Kimberley Holt

P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study.

BACKGROUND Preclinical studies suggest that P2X3 receptors are expressed by airway vagal afferent nerves and contribute to the hypersensitisation of sensory neurons. P2X3 receptors could mediate sensitisation of the cough reflex, leading to chronic cough. We aimed to investigate the efficacy of a first-in-class oral P2X3 antagonist, AF-219, to reduce cough frequency in patients with refractory chronic cough. METHODS We did a double-blind, placebo-controlled, two-period, crossover study at one UK centre. With a computer-generated sequence, we randomly assigned patients with refractory chronic cough to AF-219, 600 mg twice a day, or to placebo (1:1), and then, after a 2 week washout, assigned patients to receive the other treatment. Patients, health-care providers, and investigators were masked to sequence assignment. We assessed daytime cough frequency (primary endpoint) at baseline and after 2 weeks of treatment using 24 h ambulatory cough recordings. The primary analysis used a mixed effects model with the intention-to-treat population. This study was registered at ClinicalTrials.gov, number NCT01432730. FINDINGS Of 34 individuals assessed between Sept 22, 2011, and Nov 29, 2012, we randomly assigned 24 patients (mean age 54·5 years; SD 11·1). In the observed case analysis, cough frequency was reduced by 75% when patients were allocated to AF-219 compared when allocated to placebo (p=0·0003). Daytime cough frequency fell from a mean 37 coughs per h (SD 32) to 11 (8) coughs per h after AF-219 treatment versus 65 (163) coughs per h to 44 (51) coughs per h after placebo. Six patients withdrew before the end of the study because of taste disturbances, which were reported by all patients taking AF-219. INTERPRETATION P2X3 receptors seem to have a key role in mediation of cough neuronal hypersensitivity. Antagonists of P2X3 receptors such as AF-219 are a promising new group of antitussives. FUNDING Afferent Pharmaceuticals.

Neurophenotypes in Airway Diseases. Insights from Translational Cough Studies

RATIONALE Most airway diseases, including chronic obstructive pulmonary disease (COPD), are associated with excessive coughing. The extent to which this may be a consequence of increased activation of vagal afferents by pathology in the airways (e.g., inflammatory mediators, excessive mucus) or an altered neuronal phenotype is unknown. Understanding whether respiratory diseases are associated with dysfunction of airway sensory nerves has the potential to identify novel therapeutic targets. OBJECTIVES To assess the changes in cough responses to a range of inhaled irritants in COPD and model these in animals to investigate the underlying mechanisms. METHODS Cough responses to inhaled stimuli in patients with COPD, healthy smokers, refractory chronic cough, asthma, and healthy volunteers were assessed and compared with vagus/airway nerve and cough responses in a cigarette smoke (CS) exposure guinea pig model. MEASUREMENTS AND MAIN RESULTS Patients with COPD had heightened cough responses to capsaicin but reduced responses to prostaglandin E2 compared with healthy volunteers. Furthermore, the different patient groups all exhibited different patterns of modulation of cough responses. Consistent with these findings, capsaicin caused a greater number of coughs in CS-exposed guinea pigs than in control animals; similar increased responses were observed in ex vivo vagus nerve and neuron cell bodies in the vagal ganglia. However, responses to prostaglandin E2 were decreased by CS exposure. CONCLUSIONS CS exposure is capable of inducing responses consistent with phenotypic switching in airway sensory nerves comparable with the cough responses observed in patients with COPD. Moreover, the differing profiles of cough responses support the concept of disease-specific neurophenotypes in airway disease. Clinical trial registered with www.clinicaltrials.gov (NCT 01297790).

Data reduction for cough studies using distribution of audio frequency content

BackgroundRecent studies suggest that objectively quantifying coughing in audio recordings offers a novel means to understand coughing and assess treatments. Currently, manual cough counting is the most accurate method for quantifying coughing. However, the demand of manually counting cough records is substantial, demonstrating a need to reduce record lengths prior to counting whilst preserving the coughs within them. This study tested the performance of an algorithm developed for this purpose.Methods20 subjects were recruited (5 healthy smokers and non-smokers, 5 chronic cough, 5 chronic obstructive pulmonary disease and 5 asthma), fitted with an ambulatory recording system and recorded for 24 hours. The recordings produced were divided into 15 min segments and counted. Periods of inactive audio in each segment were removed using the median frequency and power of the audio signal and the resulting files re-counted.ResultsThe median resultant segment length was 13.9 s (IQR 56.4 s) and median 24 hr recording length 62.4 min (IQR 100.4). A median of 0.0 coughs/h (IQR 0.0-0.2) were erroneously removed and the variability in the resultant cough counts was comparable to that between manual cough counts. The largest error was seen in asthmatic patients, but still only 1.0% coughs/h were missed.ConclusionsThese data show that a system which measures signal activity using the median audio frequency can substantially reduce record lengths without significantly compromising the coughs contained within them.

