Gefapixant shows promise in unexplained chronic cough

The first-in-class P2X3 receptor antagonist gefapixant effectively lessens the frequency of cough in patients with refractory or unexplained chronic cough of ≥1 year, a study has shown.

Chronic cough refers to a cough that lasts more than 8 weeks, and may be associated with underlying conditions such as asthma or GERD*. However, a chronic cough that does not improve with treatments of the associated conditions is classified as refractory, while that which occurs without evidence of underlying condition is considered as unexplained chronic cough.    

Calling unexplained chronic cough as “a challenging clinical disorder that has defied either diagnosis or treatment”, editorialists led by Dr Richard Irwin from the University of Massachusetts Medical School, Worcester, Massachusetts, US stressed the urgent need for development of therapies. [Lancet Respir Med 2020;doi: 10.1016/S2213-2600(20)30083-7]

“[Treatment of] refractory or unexplained chronic cough is an important unmet clinical need because there are no approved therapies,” said the researchers.

Gefapixant is a noncompetitive inhibitor of the purinergic receptor P2X3, an ATP-gated ion channel involved in the cough reflex.  

After 12 weeks, patients treated with gefapixant 50 mg had significantly fewer coughs from baseline compared with the placebo group (geometric mean frequency, 11.3 vs 18.2 coughs per hour), which translates to a 37.0 percent reduction vs placebo (p=0.0027). [Lancet Respir Med 2020;doi:10.1016/S2213-2600(19)30471-0]

“Efficacy was apparent as early as 4 weeks after initiation of treatment,” the researchers noted.

“Cough frequency remained below baseline for 2 weeks after the drug was stopped and did not show evidence of a rebound effect,” Irwin and co-authors pointed out.    

Other gefapixant doses tested also led to less frequent coughs (geometric mean frequency, -22.0 percent; p=0.097 for 7.5 mg and -22.2 percent; p=0.093 for 20 mg), although the differences between these lower doses and placebo were not significant.    

In addition, subjective measures of cough severity, as reported by patients on the visual analogue scale (least-squares [LS] mean difference vs placebo, -11.2 mm; p=0.0108) and diary total score (LS mean difference, -0.7; p=0.0197) showed similar reductions in favour of gefapixant 50 mg — supporting the findings from objective outcome of cough frequency.     

“In our study, gefapixant had a positive safety profile, with only one serious adverse event, deemed to be unrelated to the study drug,” said the researchers.

The most common adverse event was taste disturbance, occurring in 10 percent of patients in the gefapixant 7.5 mg group, 33 percent in the 20 mg group, and 48 percent in the 50 mg group, compared with 5 percent in the placebo group.

In the phase IIb, double-blind, multicentre trial, 253 patients (mean age 60.2 years, 76 percent women) with refractory or unexplained cough were randomized 1:1:1:1 to receive placebo or oral gefapixant at 7.5, 20, or 50 mg doses, twice daily for 84 days.

“The evidence from this trial supports further development of gefapixant [in] phase III studies … [which] are ongoing,” the researchers said. “[These further studies would provide further information on] whether cough reduction can be achieved without taste disturbance with this therapy.”

Caveats for practice

“[Clinicians should] practise intervention fidelity by closely adhering to the best clinical practice guidelines for chronic cough management … [This is] important to avoid cough due to treatable underlying causes being left undiagnosed and falsely labelled as unexplained,” cautioned Irwin and co-authors.

“[Also,] it is important to discuss with the patients the potential side-effects and risk–benefit profiles of treatment options, and to reassess at prearranged intervals the risk–benefit profiles before continuing the drugs,” they added.