A new agent, gefapixant (Afferent Pharmaceuticals/Merck) shows promise in relieving chronic cough, even when the cough has persisted for more than 15 years, results from a company-funded phase 2b trial suggest. Between 4% and 10% of adults worldwide suffer from an unexplained chronic cough lasting longer than 8 weeks, yet no approved treatments are currently available, according to the study published online today in The Lancet Respiratory Medicine. Gefapixant, a P2X3 agonist that blocks a receptor involved in the cough reflex, has been found in prior studies to reduce coughing frequency when given at a high dose (600 mg, twice daily) for two weeks. Further studies suggest that doses as low as 50 mg, given twice a day, may be effective as well. The current 12-week trial was a randomized, double-blind, placebo-controlled, multicenter trial testing three doses of gefapixant. Patients with chronic cough were recruited from 44 sites across the United Kingdom and the United States. "[P]hase 3 trials are already underway with an even larger group of people and over a longer timeframe," lead author Jaclyn Smith, MB, ChB, FRCP, PhD, from the University of Manchester, United Kingdom, said in a press release. Smith has received support from the drug's maker Afferent Pharmaceuticals/Merck. A total of 253 patients who had unexplained cough for an average 14.5 years were randomly assigned to receive either gefapixant or placebo (n = 63) twice a day, for 84 days. Gefapixant was administered in one of three doses: 7.5 mg (n = 64), 20 mg (n = 63), or 50 mg (n = 63). Cough frequency was recorded both in patient diaries and by sound recording device over four 24-hour periods, Smith and colleagues write. (Smith and several coauthors received grants and personal fees from Afferent Pharmaceuticals/Merck, and two coauthors are or were employees of the company.) Coughing Reduced by More Than Half Before treatment, patients coughed about 24 to 29 times per hour. After 12 weeks of treatment, the placebo group coughed 18 times per hour and the 50-mg dose group coughed 11 times per hour. The percentage reduction relative to placebo was –37.0% (95% Confidence Interval, –53.3 to –14.9; P = .0027), a reduction from baseline of 57.6% (47.2 to –65.9). The reductions in the other two dosage groups were not statistically significant. The most common side effect involved change in patients' sense of taste, which has been seen in previous trials with the drug. Distorted sense of taste and other taste-related side effects led 10 patients in the 50-mg group to withdraw from the trial, but most of the remaining patients said they would continue on the medication for at least a year. Exclusion criteria included current smokers, those who had quit smoking within 6 months of enrollment, and anyone who had used an opioid within 1 week of the study or had an upper or lower respiratory tract infection within 4 weeks of the study. A full list of exclusion and inclusion criteria is available with the paper. In an invited commentary, Richard Irwin, MD, from the University of Massachusetts Medical School in Worcester, and colleagues said that a strength of the study is the use of an objective measure of cough frequency with the acoustic device. They note that there was an apparent dose-dependent decrease in cough frequency in the unadjusted analysis, but a decrease was also seen among patients in the placebo group. "Because large placebo effects have been seen in other randomized, placebo-controlled cough treatment studies, the authors took this into account by analyzing cough frequency relative to placebo. When this was done, the improvement with the 50 mg dose, but not other doses, did reach statistical significance compared with placebo," Irwin and colleagues write. The ongoing phase 3 trial will be important, the editorialists say, so they can better gauge the efficacy of the 50-mg dose and whether the taste side effects are deemed tolerable. Until new drugs are available, Irwin and colleagues advise clinicians to first manage their patients under current practice guidelines. If the cough persists, "clinicians should consider, singly or in combination, multimodality speech pathology therapy with a knowledgeable speech pathologist trained in managing patients with chronic cough, or therapeutic trials of off-label neuromodulator therapy with gabapentin, pregabalin, amitriptyline, or, if those are not available, morphine." Before giving one of these drugs, they warn, it's important to discuss the risks and benefits with patients and reassess periodically. Smith and colleagues presented preliminary data from the phase 2b study at the American Thoracic Society (ATS) International Conference in 2017 in Washington, DC. This study was funded by Afferent Pharmaceuticals and supported by the Northern Ireland Clinical Research Network and the United Kingdom National Institute for Health Research. A full list of disclosures for other authors is included with the paper. Lancet Respiratory Medicine. Published online February 25, 2020. Full text Source