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-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).

Capsaicin-evoked cough responses in asthmatic patients: Evidence for airway neuronal dysfunction

Background: Cough in asthmatic patients is a common and troublesome symptom. It is generally assumed coughing occurs as a consequence of bronchial hyperresponsiveness and inflammation, but the possibility that airway nerves are dysfunctional has not been fully explored. Objectives: We sought to investigate capsaicin‐evoked cough responses in a group of patients with well‐characterized mild‐to‐moderate asthma compared with healthy volunteers and assess the influences of sex, atopy, lung physiology, inflammation, and asthma control on these responses. Methods: Capsaicin inhalational challenge was performed, and cough responses were analyzed by using nonlinear mixed‐effects modeling to estimate the maximum cough response evoked by any concentration of capsaicin (Emax) and the capsaicin dose inducing half‐maximal response (ED50). Results: Ninety‐seven patients with stable asthma (median age, 23 years [interquartile range, 21‐27 years]; 60% female) and 47 healthy volunteers (median age, 38 years [interquartile range, 29‐47 years]; 64% female) were recruited. Asthmatic patients had higher Emax and lower ED50 values than healthy volunteers. Emax values were 27% higher in female subjects (P = .006) and 46% higher in patients with nonatopic asthma (P = .003) compared with healthy volunteers. Also, patients with atopic asthma had a 21% lower Emax value than nonatopic asthmatic patients (P = .04). The ED50 value was 65% lower in female patients (P = .0001) and 71% lower in all asthmatic patients (P = .0008). ED50 values were also influenced by asthma control and serum IgE levels, whereas Emax values were related to 24‐hour cough frequency. Age, body mass index, FEV1, PC20, fraction of exhaled nitric oxide, blood eosinophil counts, and inhaled steroid treatment did not influence cough parameters. Conclusion: Patients with stable asthma exhibited exaggerated capsaicin‐evoked cough responses consistent with neuronal dysfunction. Nonatopic asthmatic patients had the highest cough responses, suggesting this mechanism might be most important in type 2–low asthma phenotypes.

P152 The Impact of a Selective oral TRPV1 Antagonist in Patients with Chronic Cough

Background Increased expression of TRPV1 receptors in the airways of chronic cough patients and heightened cough responses to inhaled capsaicin are suggestive of a role for TRPV1 receptors in chronic cough. We hypothesised that antagonism with a potent, selective, peripherally acting, oral TRPV1 antagonist, such as SB705498, would offer substantial cough symptom control. Methods 21 patients with unexplained chronic cough (caucasian, 71% female, mean age 53yrs) participated in a double-blind, placebo-controlled, single dose, 2-period, crossover study to investigate the relationship between pharmacokinetic (PK) derived TRPV1 receptor occupancy, change in capsaicin (C5) threshold and 24hr cough count following 600mg SB705498. PK samples were taken over the dosing interval, capsaicin threshold was determined at screening, 2hrs (Cmax) and 24hrs post-dose and 24hr objective ambulatory cough counts were recorded on each dosing day via a cough monitor (vitaloJAK™) with manual counting. In addition, CQLQ and VAS urge to cough was measured. A battery of safety and tolerability measures were also recorded, including core body temperature. Results TRPV1 receptor occupancy derived from plasma levels and factoring a plasma/lung ratio of 1, was approximately 45% at 2hrs and 25% at 24hrs. This translated to a 4 fold shift in the capsaicin C5 threshold at 2hrs (2uM to 8uM) maintained at 24hrs. However, there was no difference between hourly cough count profiles between placebo and SB705498 (see figure), with hourly counts of 20–30c/h and the characteristic nocturnal reduction. Cough counts were remarkably stable, repeated one month apart and over the 8 months of the study (including winter). Abstract P152 Figure 1 Conclusions We conclude that despite a clear relationship between receptor occupancy and engagement of the TRPV1 receptor as evidenced by the shift in the capsaicin threshold, there was no translation to any clinical efficacy parameter. This suggests peripheral TRPV1 receptor activation is not an important determinant of spontaneous cough frequency in chronic cough and that reductions in capsaicin responses do not necessarily predict anti-tussive effects.