed cough severity using the 100-mm VAS, 45 mg twice daily gefapixant had a small effect (mean difference, –6.2 mm; 95% CI, –4.1 to –8.4) with high certainty (risk difference for achieving at least the MID, 11%; 95% CI, 6.8%-15.2%).
Based on assessments using the Leicester Cough Questionnaire in eight trials (n = 2,651), 45 mg gefapixant conferred a mean increase of one point (95% CI, 0.7-1.4) on measures of cough-specific quality of life at moderate certainty (risk difference for achieving at least the MID, 9.2%; 95% CI, 5.6%-12.8%).
Further, data showed that the 45 mg twice daily dose increased the occurrence of treatment-related adverse events (RR = 2.7; 95% CI, 1.7-4.4), taste-related adverse events (RR = 9; 95% CI, 6.5-12.6) and adverse events leading to discontinuation (RR = 4.3; 95% CI, 3.2-5.8), with smaller increases in risk seen at a 15 mg twice daily dose.
Potential placebo effect
This analysis presents data suggesting gefapixant “does not appear to have satisfied the unmet need for successfully treating patients with chronic refractory or unexplained coughs with an efficacious and tolerable drug,” Richard S. Irwin, MD, and J. Mark Madison, MD, both of UMass Chan Medical School, wrote in an accompanying editorial.
However, the fact that patients on placebo showed improvements in two trials of gefapixant — COUGH-1 and COUGH-2 — included in this meta-analysis raises questions such as whether the patients included in the trials actually had true refractory or unexplained chronic cough or whether a placebo effect played a role in improving patients’ symptoms.
“If a seemingly large placebo effect is partially attributable to unknown or untreated comorbidities such as GERD leading to chronic cough in a larger proportion of the COUGH-1 and COUGH-2 participants receiving placebo compared with those receiving gefapixant, it might be premature to conclude that P2X3 antagonists have only modest effects on refractory or unexplained cough until there are new studies that selectively enroll only patients with truly refractory and truly unexplained chronic cough,” Irwin and Madison wrote.
In current practice, once chronic cough is diagnosed after physicians rule out other conditions such as underlying lung diseases, gastroesophageal reflux disease or nasal disease, not many treatment options exist, Satia told Healio.
“We badly need more treatments for refractory and unexplained chronic cough,” he said.
“Unfortunately, for this condition, there are no licensed treatments and guidelines recommend trying ‘off-label’ use of low-dose opioids, pregabalin, gabapentin or speech therapy,” he added. “However, it should be noted that the quality of evidence is very low for these treatments. Hence, compared to these drugs, which are often not very safe with a risk of more serious side effects, gefapixant may prove to be a useful treatment option.”
For more information:
Imran Satia, MD, PhD, can be reached at satiai@mcmaster.ca.
References:
- Irwin RS, et al. JAMA. 2023;doi:10.1001/jama.2023.18508.
- Kum E, et al. Poster 3033. Presented at: European Respiratory Society International Congress; Sept. 9-13, 2023; Milan.