OBJECTIVE Voltage-gated sodium channels (VGSC) are important in the initiation and propagation of action potentials in afferent sensory nerve fibers responsible for evoking cough. This study investigated the efficacy of GSK2339345, a VGSC inhibitor, in the treatment of refractory chronic cough (RCC). METHODS A three-part randomized, double-blind, placebo-controlled, cross-over study was conducted in the UK. In part A, patients with RCC received two inhaled doses of either GSK2339345 or placebo, 4 hours apart during three study periods. Patients were monitored for cough for 8 hours post-first dose using the VitaloJAK, ambulatory cough monitor. In parts B and C, patients underwent full dose-response cough challenges with capsaicin and citric acid respectively following single doses of randomly assigned GSK2339345 or placebo (4 study days). Part A was analyzed using a mixed effects model and parts B and C using population non-linear mixed effects models. RESULTS Of 16 enrolled patients, 11 completed the study. 8-hour cough counts increased following GSK2339345 treatment compared with placebo (GSK2339345/placebo ratio of adjusted geometric means: 1.26 (90% credible interval 1.10, 1.44), associated with GSK2339345-evoked coughing, recorded during the 2 minutes post-dose. This was not observed with placebo. The effect of GSK2339345 on cough responses during cough challenges was inconclusive. GSK2339345 was well tolerated. CONCLUSIONS While these data could not determine if GSK2339345 reached the target VGSC, they strongly suggest that GSK2339345 has no anti-tussive effect despite reaching airway sensory nerves as evidenced by the evoked transient cough.
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Purpose: The purpose of this study was to investigate potential systemic pharmacokinetic interactions between intranasal fluticasone furoate (FF) and levocabastine (LEVO) when delivered simultaneously via a metered atomizing spray pump.Methods: This was a randomized, open-label, crossover study. Healthy male and female subjects (n = 30) received once-daily repeat doses of FF/LEVO (100/200 mu g) as a fixed-dose combination (FDC), FF (110 mu g), or LEVO (200 mu g) for 7 days. FF and LEVO plasma pharmacokinetics (0-24 hours) were measured on day 7, with safety assessments over the study duration.Results: Systemic exposure to LEVO was similar when administered as FF/LEVO FDC or LEVO alone. Following FF/LEVO FDC or FF alone, the majority (>99%) of FF concentrations were nonquantifiable, that is, below the lower limit of quantification of 10 pg/mL. All treatments were well tolerated, and adverse event incidence was similar across the treatment groups.Conclusions: These results suggest that in healthy subjects, for LEVO, there is no pharmacokinetic interaction with FF when delivered as FF/LEVO FDC. As the majority of data were below the assay sensitivity for FF, any potential differences in the bioavailability of FF when delivered alone or as FF/LEVO FDC could not be established. There was no clinically relevant impact on safety/tolerability when FF/LEVO was coadministered.

OBJECTIVES:To test the hypothesis that intranasal levocabastine (LEVO) may provide benefits as a oncedaily treatment in allergic rhinitis (AR), this non-inferiority study compared the effect at steady state of once- and twice-daily dosing with LEVO on allergen-induced nasal symptoms in AR patients.METHODS:This was a randomized, double-blind, three-way cross over study evaluating the effects of repeat doses of LEVO 200 µg once-daily, LEVO 200 µg twice-daily (total dose 400 µg) and placebo, all via intranasal spray, in 78 AR patients. The primary endpoint was weighted mean total nasal symptom score (TNSS) during a 4-hour allergen exposure in the Environmental Exposure Chamber measured at trough pharmacokinetic levels either 12 (LEVO twice-daily) or 24 (LEVO once-daily) hours post-dose.RESULTS:After 7 days dosing, the difference in weighted mean TNSS (0-4 hours) following LEVO once-daily versus twice-daily was 0.23 units (95% CI -0.36, 0.82), demonstrating noninferiority between the two LEVO dosing regimens by meeting the pre-specified criterion of an upper limit of 95% CI<1.0. Both dosing regimens of LEVO resulted in a statistically significant reduction in mean TNSS compared with placebo (adjusted mean difference from placebo: LEVO once-daily: -1.12 (95% CI -1.71, -0.53); LEVO twice-daily: -1.35 (-1.94, -0.76)), meeting the pre-specified criterion for superiority (upper limit of 95% CI<0). All treatments were well-tolerated.CONCLUSIONS:The results of this study support the hypothesis that at steady state LEVO 200 µg taken once-daily provides similar benefit to LEVO 200 µg dosed twice-daily.

