The P2X3 receptor antagonist gefapixant is an effective treatment option for chronic cough, but studies have been plagued by a strong placebo response, hampering the likelihood of government subsidy approval, a respiratory meeting in the UK has heard.

Professor Surinder Birring from Kings College Hospital, London, told delegatesat the British Thoracic Society 2023 Winter meeting in London that stress urinary incontinence was an underappreciated consequence of chronic cough.

“It is distressing and very common as it affects two-thirds of women with chronic cough,” he told the audience at a session  entitled: ‘The drugs do work, new treatments in chronic cough’,

Prof Birring presented his findings from the phase 3 global trial on gefapixant in women with refractory or unexplained chronic cough and cough-induced urinary incontinence (C-SUI).

Following a two-week single-blind placebo run-in, participants were randomised to gefapixant 45mg twice a day [n=185] or to placebo [n=190].

Results showed a significantly greater reduction in C-SUI episodes at week 12 compared to the placebo group, with an estimated difference of -11.67% [-19.67%, -3.67% p=0.004].

One or more adverse events were reported in 69.7% and 37.4% of participants receiving gefapixant or placebo, respectively, with the most commonly reported event being dysgeusia, which reversed on discontinuation.

An exploratory analysis of the Cough Severity Diary (CSD) total score also demonstrated that gefapixant 45mg twice a day meaningfully reduced cough frequency, intensity and disruption.

Responding to a question from the floor on the 40 per cent reduction in stress incontinence seen in the control group, Prof. Birring noted that trials in chronic cough and urinary incontinence were ‘plagued’ by the placebo response.

“Here we have a double whammy.. the [treatment and placebo] arms were identical otherwise. Certainly, for the placebo effect in chronic cough, we can debate the causes, but we don’t really know. We have some ideas, but we do have to work out how to minimise them for regulatory purposes,” he said.

Duration of disease does not impact response

Speaking at the same session, Professor Jaclyn Smith from the Division of Infection, Immunity and Respiratory Medicine at the University of Manchester said gefapixant 45mg twice daily had shown efficacy for treating refractory or unexplained cough in patients with a chronic cough duration of ≥ 1 year in the phase 3 COUGH 1 and COUGH 2 trials or < 1 year in the phase 3 ROCC trial.

“Because participants in COUGH-1 and COUGH-2 had a mean chronic cough duration of ~11 years, it is not known if the duration of CC affects subjective treatment efficacy of gefapixant or represents different phenotypes of patients with CC,” she explained.

She presented the results of a post-hoc analysis of COUGH 1 and COUGH 2 trials evaluating whether the duration of chronic cough impacted the efficacy of gefapixant 45mg twice a day.

Results showed similar baseline characteristics and favourable responses for the treatment group compared to placebo, regardless of disease duration.

“It seems to suggest that when you look at patients who have had refractory or unexplained chronic cough for less than a year or greater than a year, they have very similar characteristics, and they respond very similar way to 45mg gefapixant twice a day…so it seems to be independent of chronic cough duration,” she said.

However, Professor Smith agreed that the significant placebo effects seen in the control groups of chronic cough trials were a problem that needed addressing if new treatments were to be approved by regulatory bodies.

“The FDA is very much focused on the difference over and above placebo. I think we will have to figure out what we can do to try and minimise placebo effects,” she said.

The FDA had recently voted against the P2X3 receptor antagonist largely due to the clinical benefit shown versus placebo, with experts describing the clinical benefit as ‘marginal’ [see the PADAC meeting here], she added.