XEN-D0501, a Novel Transient Receptor Potential Vanilloid 1 Antagonist, Does Not Reduce Cough in Patients with Refractory Cough.

Abstract

RATIONALE:

Heightened cough responses to inhaled capsaicin, a transient receptor potential vanilloid 1 (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 (a potent TRPV1 antagonist) was compared with SB-705498 in preclinical 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, randomized, placebo-controlled crossover study evaluating the effect of 14 days of XEN-D0501 (oral, 4 mg twice daily) 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 1,000-fold more potent than SB-705498 at inhibiting capsaicin-induced depolarization of guinea pig and human isolated vagus nerve. 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; placebo, -1.8 ± 5.8 coughs; P < 0.0001), but not spontaneous awake cough frequency (mean change from baseline, XEN-D0501, 6.7  ± 16.9 coughs/h; placebo, 0.4 ± 13.7 coughs/h; P = 0.41).

CONCLUSIONS:

XEN-D0501 demonstrated superior efficacy and potency in preclinical 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 registered with www.clinicaltrialsregister.eu (2014-000306-36).

• Authors: Maria G Belvisi, Mark A Birrell, Michael A Wortley, Sarah A Maher, Imran Satia, Huda Badri, Kimberley Holt, Patrick Round, Lorcan McGarvey, John Ford, Jaclyn A Smith
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 196 Issue 10 Pg. 1255-1263 (11 15 2017) ISSN: 1535-4970 [Electronic] United States
• PMID: 28650204 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antitussive Agents
• TRPV Cation Channels
• TRPV1 protein, human
• TRPV1 receptor
• Capsaicin

Topics

• Adult
• Aged
• Aged, 80 and over
• Antitussive Agents (therapeutic use)
• Capsaicin (therapeutic use)
• Chronic Disease (drug therapy)
• Cough (drug therapy)
• Cross-Over Studies
• Double-Blind Method
• Female
• Humans
• Male
• Middle Aged
• TRPV Cation Channels (agonists, therapeutic use)