Background Practical methods of monitoring innate immune mucosal responsiveness are lacking. Lipopolysaccharide (LPS) is a component of the cell wall of Gram negative bacteria and a potent activator of Toll-like receptor (TLR)-4. To measure LPS responsiveness of the nasal mucosa, we administered LPS as a nasal spray and quantified chemokine and cytokine levels in mucosal lining fluid (MLF). Methods We performed a 5-way cross-over, single blind, placebo-controlled study in 15 healthy non-atopic subjects (n = 14 per protocol). Doses of ultrapure LPS (1, 10, 30 or 100μg/100μl) or placebo were administered by a single nasal spray to each nostril. Using the recently developed method of nasosorption with synthetic adsorptive matrices (SAM), a series of samples were taken. A panel of seven cytokines/chemokines were measured by multiplex immunoassay in MLF. mRNA for intercellular cell adhesion molecule-1 (ICAM-1) was quantified from nasal epithelial curettage samples taken before and after challenge. Results Topical nasal LPS was well tolerated, causing no symptoms and no visible changes to the nasal mucosa. LPS induced dose-related increases in MLF levels of IL-1β, IL-6, CXCL8 (IL-8) and CCL3 (MIP-1α) (AUC at 0.5 to 10h, compared to placebo, p<0.05 at 30 and 100μg LPS). At 100μg LPS, IL-10, IFN-α and TNF-α were also increased (p<0.05). Dose-related changes in mucosal ICAM-1 mRNA were also seen after challenge, and neutrophils appeared to peak in MLF at 8h. However, 2 subjects with high baseline cytokine levels showed prominent cytokine and chemokine responses to relatively low LPS doses (10μg and 30μg LPS). Conclusions Topical nasal LPS causes dose-dependent increases in cytokines, chemokines, mRNA and cells. However, responsiveness can show unpredictable variations, possibly because baseline innate tone is affected by environmental factors. We believe that this new technique will have wide application in the study of the innate immune responses of the respiratory mucosa. Key Messages Ultrapure LPS was used as innate immune stimulus in a human nasal challenge model, with serial sampling of nasal mucosal lining fluid (MLF) by nasosorption using a synthetic absorptive matrix (SAM), and nasal curettage of mucosal cells. A dose response could be demonstrated in terms of levels of IL-1β, IL-6, CXCL8 and CCL3 in MLF, as well as ICAM-1 mRNA in nasal curettage specimens, and levels of neutrophils in nasal lavage. Depending on higher baseline levels of inflammation, there were occasional magnified innate inflammatory responses to LPS. Trial Registration Clinical Trials.gov NCT02284074

