The P2X3 receptor antagonist filapixant in patients with refractory chronic cough: a randomized controlled trial

Abstract

Background: P2X3 receptor antagonists seem to have a promising potential for treating patients with refractory chronic cough. In this double-blind, randomized, placebo-controlled study, we investigated the efficacy, safety, and tolerability of the novel selective P2X3 receptor antagonist filapixant (BAY1902607) in patients with refractory chronic cough.

Methods: Following a crossover design, 23 patients with refractory chronic cough (age: 60.4 ± 9.1 years) received ascending doses of filapixant in one period (20, 80, 150, and 250 mg, twice daily, 4-days-on/3-days-off) and placebo in the other. The primary efficacy endpoint was the 24-h cough frequency on Day 4 of each dosing step. Further, subjective cough severity and health-related quality of life were assessed.

Results: Filapixant at doses ≥ 80 mg significantly reduced cough frequency and severity and improved cough health-related quality of life. Reductions in 24-h cough frequency over placebo ranged from 17% (80 mg dose) to 37% (250 mg dose), reductions over baseline from 23% (80 mg) to 41% (250 mg) (placebo: 6%). Reductions in cough severity ratings on a 100-mm visual analog scale ranged from 8 mm (80 mg) to 21 mm (250 mg). No serious or severe adverse events or adverse events leading to discontinuation of treatment were reported. Taste-related adverse events occurred in 4%, 13%, 43%, and 57% of patients treated with filapixant 20, 80, 150, and 250 mg, respectively, and in 12% treated with placebo.

Conclusions: Filapixant proved to be efficacious, safe, and-apart from the occurrence of taste disturbances, especially at higher dosages-well tolerated during the short therapeutic intervention. Clinical trial registration EudraCT, eudract.ema.europa.eu, 2018-000129-29; ClinicalTrials.gov, NCT03535168.

Keywords: Airway hyperreactivity; Airway hyperresponsiveness; Cough reflex sensitivity; P2X3 receptor antagonist; Proof of concept; Receptor pharmacology; Refractory chronic cough; Taste disturbances.

Fig. 1

Study design and study procedures. Patients were randomized either to the treatment sequence ‘active drug followed by placebo’ or to the sequence ‘placebo followed by active drug’. Doses of filapixant or placebo were administered twice daily for 4 days at each dose step. On D3, 10, 17, and 24, the patient stayed at the clinical unit until about 6 h after the morning dose and returned on the next morning. PK blood samples were taken predose and 1, 2, 4, 6, and 12 h postpose. D…, day number …; LCQ, Leicester Cough Questionnaire; PK, pharmacokinetic(s); VAS, visual analog scale

Fig. 2

Patient disposition

Fig. 3

Cough frequency and severity (Day 4): Changes from baseline and differences to placebo (Bayesian analyses). Error bars represent 90% credible limits. Placebo data were pooled across the four placebo ‘dose’ steps. Lower VAS scores indicate less severe cough. Total number of patients = 23

Fig. 4

Leicester Cough Questionnaire: Mean total score and domain scores at baseline and at the end of treatment (EOT). Red lines and symbols: active treatment period; gray lines and symbols: placebo period. Higher values indicate a better quality of life. Total number of patients = 23