Chronic Cough Drug Shows Some Benefit, but Taste-Related Events an Issue

MILAN -- Twice-daily doses of the oral P2X3 receptor antagonist gefapixant may improve refractory or unexplained chronic cough, but at the cost of adverse events, a meta-analysis and systematic review found.

Moderate-certainty evidence indicated that a 45-mg dose led to a small (17.6%, 95% CI 10.6-24.0) decrease in awake cough frequency, a small (16.0%, 95% CI 9.4-22.0) reduction in 24-hour cough frequency, and a 1-point improvement in cough-specific quality of life (95% CI 0.7-1.4) via the Leicester Cough Questionnaire (LCQ), reported Elena Kum, BSc, of McMaster University in Hamilton, Ontario, at the European Respiratory Society meeting.

Similarly, high-certainty evidence revealed a 6.2-mm decrease (95% CI -4.1 to -8.4) in cough severity on the 100-mm visual analog scale (VAS). Findings were published simultaneously in JAMA.

Despite these improvements, the 45-mg dose of the P2X3 antagonist likely led to an important increase in treatment-related adverse events (AEs) and taste-related AEs versus placebo, each by 32 more events per 100 patients treated. A 15-mg dose of the drug was also associated with similar, but smaller, increases in taste-related AEs, at six more events per 100 patients, according to high-certainty evidence.

These findings come just before the FDA is set to hold an advisory committee regarding the drug's efficacy on November 17. The agency previously rejected the drug for chronic cough, requesting further data. While a 45-mg dose of gefapixant met its primary endpoint of reducing 24-hour cough frequency in two previous phase III trials, COUGH-1 and COUGH-2, 15-mg doses failed to meet those endpoints in both instances.

"We badly need more treatments for refractory and unexplained chronic cough," said co-investigator Imran Satia, MD, PhD, also of McMaster University.

"Unfortunately, for this condition, there are no licensed treatment and guidelines recommend trying 'off-label' use of low-dose opioids, pregabalin, gabapentin, or speech therapy," he told MedPage Today. "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."

Satia emphasized that "for patients who are initially presenting with chronic cough in primary care, it is important to rule out any serious underlying lung diseases, or any symptoms of gastroesophageal reflux disease or nasal disease. However, many patients have no underlying condition or despite treatment targeting identified conditions, the chronic cough persists."

In the meta-analysis, patient improvements were also seen in placebo groups, with awake cough frequency improved by 54.8%, cough-specific quality of life up 3 points on LCQ, and cough severity lowered by 24.2 mm on VAS. The researchers cited the potential impact of the placebo effect.

Richard S. Irwin, MD, and J. Mark Madison, MD, both of the University of Massachusetts Chan Medical School in Worcester, said in an accompanying editorial that it was still important to have placebo groups in these kinds of trials.

"Why should patients with a truly chronic refractory and unexplained cough consistently respond so favorably to mere placebo and do so for 12 weeks in COUGH-1 and 24 weeks in COUGH-2 and then for 52 weeks in blinded extension periods of 40 weeks in COUGH-1 and 28 weeks in COUGH-2?" they wrote. "The most likely explanation is that it is due to the importance of the placebo effect in cough clinical trials, a phenomenon that has been known for years primarily in acute cough studies but one that is especially prominent in the gefapixant trials."

"Also, it would not be surprising if study participants with taste-related adverse effects suspected that they were receiving the active drug, effectively unblinding some participants," they said. "Whatever the reason(s) for the large placebo effect, it is important to compare any new drug with placebo; it is the only way to control for the placebo effect of the trial drug and estimate the true, specific, drug effect."

When compared to placebo, both doses of gefapixant were associated with a rise in AEs leading to discontinuation:

• 45-mg dose: RR 4.3 (95% CI 3.2-5.8)
• 15-mg dose: RR 1.9 (95% CI 1.6-2.2)

Nine randomized controlled trials were included in the meta-analysis, with 2,980 adult patients receiving twice-daily gefapixant doses (15 mg, 30 mg, 45 mg, or 60 mg) or placebo. Of those, 75.7% were women, the average age was 58.5, and participants had experienced cough symptoms for an average of 11.6 years.

All nine trials measured taste disturbance, while 24-hour cough severity and awake cough frequency was measured in six trials, sleep cough frequency in four, cough severity and cough-specific quality of life in eight trials, and five trials measured treatment-related AEs.

Benefit in cough-related outcomes was most clear with the 60-mg dose of gefapixant, but this dose was also the least tolerable. Researchers focused their analysis primarily on the 15 mg and 45 mg doses, given that regulators are most likely to consider these doses for approval. Data from November 2014 to July 2023 were analyzed.

Study limitations included the fact that there were no participants who were current smokers or had a 20 pack-year history, and uncertainty if patients had appropriate work-up before entering the trials.