Introduction and objectives Voltage gated sodium channels (VGSC) are important in the initiation and propagation of action potentials in the afferent sensory nerve fibres innervating the airways responsible for evoking cough. Therefore a VGSC inhibitor may be an effective anti-tussive agent, inhibiting cough irrespective of the type of stimuli. We aimed to investigate the efficacy of a novel use-and frequency-dependent VGSC inhibitor (GSK2339345) in patients with chronic idiopathic cough. Methods We performed a two-part randomised, double-blind, placebo-controlled, cross-over study recruiting patients with chronic idiopathic cough from two specialist clinics. In the first part of the study, patients were randomly assigned to receive two inhaled doses of either GSK2339345 or placebo, 4 h apart during three study periods. The primary endpoint was the objective cough frequency (VitaloJAK, Vitalograph Ltd) during the 8 h post-treatment (4 hrs following each dose). The difference between GSK2339345 and placebo in log-transformed cough counts was investigated using a mixed effects model with fixed effects terms for treatment and period, and subject fitted as a random effect. In the second part, subjects attended on four study days, and underwent full dose-response cough challenges with capsaicin and citric acid following single doses of GSK2339345 or placebo. This was analysed using dose response modelling. Results Of 16 patients enrolled (56.7 ± 9.6 yrs; 13 female), 11 completed the study. Eight hour cough counts showed a 26% increase in cough counts with GSK2339345 vs placebo. However, on exclusion of the coughs occurring within 2 min of inhalation of the study drug, there was only a 1.6% increase in coughs; see Table 1 for ratio of adjusted geometric means. There appeared to be no impact of GSK2339345 on either of the cough challenges however, the dataset was too small to draw definitive conclusions. Conclusion There was no evidence of an anti-tussive effect of GSK2339345 over the 8 h analysis for any subject, despite cough frequency being highly reproducible within patients. Inhalation of GSK2339345 had a pro-tussive effect in all subjects following actuation of the device, not seen with placebo. The novel cough challenge methodology warrants further investigation as a development tool.

SummaryBackgroundAllergic rhinitis (AR) is a common chronic disease, which has significant detrimental effect on well‐being and quality of life as well as substantial socio‐economic impact. Combination pharmacotherapy is utilized by 40–50% of patients to treat their symptoms.ObjectiveTo compare the effects of intranasal fluticasone furoate (FF)/levocabastine (LEVO) fixed‐dose combination (FDC) with each component alone on allergen‐induced nasal and ocular symptoms.MethodsA randomized, double‐blind, placebo‐controlled, three‐way, incomplete block, cross‐over, proof‐of‐concept study in 71 patients with AR, evaluated FF 100 μg, LEVO 200 μg and FDC (FF 100/LEVO 200 μg), once daily via intranasal spray for 8 days. On days 1 and 8, total nasal symptom score (TNSS) and total ocular symptom score (TOSS) were assessed every 15 min during a 4‐h allergen exposure in the Vienna Challenge Chamber. The primary endpoint was Day 8 weighted mean TNSS.ResultsAfter 8 days, FDC resulted in both statistically and clinically significant reductions in mean TNSS compared with FF and LEVO alone [adjusted mean differences (95% CI): FDC vs. FF: −2.26 (−2.90, −1.62); FDC vs. LEVO: −2.57 (−3.21, −1.93)]. All active treatments were significantly superior to placebo [adjusted mean difference (95% CI) from placebo: FDC: −4.1 (−4.86, −3.34); FF: −1.84 (−2.66, −1.03); LEVO: −1.53 (−2.34, −0.72)]. Onset of action was rapid following FDC and LEVO treatment with an approximate two unit reduction in mean TNSS from pre‐dose levels by 30 min and 1 h. Mean TOSS was also reduced following all active treatments relative to placebo (range 0.6–0.8 unit reduction). All treatments were equally well tolerated.Conclusions and Clinical RelevanceThese results suggest that once daily FF/LEVO FDC could provide a clinical therapeutic advantage to existing standard monotherapies in the treatment of moderate‐to‐severe AR, and support progression to evaluation in larger phase III clinical studies.

