XEN-D0501, a Novel TRPV1 Antagonist, Does Not Reduce Cough in Refractory Cough Patients

Maria G Belvisi, Mark A Birrell, Michael A Wortley, Sarah A Maher, Imran Satia, Huda Badri, Kimberley Holt, Patrick Round, Lorcan McGarvey, John Alexander Ford, Jaclyn A Smith

Research output: Contribution to journalArticlepeer-review

70 Citations (Scopus)
344 Downloads (Pure)

Abstract

RATIONALE: Heightened cough responses to inhaled capsaicin, a TRPV1 agonist, are characteristic of patients with chronic cough. However, previously a TRPV1 antagonist (SB-705498) failed to improve spontaneous cough frequency in these patients despite small reductions in capsaicin-evoked cough.

OBJECTIVES: XEN-D0501 (potent TRPV1 antagonist) was compared with SB-705498 in pre-clinical studies to establish whether an improved efficacy profile would support a further clinical trial of XEN-D0501 in refractory chronic cough.

METHODS: XEN-D0501 and SB-705498 were profiled against capsaicin in a sensory nerve activation assay and in vivo potency established against capsaicin-induced cough in the guinea pig. Twenty patients with refractory chronic cough participated in a double-blind, randomised, placebo-controlled, crossover study evaluating the effect of 14 days XEN-D0501 (oral, 4mg bd) versus placebo on awake cough frequency (primary outcome), capsaicin-evoked cough and patient reported outcomes.

MEASUREMENTS AND MAIN RESULTS: XEN-D0501 was more efficacious and 1000-fold more potent than SB-705498 at inhibiting capsaicin-induced depolarization of guinea pig and human isolated vagus. In vivo, XEN-D0501 completely inhibited capsaicin-induced cough whereas 100-times more SB-705498 was required to achieve the same effect. In patients, XEN-D0501 substantially reduced maximal cough responses to capsaicin (mean change from baseline XEN-D0501 -19.3(±16.4) coughs vs. placebo -1.8(±5.8), p<0.0001), but not spontaneous awake cough frequency (mean change from baseline XEN-D0501 6.7c/h(±16.9) vs. placebo 0.4c/h(±13.7), p =0.41).

CONCLUSIONS: XEN-D0501 demonstrated superior efficacy and potency in pre-clinical and clinical capsaicin challenge studies; despite this improved pharmacodynamic profile, spontaneous cough frequency did not improve, ruling out TRPV1 as an effective therapeutic target for refractory cough. 

Original languageEnglish
JournalAmerican Journal of Respiratory and Critical Care Medicine
Early online date26 Jun 2017
DOIs
Publication statusEarly online date - 26 Jun 2017

Keywords

  • Journal Article

Fingerprint

Dive into the research topics of 'XEN-D0501, a Novel TRPV1 Antagonist, Does Not Reduce Cough in Refractory Cough Patients'. Together they form a unique fingerprint.

Cite this