Fevipiprant inhibits eosinophil activation induced by multiple metabolites of prostaglandin D2

Introduction: Fevipiprant is a selective prostaglandin D2 receptor 2 (DP2) antagonist which reduces eosinophilic airway inflammation in patients with persistent asthma and raised sputum eosinophil counts. The DP2 receptor is activated by prostaglandin D2 (PGD2), together with multiple PGD2 metabolites which persist longer in vivo than the parent, thereby prolonging DP2 mediated duration of inflammation.

Aims: To characterize the inhibitory effect of fevipiprant on DP2 pathway-mediated eosinophil activation as measured by shape change induced by a panel of PGD2 metabolites.

Methods: Eosinophils were isolated from peripheral blood of allergic donors (n = 8) with a range of asthma severities up to GINA 4. The shape change responses to PGD2 and a panel of the reported major PGD2 metabolites (including Δ12PGJ2) were determined by flow cytometry. Using the agonist EC70 concentrations, the inhibitory potencies of fevipiprant were measured for each metabolite.

Results: Shape change stimulatory responses were confirmed for each metabolite, and fevipiprant showed similar sub-nM inhibitory potencies ([Table 1]) against PGD2 and six metabolites.

Table 1 

	PGD2	13,14-dihydro-15-keto-PGD2	PGJ2	Δ12PGJ2	Δ12PGD2	15-deoxy-Δ12,14PGD2	9α,11β-PGF2
IC50 (nM)	0.87	0.10	0.53	0.56	0.08	0.45	0.87

Conclusions: Fevipiprant inhibits eosinophil shape change induced by the major metabolites of PGD₂, which are known to be associated with the extended duration of DP2-mediated inflammation. The findings align with the demonstrated benefit of reduced sputum and tissue eosinophilia and support the mechanism of action of fevipiprant in patients with asthma.