Background: The transient receptor potential vanilloid 1 (TRPV1)-expressing sensory C-fibers may play a role in the development of nasal hyper-responsiveness and symptoms of non-allergic rhinitis (NAR).Objective: To evaluate the effects of a TRPV1-antagonist, SB-705498, on cold dry air (CDA)-induced symptoms in patients with NAR.Methods: This randomized, double-blind, placebo-controlled, crossover study evaluated 14 days of once daily, topical intranasal SB-705498 12 mg in 40 patients with NAR using a CDA challenge experimental model in an environmental exposure chamber (EEC, Cetero Research, Mississauga, Ontario). The primary endpoint was total symptom score (TSS), expressed as weighted mean over 60 minutes (WM0-60) or maximum TSS at 1 hour. and 24 hours post-dosing.Results: Treatment with SB-705498, relative to placebo, did not improve WM0-60 or maximum TSS at 1 hour and 24 hours post-dosing on days 1 or 14. Mean (95% CI) treatment differences (SB-705498 placebo) on day 14 were, for WM0-60 at 1 hour: -0.12 (-0.60, 0.36); for maximum TSS at 1 hour: -0.03 (-0.58, 0.51). SB-705498 had no impact on any other efficacy parameters. SB-705498 was well tolerated and pharmacokinetics analysis supported the dosing regimen.Conclusion: SB-705498 12 mg for 14 days did not alleviate the CDA-induced symptoms of NAR. Despite engagement of the TRPV1 receptor, there was no translation to clinical efficacy, suggesting redundancy in symptom pathways.

Background: Inhalation of capsaicin, the extract of hot chili peppers, induces coughing in both animals and human subjects through activation of transient receptor potential vanilloid 1 (TRPV1) on airway sensory nerves. Therefore the TRPV1 receptor is an attractive target for the development of antitussive agents.Objective: We sought to assess the antitussive effect of TRPV1 antagonism in patients with refractory chronic cough.Methods: Twenty-one subjects with refractory chronic cough (> 8 weeks) attending a specialist clinic were recruited to a randomized, double-blind, placebo-controlled crossover trial assessing a TRPV1 antagonist (SB-705498). Cough reflex sensitivity to capsaicin (concentration of capsaicin inducing at least 5 coughs) and 24-hour cough frequency were coprimary end points assessed after a single dose of SB-705498 (600 mg) and matched placebo. Cough severity and urge to cough were reported on visual analog scales, and cough-specific quality of life data were also collected.Results: Treatment with SB-705498 produced a significant improvement in cough reflex sensitivity to capsaicin at 2 hours and a borderline significant improvement at 24 hours compared with placebo (adjusted mean difference of +1.3 doubling doses at 2 hours [95% CI, +0.3 to +2.2; P=.0049] and +0.7doubling doses at 24 hours [95% CI, +0.0 to +1.5; P =.0259]). However, 24-hour objective cough frequency was not improved compared with placebo. Patient-reported cough severity, urge to cough, and cough-specific quality of life similarly suggested no effect of SB-705498.Conclusion: This study raises important questions about both the role of TRVP1-mediated mechanisms in patients with refractory chronic cough and also the predictive value of capsaicin challenge testing in the assessment of novel antitussive agents.

Background: Inhalation of the extract of hot chilli peppers, capsaicin, induces coughing in both animals and humans, via activation of Transient Receptor Potential Vanilloid 1 (TRPV1) on airway sensory nerves. The TRPV1 receptor is therefore an attractive target for the development of anti-tussive agents. Objective: To assess the anti-tussive effect of TRPV1 antagonism in patients with refractory chronic cough. Methods: Twenty-one subjects with refractory chronic cough (>8 weeks) attending a specialist clinic, were recruited to a randomised, double-blind, placebo-controlled crossover trial assessing a TRPV1 antagonist (SB-705498). Cough reflex sensitivity to capsaicin (C5) and 24hr cough frequency were co-primary endpoints, assessed following a single dose of SB-705498 (600mg) and matched placebo. Cough severity and urge to cough were reported on visual analogue scales and cough specific quality of life also collected. Results: Treatment with SB-705498 produced a significant improvement in cough reflex sensitivity to capsaicin at 2hrs and a borderline significant improvement at 24hrs compared with placebo; adjusted mean difference of +1.3 doubling doses at 2hrs (95% CI +0.3 to +2.2), p=0.0049 and +0.7 at 24hrs (95% CI +0.0 to +1.5), p=0.0259. However, 24hr objective cough frequency was not improved compared with placebo. Patient reported cough severity, urge to cough and cough specific quality of life similarly suggested no effect of SB-705498. Conclusion: This study raises important questions about both the role of TRVP1 mediated mechanisms in patients with refractory chronic cough and also the predictive value of capsaicin challenge testing in the assessment of novel anti-tussive agents.

