PGD2 receptor antagonists
In sensitized subjects, PGD2 is initially released by allergen-triggered mast cells and plays a key role in the sequelae of the allergic response. Its pro-inflammatory effects are mediated through the interaction with G-protein-coupled receptors (GPCR): DP1, thromboxane (TP) and chemoattractant-homologous receptors (CRTH2 or DP2).112 Apart from its broncho- and vaso-active properties in allergic airway disease, PGD2 also acts as an important link between the allergen-induced early (EAR) and late phase allergic response (LAR) through the interaction with the DP2-receptors on key effector cells. DP2-receptors are expressed on immune (ILCs, Th2), inflammatory (eosinophils, basophils) and structural (epithelial) cells and involved in the recruitment and activation of these cells as well as the subsequent release of Th2-cytokines during the LAR.112 113-115 Therefore, DP2 (CRTH2) antagonists have been initially aimed for the treatment of allergic airway disease (allergic rhinitis, asthma).116,117
In two proof-of-concept studies in (unphenotyped) allergic asthmatics, DP2 (CRTH2) antagonists (timapiprant and setipiprant, respectively) showed only modest reduction (approx. 25%) in the allergen-induced LAR118,119 while no convincing effects were observed on the allergen-induced changes in T2 biomarkers (blood eosinophils, FeNO)119 with only a minimal reduction in sputum eosinophils post-allergen.118 In addition, there was no decrease in the EAR in either study. The (relative) lack of protection against allergen-induced airway responses may (partly) consist with the fact that even with effective DP2-blockade, an allergen-triggered mast-cell (lacking DP2)120 mediator release (histamine, PGD2, cysteinyl-LTs) may still occur which is capable of causing an EAR and/or an LAR121122 and therefore, especially in allergic asthma, a combined blockade of e.g. DP2 ± DP1 ± TP ± cysteinyl-LT-R might provide a superior protection.
In line with this reasoning - and despite prior evidence of superior efficacy in phase 2B studies of patients with an allergic (T2-) profile (atopy ± eosinophils ≥250/mcL)123,124- several DP2 (CRTH2) antagonists (e.g., setipiprant, fevipiprant) failed in phase 3 clinical trials of allergic airway disease.124 More recently, DP2-blockade has been associated with the reduction in airway smooth muscle mass by decreasing airway eosinophilia and the recruitment of myofibroblasts and fibrocytes.125 Therefore, with several clinical trials still ongoing, (add-on) DP2-blockade may show efficacy in more severe T2 asthma126 and related conditions based on its anti-inflammatory and disease modifying potential.125,127
Respiratory viruses (e.g. RSV) represent other important triggers of chronic inflammatory airway disease capable of activating the PGD2/DP2 receptor-mediated pathway, thereby eliciting a ”non-allergen-induced” T2-immune response through airway epithelial cells and innate immune cells.128 Indeed, RSV has been associated with upregulation of the PGD2/DP2 pathway and increased PGD2 levels both in experimental and clinical studies, while (combined) DP1/DP2-blockade showed protective potential in preclinical studies.129 Therefore, blocking PGD2 through (combined) DP1/DP2 blockade has been postulated to protect against respiratory viral infections, and more recently, including SARS-CoV-2.130 Presently, this hypothesis awaits clinical evidence. In addition, the potent bronchoconstrictive actions of PGD2 and other constrictive prostanoids in human airways, call for trials with TP receptor antagonists in patients with asthma131