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

Abstract

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.

Dual therapy with corticosteroid ablates the beneficial effect of DP2 antagonism in chronic experimental asthma

“…In a Phase II study that employed an experimental RV challenge of patients with asthma, DP2 antagonism did not affect exacerbation severity and of note, the investigators reported a negative correlation between PGD2 levels during RV infection and prescribed ICS dose. 35 This observation and our findings would suggest that combining a DP2 antagonist with a DP1 agonist or a drug that induces endogenous PGD2, such as a TLR7 ligand, would elicit a more favourale outcome.…”

“…16 Our study highlights that the effectiveness of DP2 antagonism is critically dependent on the production of endogenous PGD2, and thus the inhibitory effects of steroids on COX2 activity and expression may have counteracted the positive effects of DP2 antagonism in some patients, potentially explaining the mixed success of the various Phase II and III trials. 9–18,35 Our findings revealed that DP2 antagonism in the absence of a RV-induced exacerbation has no benefit and that dual DP2 antagonism/steroid therapy is ineffective. Paradoxically, these observations suggest that therapy with a DP2 antagonist would work best in those patients who frequently exacerbate (given the need for endogenous PGD2), who are poorly compliant with their ICS/OCS therapy, or whose steroid insensitivity/resistance fails to dampen the production of PGD2.…”

Indole-Based and Cyclopentenylindole-Based Analogues Containing Fluorine Group as Potential 18F-Labeled Positron Emission Tomography (PET) G-Protein Coupled Receptor 44 (GPR44) Tracers

“…in 2021 found that OC-459 treatment had little impact on the clinicopathological changes induced by rhinovirus RV-A16 infection in patients treated with inhaled corticosteroids, though the same study also concluded that OC-459 was safe and well-tolerated [76].…”

“…Of note, the structure included in this review has not been confirmed by Oxagen, but was characterized as OC-459 by Amira. In addition, although Pettipher et al were the first to publish a non-clinical study of OC-459, it appears that the unpublished development of OC-459 had already been undertaken by other parties [ 73 , 74 , 75 , 76 , 77 , 78 ].…”

“…However, in 2010, progress on OC-459 decreased following licensing of rights to Eleventa and Atopix, reportedly due to financial concerns. Later, another study published in 2021 found that OC-459 treatment had little impact on the clinicopathological changes induced by rhinovirus RV-A16 infection in patients treated with inhaled corticosteroids, though the same study also concluded that OC-459 was safe and well-tolerated [ 76 ].…”