The pathogenesis of chronic cough is not well understood and treatment options are limited. In this study we sought to explore the current understanding and management of chronic cough across an international group of specialists.

BACKGROUND Current pharmacotherapy for allergic rhinitis (AR) does not totally ameliorate all symptoms for all patients. Residual symptoms could be due to nasal neuronal hyperresponsiveness caused by stimulation of the ion channel transient receptor potential vanilloid 1 (TRPV1). SB-705498 is a TRPV1 antagonist that has been developed in an intranasal formulation for treatment of AR. METHODS This randomized, double-blind, 3-way incomplete block crossover study evaluated the effects of 8 days treatment with SB-705498 12 mg alone, SB-705498 12 mg plus fluticasone propionate 200 μg (FP), FP 200 μg alone or placebo on allergen-induced symptoms in 70 patients with AR. The primary endpoint was total nasal symptom score (TNSS), expressed as mean over 4 hours or maximum TNSS during allergen challenge in the Vienna Challenge Chamber on 8th day of treatment. RESULTS At the end of treatment, there were no differences in allergen-induced mean TNSS between SB-705498 alone and placebo or between SB-705498 plus FP and FP alone. Treatment with FP and SB-705498 plus FP resulted in a significant decrease in TNSS vs. placebo. Mean (90% CI) treatment differences in TNSS over 0 - 4 hours were: SB-705498 - placebo: -0.2 (-0.9, 0.4); SB-705498 plus FP - FP: 0.7 (0.2, 1.2); FP - placebo: -2.9 (-3.4, -2.5); SB-705498 plus FP - placebo: -2.3 (-2.8, -1.8). SB-705498 had no impact on diary card symptoms, nasal airflow or Rhinoconjunctivitis Quality of Life Questionnaire scores. SB-705498 was well tolerated and pharmacokinetics exposure results supported the dosing regimen. CONCLUSION SB-705498 12 mg for 8 days did not alleviate the allergen-induced symptoms of AR, or provide additional relief of symptoms when in combination with FP. Despite engagement of the TRPV1 receptor there was no translation to clinical efficacy, suggesting redundancy in symptom pathways.

Introduction There are no consistently effective treatments for chronic cough. Patients frequently report an urge to cough sensation in the throat. Nebulised Lidocaine has previously been reported to subjectively improve cough but there are no objective data. Aims To compare the effect of lidocaine throat spray, nebulised lidocaine and placebo on subsequent 10-hour ambulatory cough rate (Vitalojak®) and urge to cough visual analogue scores. Methods 26 patients with chronic cough completed a randomised double blind, placebo controlled, three-way crossover study. The different treatments were: · Placebo: nebulised placebo followed by placebo throat spray · Nebulised lidocaine (600 mg): nebulised lidocaine followed by placebo throat spray · Throat spray Lidocaine (100 mg): nebulised placebo followed by lidocaine throat spray Data were analysed using generalised estimating equation models. Results 26 patients completed (22 female, mean age 53.5 yrs, median cough duration 10 yrs). Median 10 hour cough rate (n=25) (coughs/hr; IQR) was nebulised lidocaine 34.4 (13.5–57) vs lidocaine throat spray 23.9 (12–55.8) vs placebo 32.7 (19–56.1). For the natural log transformed cough rate, there was significant difference between placebo and lidocaine throat spray (p= 0.02), but not nebulised lidocaine (p = 0.8), with most of the effect in the first 3hrs. Compared with placebo, both nebulised (p=0.01) and throat spray lidocaine (p=0.02) substantially reduced the urge to cough, but with no difference between them (p=0.6). Conclusion Unlike nebulised lidocaine, throat spray significantly reduced the 10-hour cough rate compared with placebo. This suggests that local treatment targeting the pharynx may be an effective anti-tussive in chronic cough patients.

