BibTex format
@article{Belvisi:2017:10.1164/rccm.201704-0769OC,
author = {Belvisi, MG and Birrell, MA and Wortley, MA and Maher, SA and Satia, I and Badri, H and Holt, K and Round, P and McGarvey, L and Ford, J and Smith, JA},
doi = {10.1164/rccm.201704-0769OC},
journal = {American Journal of Respiratory and Critical Care Medicine},
pages = {1255--1263},
title = {XEN-D0501, a novel TRPV1 antagonist, does not reduce cough in refractory cough patients},
url = {http://dx.doi.org/10.1164/rccm.201704-0769OC},
volume = {196},
year = {2017}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - 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. Clinical trial registration available ww
AU - Belvisi,MG
AU - Birrell,MA
AU - Wortley,MA
AU - Maher,SA
AU - Satia,I
AU - Badri,H
AU - Holt,K
AU - Round,P
AU - McGarvey,L
AU - Ford,J
AU - Smith,JA
DO - 10.1164/rccm.201704-0769OC
EP - 1263
PY - 2017///
SN - 1073-449X
SP - 1255
TI - XEN-D0501, a novel TRPV1 antagonist, does not reduce cough in refractory cough patients
T2 - American Journal of Respiratory and Critical Care Medicine
UR - http://dx.doi.org/10.1164/rccm.201704-0769OC
UR - https://www.atsjournals.org/doi/10.1164/rccm.201704-0769OC
UR - http://hdl.handle.net/10044/1/52994
VL - 196
ER -