Journal Article

Effect of CRTH2 antagonism on the response to experimental rhinovirus infection in asthma: a pilot randomised controlled trial

Singanayagam, Aran, Prevost, A Toby, Johnston, Sebastian L, Kon, Onn Min, Trujillo-Torralbo, Maria-Belen, Regis, Eteri, Johnson, Nicholas, Farne, Hugo, Jackson, David J, Aniscenko, Julia, Mallia, Patrick, Glanville, Nicholas, Kebadze, Tata, Zhu, Jie, Edwards, Michael R

2022

Overview

Background and aimsThe chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2) antagonist timapiprant improved lung function and asthma control in a phase 2 study, with evidence suggesting reduced exacerbations. We aimed to assess whether timapiprant attenuated or prevented asthma exacerbations induced by experimental rhinovirus (RV) infection. We furthermore hypothesised that timapiprant would dampen RV-induced type 2 inflammation and consequently improve antiviral immune responses.MethodsAtopic patients with partially controlled asthma on maintenance inhaled corticosteroids were randomised to timapiprant (n=22) or placebo (n=22) and challenged with RV-A16 3 weeks later. The primary endpoint was the cumulative lower respiratory symptom score over the 14 days post infection. Upper respiratory symptoms, spirometry, airway hyperresponsiveness, exhaled nitric oxide, RV-A16 virus load and soluble mediators in upper and lower airways samples, and CRTH2 staining in bronchial biopsies were additionally assessed before and during RV-A16 infection.ResultsSix subjects discontinued the study and eight were not infected; outcomes were assessed in 16 timapiprant-treated and 14 placebo-treated, successfully infected subjects. There were no differences between treatment groups in clinical exacerbation severity including cumulative lower respiratory symptom score day 0–14 (difference 3.0 (95% CI −29.0 to 17.0), p=0.78), virus load, antiviral immune responses, or RV-A16-induced airway inflammation other than in the bronchial biopsies, where CRTH2 staining was increased during RV-A16 infection in the placebo-treated but not the timapiprant-treated group. Timapiprant had a favourable safety profile, with no deaths, serious adverse events or drug-related withdrawals.ConclusionTimapiprant treatment had little impact on the clinicopathological changes induced by RV-A16 infection in partially controlled asthma.

• Publisher: BMJ Publishing Group Ltd and British Thoracic Society,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Adrenal Cortex Hormones - therapeutic use / Antiviral drugs / Asthma / Biopsy / Clinical trials / Humans / Infections / Inflammation / Lavage / Pilot Projects / Rhinovirus / Sample size / Spirometry / Steroids / viral infection