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). 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.

Nonallergic rhinitis (NAR) subjects present clinically with similar symptoms to subjects with allergic rhinitis, but which mechanistically are not IgE- mediated. NAR is difficult to study because of multiple, as yet unknown, disease mechanisms and lack of biomarkers and diagnostic tests. The purpose of this proof of concept pilot study was to develop an environmental exposure chamber (EEC) model to simulate weather conditions in a controlled setting to objectively diagnose NAR subjects and ultimately to investigate novel NAR therapies. Thirty-seven subjects with a history of NAR confirmed by negative skin-prick test to a panel of aeroallergens were tested with cold dry air (CDA) and temperature change challenges. Objective (acoustic rhinometry [AcR] and nasal secretions) and subjective measures (total nasal symptom scores [TNSSs]: congestion, rhinorrhea, and postnasal drip [0-3]) were collected. Data was presented as mean ± SEM and statistical significance was assessed by paired t-test. The NAR EEC AcR responders to CDA had a significant decrease in mean minimal cross-sectional area (MCA; a measure of nasal patency) of 22.2 ± 2.43% (p < 0.0001) and 6.7 ± 7.22% (not statistically significant) at 30 and 60 minutes, respectively, with a concomitant increase in TNSS of 1.0 ± 0.24 U and 1.4 ± 0.30 U, respectively. AcR responders to temperature change showed a significant decrease in mean MCA to warm air of 16.0 ± 3.82% (p < 0.001) and 19.4 ± 3.88% (p < 0.0001) at 30 and 60 minutes, respectively, with an increase of TNSS of 0.4 ± 0.25 U and 0.4 ± 0.27 U, respectively. With rapid conversion to cold air, further decrease in mean MCA accompanied by an increase in TNSS was observed at 30 and 60 minutes. Increase in rhinorrhea was highest for CDA and the cold air phase of the temperature change challenge. Using the NAR EEC model, significant symptoms were induced in response to simulated weather changes in NAR patient responders. This proof of concept pilot study shows that the EEC model provides a consistent and reliable method to phenotype weather-induced NAR subjects that could be used to investigate disease mechanisms and novel therapies for NAR.

Cough is one of the commonest reasons for medical consultation and acute cough associated with upper respiratory tract infections (URTIs) is a global problem. In otherwise healthy volunteers complaining of cough associated with symptoms of URTI, we aimed to assess objective and subjective measures of cough and their repeatability and perform power calculations for the design of future studies to test therapies. We studied 54 otherwise healthy volunteers with acute cough (<3 weeks) (median age 22 yrs (interquartile range 21-26 yrs), 64% female, mean forced expiratory volume in 1 s 97.6±10.5% predicted). All subjects performed 24-h ambulatory cough monitoring and reported cough frequency and severity using visual analogue scales (VAS) on 2 consecutive days. Sample size calculations were performed for crossover and parallel group study designs. Objective cough frequency was high (session 1: geometric mean 12.1 coughs·h(-1) (95%CI 9.7-15.2)) and fell significantly (session 2: 9.0 coughs·h(-1) (95%CI 6.9-11.6); p<0.001). Repeatability was higher for objective cough frequency (intra-class correlation coefficient (ICC)=0.94, p<0.001) than reported cough frequency (daytime VAS ICC=0.784, p<0.001). Crossover/parallel studies require <15 and <41 subjects per arm to detect a 50% reduction in cough frequency with 90% power, respectively. Acute cough frequency is highly repeatable over any 48-h period, allowing small sample sizes to be used when investigating the effectiveness of novel anti-tussives.

