Amy Newlands

Inhibition of capsaicin‐driven nasal hyper‐reactivity by SB‐705498, a TRPV1 antagonist

AIMS To assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of intranasal SB-705498, a selective TRPV1 antagonist. METHODS Two randomized, double-blind, placebo-controlled, clinical studies were performed: (i) an intranasal SB-705498 first time in human study to examine the safety and PK of five single escalating doses from 0.5 to 12 mg and of repeat dosing with 6 mg and 12 mg twice daily for 14 days and (ii) a PD efficacy study in subjects with non-allergic rhinitis (NAR) to evaluate the effect of 12 mg intranasal SB-705498 against nasal capsaicin challenge. RESULTS Single and repeat dosing with intranasal SB-705498 was safe and well tolerated. The overall frequency of adverse events was similar for SB-705498 and placebo and no dose-dependent increase was observed. Administration of SB-705498 resulted in less than dose proportional AUC(0,12 h) and Cmax , while repeat dosing from day 1 to day 14 led to its accumulation. SB-705498 receptor occupancy in nasal tissue was estimated to be high (>80%). Administration of 12 mg SB-705498 to patients with NAR induced a marked reduction in total symptom scores triggered by nasal capsaicin challenge. Inhibition of rhinorrhoea, nasal congestion and burning sensation was associated with 2- to 4-fold shift in capsaicin potency. CONCLUSIONS Intranasal SB-705498 has an appropriate safety and PK profile for development in humans and achieves clinically relevant attenuation of capsaicin-provoked rhinitis symptoms in patients with NAR. The potential impact intranasal SB-705498 may have in rhinitis treatment deserves further evaluation.

TRPV1 inhibition does not prevent cold dry air-elicited symptoms in non-allergic rhinitis.

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 postdosing. 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.

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.

P154 TRPV1 is not a Target for the Treatment of non-allergic Rhinitis: A Clinical Study

Background TRPV1 is a ligand gated ion channel activated by a range of physiological factors such at Temperature, pH, and osmotic stress. In the nose, the TRPV1-expressing sensory c-fibres are thought to play a key role in the development of nasal hyper-responsiveness resulting in symptoms in NAR patients. We hypothesise that topical antagonism with a selective TRPV1 antagonist would offer substantial symptom control. SB705498 is a potent selective TRPV1 antagonist in animal and human models. Methods 40 M&F NAR patients were enrolled into a randomised, double-blind, placebo controlled, 2 period crossover study of either 12mg SB705498 i.n. or placebo for 14 days with a 4 week washout. The study was conducted in a validated Environmental Challenge Chamber (Cetero) where patients were exposed to Cold Dry Air (CDA) at 14c, 15% RH, air speed 5 feet/sec. Exposure was over the winter months in Canada. Diary card symptoms were analysed during home dosing on days when the temp was less than 14c. Two chamber sessions of 1hr duration, as well as medical history and neg skin prick testing, at screening were performed to establish a consistent diagnosis with a single challenge on Day 1+1hr, Day14+1hr and Day 14+24hr to establish the drug response. Post dose TSS (rhinorrhoea, congestion, PND), sneezing and ocular symptoms were recorded, as was acoustic rhinomanometry, RQLQ, PK and Safety monitoring. Results The primary outcome of weighted mean TSS over the challenge period or the maximum TSS was not impacted by administration of SB705498 relative to placebo (see figure). There was no impact on sneezing, ocular symptoms, acoustic rhinimanometry, or RQLQ Compared with placebo, repeated doses of SB705498 did not alleviate TSS triggered by cold in a multistimuli wild type setting. PK analysis supported an o.d. regimen with 2 fold accumulation over the dosing period. Abstract P154 Figure 1 Conclusions In a robust clinical model of non-allergic rhinitis, intranasal SB705498 12mg o.d. for 14 days did not alleviate the symptoms of NAR triggered by the most common provocation agent: Cold Dry Air. We conclude that despite engagement of the TRPV1 receptor there was no translation to clinical efficacy, suggesting redundancy in symptom pathways.

Book review: Hauschke D, Steinijans V and Pigeot I 2007: Bioequivalence studies in drug development methods and application. Chichester: John Wiley & Sons Ltd. 311 p. ISBN 978-0-470-09475-4

a thorough introduction to multilevel modelling and a tutorial on Stata commands for analysing such models. This is a major advantage to other textbooks that may show how to run the main analysis in software but leave the reader alone with assessing the model fit or visualising the results. The excellent integration of Stata analyses within the text, however, restricts the audience of this book to Stata users. Examples in the text and exercises at the end of each chapter are stimulating and cover a wide range of real life applications from medical, behavioural and social science research. All data sets and Stata commands used in the text are available from an accompanying webpage or can be downloaded directly from within Stata. Answers to the exercises are only available to instructors adopting the book for a course. There are only a few topics I missed: One is that problems with missing data are only briefly discussed. The authors explain that multilevel models are less restrictive in the assumption of missingness (missing at random) than complete case or GEE analysis (missing completely at random). However, they do not provide guidance to assess the type of randomness or provide recommendations how to analyse data if missingness is not at random. I also missed a paragraph on model selection, e.g. the use (and its potential problems) of information criteria. My only minor criticism of this book is the index. It is not very extensive, which makes it difficult for the reader to find minor topics, like power or explained variance. In summary, the book is a very well-written and provides comprehensive guide to multilevel modelling, both from a practical and a theoretical point of view. The second edition of this book will continue to be an invaluable help for every Stata user involved in the analysis of clustered data and it will replace the tattered first edition in my bookshelf.