XEN-D0501, a novel TRPV1 antagonist, does not reduce cough in refractory cough patients

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-e...

[1]  Gary Layton,et al.  P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study , 2015, The Lancet.

[2]  K. Chung,et al.  Capsazepine inhibits cough induced by capsaicin and citric acid but not by hypertonic saline in guinea pigs. , 1995, Journal of applied physiology.

[3]  J. Smith,et al.  Clinical features of the urge-to-cough in patients with chronic cough. , 2015, Respiratory medicine.

[4]  I. Cuthill,et al.  Reporting : The ARRIVE Guidelines for Reporting Animal Research , 2010 .

[5]  M. Belvisi,et al.  Transient receptor potential channels mediate the tussive response to prostaglandin E2 and bradykinin , 2012, Thorax.

[6]  J. Karlsson,et al.  Cough induced by stimulation of capsaicin-sensitive sensory neurons in conscious guinea-pigs. , 1986, Acta physiologica Scandinavica.

[7]  P. Calverley,et al.  Capsaicin responsiveness and cough in asthma and chronic obstructive pulmonary disease , 2000, Thorax.

[8]  Kevin McGuinness,et al.  P159 Validation of the VitaloJAK™ 24 Hour Ambulatory Cough Monitor , 2012, Thorax.

[9]  J. Smith,et al.  Transient receptor potential cation channel, subfamily V, member 4 and airway sensory afferent activation: Role of adenosine triphosphate , 2016, The Journal of allergy and clinical immunology.

[10]  N. Choudry,et al.  Sensitivity of the cough reflex in patients with chronic cough. , 1992, The European respiratory journal.

[11]  T. Fahey,et al.  Systematic review of randomised controlled trials of over the counter cough medicines for acute cough in adults , 2002, BMJ : British Medical Journal.

[12]  J. Smith,et al.  Transient receptor potential vanilloid 1 (TRPV1) antagonism in patients with refractory chronic cough: a double-blind randomized controlled trial. , 2014, The Journal of allergy and clinical immunology.

[13]  I. Pavord,et al.  Cough and glottic-stop reflex sensitivity in health and disease. , 2005, Chest.

[14]  J. Smith,et al.  Capsaicin‐evoked cough responses in asthmatic patients: Evidence for airway neuronal dysfunction , 2017, The Journal of allergy and clinical immunology.

[15]  Laura R. Sadofsky,et al.  TRPA1 agonists evoke coughing in guinea pig and human volunteers. , 2009, American journal of respiratory and critical care medicine.

[16]  M. Belvisi,et al.  Tiotropium modulates transient receptor potential V1 (TRPV1) in airway sensory nerves: A beneficial off-target effect?⋆☆ , 2014, The Journal of allergy and clinical immunology.

[17]  Sally J. Singh,et al.  Development of a symptom specific health status measure for patients with chronic cough: Leicester Cough Questionnaire (LCQ) , 2003, Thorax.

[18]  J. Smith,et al.  Pharmacodynamic modeling of cough responses to capsaicin inhalation calls into question the utility of the C5 end point. , 2013, The Journal of allergy and clinical immunology.

[19]  J. Smith,et al.  Targeting TRP channels for chronic cough: from bench to bedside , 2015, Naunyn-Schmiedeberg's Archives of Pharmacology.

[20]  D. Julius,et al.  A capsaicin-receptor homologue with a high threshold for noxious heat , 1999, Nature.

[21]  P. Barnes,et al.  Capsazepine as a selective antagonist of capsaicin-induced activation of C-fibres in guinea-pig bronchi. , 1992, European journal of pharmacology.

[22]  L. McGarvey,et al.  Are there clinical features of a sensitized cough reflex? , 2009, Pulmonary pharmacology & therapeutics.

[23]  J. Smith,et al.  Neurophenotypes in Airway Diseases. Insights from Translational Cough Studies. , 2016, American journal of respiratory and critical care medicine.

[24]  D. Forman,et al.  Cough in the community: a cross sectional survey and the relationship to gastrointestinal symptoms , 2006, Thorax.

[25]  I. Pavord,et al.  Recommendations for the management of cough in adults , 2006, Thorax.

[26]  Mark J. Rose,et al.  Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans , 2008, PAIN.

[27]  Jim A. Wright,et al.  Characterization of SB-705498, a Potent and Selective Vanilloid Receptor-1 (VR1/TRPV1) Antagonist That Inhibits the Capsaicin-, Acid-, and Heat-Mediated Activation of the Receptor , 2007, Journal of Pharmacology and Experimental Therapeutics.

[28]  P. Calverley,et al.  Capsaicin induced cough in cryptogenic fibrosing alveolitis , 2000, Thorax.

[29]  Discovery of SB-705498: a potent, selective and orally bioavailable TRPV1 antagonist suitable for clinical development. , 2006, Bioorganic & medicinal chemistry letters.