Background Topical intranasal steroids are widely considered to be the most efficacious pharmacotherapy for the treatment of allergic rhinitis, and yet, for many, symptoms still remain troublesome. We hypothesise that the residual symptoms are a result of nasal neuronal hyperresponsiveness during the pollen season and should be ameliorated by a topical intranasal TRPV1 antagonist. SB705498 is a selective TRPV1 antagonist shown to produce significant inhibition in animal and human models involving nasal sensory nerves. Methods The study involved 70, male and female, subjects with proven rhinitis in a randomised, double-blind, placebo-controlled, 3-way incomplete block crossover design in a well validated Allergen Challenge Chamber paradigm in Vienna. Subjects received Placebo, FP (200ug), SB705498 (12mg), or FP+498. Subjects were dosed for 8 days, within the pollen season, before being exposed to a chamber challenge on the 8th day. TNSS was the primary endpoint recorded for the 4 hours in the chamber. The comparisons of interest were FP+498 vs. FP, and 498 vs. Placebo. Additional endpoints consisted of symptoms over the 8 days of dosing, Active Anterior Rhinomanometry, Rhinoconjunctivitis QLQ, PK and tolerability. Each period was separated by 14–20 days. Results There was no evidence of a decrease in symptoms with FP+498 compared to FP alone, or for 498 compared to placebo. Statistically significant and clinically relevant reductions in TNSS compared with Placebo were observed at all time points during the challenge for FP and FP+498. The mean (95% CI) reduction in weighted mean TNSS was –2.94 (–3.38, –2.50) for FP alone and-2.28 (–2.79, –1.78) for the combination. There was no positive impact over FP, or 498 over Placebo, for Diary Card symptoms, RQLQ or Nasal Airflow. Tmax occurred at approximately 5 hrs post dose, in keeping with previous studies. SB705498 was very well tolerated. Conclusions In a robust clinical model of allergic rhinitis, there was no intrinsic activity demonstrated by SB705498 and no additive effect on a background of intranasal steroids. FP was highly effective in this study. We conclude that despite engagement of the TRPV1 receptor there was no translation to clinical efficacy, suggesting redundancy in symptom pathways.

Oligonucleotides (ONs) are an emerging class of drugs being developed for the treatment of a wide variety of diseases including the treatment of respiratory diseases by the inhalation route. As a class, their toxicity on human lungs has not been fully characterized, and predictive toxicity biomarkers have not been identified. To that end, identification of sensitive methods and biomarkers that can detect toxicity in humans before any long term and/or irreversible side effects occur would be helpful. In light of the public's greater interests, the Inhalation Subcommittee of the Oligonucleotide Safety Working Group (OSWG) held expert panel discussions focusing on the potential toxicity of inhaled ONs and assessing the strengths and weaknesses of different monitoring techniques for use during the clinical evaluation of inhaled ON candidates. This white paper summarizes the key discussions and captures the panelists' perspectives and recommendations which, we propose, could be used as a framework to guide both industry and regulatory scientists in future clinical research to characterize and monitor the short and long term lung response to inhaled ONs.

