Imperial College London
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DrMarkBirrell

Faculty of Medicine, National Heart & Lung Institute

Senior Research Fellow
 
 
 
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Contact

 

+44 (0)20 7594 8578m.birrell

 
 
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Location

 

103Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

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}
}
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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  -
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