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