printing supported by . Visit Chiesi at Stand B2.10 MONDAY, SEPTEMBER 3RD 2012 Methods: The study was double-blind, randomized trial, single crossed, conducted for 4 months with 4 visits (V1 V4). The total patient population 128 individuals (76 asthma and 52 COPD stages II and III) was divided in 2 arms, crossed after first visit (V1). We instructed the patients to use the salt-inhaler 20 minutes/day. We analyzed the evolution of spirometry parameters FVC, FEV1 and PEF and a Quality of Life Questionnaire with 5 items concerning: the quality of sleep and the simptomatology. Results: The study revealed an improvement of all spirometry parameters after the first month of treatment with salt aerosols versus placebo. The final data showed an overall improvement of FVC by 4%, 14% improvement of the FEV1 and 25% improvement of PEF parameter showing significant improvement in asthma patients condition. Correlating quality of life responses we found out that they were improved throughout the study by 24% showing a significant impact on the quality of life. Conclusions: Correlating both the improvements of spirometry parameters and the scores from the QoL questionnaire we found that the NaCl aerosols from a dry salt inhaler (home halotherapy) seems to be efficient versus placebo when added to regular bronchodilatatory medication but further studies are necessary. P2166 Safety and efficacy of ectoine inhalation solution in patients with inflammation and airway obstruction: The EFECT study Roman Berndt1, Ulrich Sydlik2, Andreas Bilstein1, Alessandra Marini2, Thomas Jaenicke2, Gabriele Seitner-Sorge2, Sabine Stolz2, Jean Krutmann1, Ursula Krämer1, Klaus Unfried1. 1R & D, bitop AG, Witten, Germany; 2Leibniz Research Institute of Environmental Health, IUF, Duesseldorf, Germany Introduction: Ectoine is a compatible solute used for symptomatic treatment of rhinitis allergica, inflammatory dermatoses and irritated epithelia. Results from different studies demonstrated the efficacy of ectoine in reducing inflammation in the airways. Based on the positive results of a trial with asthmatic patients a study was set up to evaluate Ectoine Inhalation Solution (EIL) in subjects with mild airway obstruction and inflammation. Methods: The study was designed as double blind, placebo-controlled cross-over trial. Subjects were randomly assigned to EIL or placebo (0.9% saline). Primary endpoint was defined as reduction of inflammatory markers IL 8 and % neutrophilic granulocytes in sputum. Other sputum and breath condensate biomarkers were analysed. QoL and spirometry data were collected on visit days. Results: Reduction of inflammatory markers IL8 and granulocytes was greater after treatment with Ectoin compared to placebo (12% for IL8, 29% for neutrophils). Statistical significance could not be demonstrated. However, total Nitrogen from sputum showed a significant reduction after Ectoin (35%, p=0.02). Other biomarkers included in the investigation indicated advantages for Ectoin (granulocytes), or placebo (TNFα, LTB4, CRP). Analysis of QoL and spirometry data did not show significance to support superiority of one of the treatment arms. No indication for increased health risks could be detected. Conclusions: Inhalation of Ectoin can reduce inflammatory markers and shows an excellent safety profile. The results of the EFECT study support the outcome of other studies that the membrane stabilizing Ectoin reduces epithelia derived inflammatory processes. P2167 Lebrikizumab reduces serum periostin in asthma patients with elevated baseline periostin Heleen Scheerens1, Joseph Arron2, David Choy2, Sofia Mosesova3, Preeti Lal4, John Matthews4. 1PD Biomarkers, Genentech Inc, South San Francisco, CA, United States; 2Research and Early Development, Genentech Inc, South San Francisco, CA, United States; 3Inflammation & Opthalmology Biostatistics, Genentech Inc, South San Francisco, CA, United States; 4Product Development Immunology, Genentech Inc, South San Francisco, CA, United States Background: Periostin is a matricellular protein induced in airway epithelia by interleukin-13 (IL13) and a good systemic biomarker for IL13 activity. Lebrikizumab, a humanized monoclonal antibody, binds IL13 and improved lung function in moderate-to-severe asthma patients (pts) with elevated baseline serum periostin in a Phase II study. Aims: To examine the effect of blocking IL13 on systemic periostin levels in pts with uncontrolled asthma, despite inhaled corticosteriods. Methods: Pts (n=218) were randomized to lebrikizumab 250 mg (n=106) or placebo (PB) (n=112) SC every 4 weeks for 6 doses, with 12 weeks follow-up (NCT00930163). Serum periostin was measured at baseline and throughout the study. Pts were classified as periostin-high (≥median) or periostin-low (90%) who were periostin-low at baseline maintained the periostin levels