Effect of AX-8, a TRPM8 Agonist, on Cough Bouts in Refractory or Unexplained Chronic Cough Patients, a Proof-of-Concept Study

<bold>Background:</bold> The efficacy of new drugs to treat refractory or unexplained chronic cough (RCC/UCC) is assessed by quantifying cough in sound recordings. Our 2-week, randomised, double-blind, placebo-controlled crossover study, evaluated the efficacy and safety of AX-8, a TRPM8 agonist, in RCC/UCC patients. Here, we compare the effect of AX-8 on cough bouts relative to the change in the frequency of individual coughs. <bold>Methods:</bold> Participants had RCC/UCC ≥1yr, cough severity visual analogue scale (VAS) score ≥40mm and 24h cough frequency ≥10 coughs/h at screening. 51 participants received two doses of AX-8 (40mg orally disintegrating tablet) or placebo 8 hours apart. We studied how day 1 treatment affected frequency of cough vs cough bouts (inter-cough intervals ≤2s or ≤3s, as best-supported values in literature) in a predefined subset of patients with moderate-to-severe throat discomfort i.e., with baseline throat discomfort VAS score ≥55mm/median value, n=24 of the per protocol set). <bold>Results:</bold> Analyses of the throat discomfort subgroup showed a significant reduction in cough frequency vs. placebo, especially in the 4h after dosing: 4h (42%, p<0.005), 24h (25%, p<0.01). Reduction in bout frequency vs placebo was more pronounced irrespective of the inter-cough interval; cough bouts with inter-cough interval ≤2s: 4h (48%, p<0.005), 24h (32%, p<0.005); with inter-cough interval ≤3s: 4h (48%, p<0.001), 24h (32%, p<0.005). <bold>Conclusions:</bold> Our data suggests that treatment with a TRPM8 agonist has potential for controlling RCC/UCC, especially in patients with throat discomfort, and that this treatment may particularly address cough bouts which are important to patients.