Discovery of Fevipiprant (NVP-QAW039), a Potent and Selective DP₂ Receptor Antagonist for Treatment of Asthma

Abstract

Further optimization of an initial DP receptor antagonist clinical candidate NVP-QAV680 led to the discovery of a follow-up molecule 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1-pyrrolo[2,3-]pyridin-3-yl)acetic acid (compound , NVP-QAW039, fevipiprant), which exhibits improved potency on human eosinophils and Th2 cells, together with a longer receptor residence time, and is currently in clinical trials for severe asthma.

Fevipiprant, a selective prostaglandin D2 receptor 2 antagonist, inhibits human group 2 innate lymphoid cell aggregation and function

“…6 Fevipiprant is in clinical development for the treatment of asthma. [6][7][8] ILC2s were isolated from blood of healthy participants and expanded in vitro by mixed lymphocyte reactions to characterize the ILC2-intrinsic inhibitory effects of fevipiprant on DP 2 signaling (see Fig E1 and the Materials and Methods section in this article's Online Repository at www.jacionline.org). ILC2 migration toward PGD 2 (200 nmol/L) was measured by using IncuCyte live-cell microscopy (IncuCyte ZOOM; Essen Bioscience, Ann Arbor, Mich).…”

“…Phase II studies showed fevipiprant to be effective in patients with uncontrolled eosinophilic asthma, patients with severe airflow limitation, and patients with low-dose steroid-resistant allergic asthma. [6][7][8] An advantage of targeting inflammation upstream of ILC2s, rather than anti-type 2 cytokine therapies, is intervention earlier in the pathway and reduction in redundancy between type 2 effector cytokines. Furthermore, blockade of PGD 2 signaling will additionally target non-ILC2 DP 2 1 populations, such as T H 2 cells, T C 2 cells, basophils, and eosinophils, all of which have been implicated in asthma immunopathology.…”

The prostaglandin D2 receptor 2 pathway in asthma: a key player in airway inflammation

“…Eosinophil activation is also associated with increased cytokine production, which has various downstream immunomodulatory effects [ 54 ]. DP 2 receptor activation at the eosinophil surface facilitates the trans-endothelial migration and influx of eosinophils, increases eosinophil degranulation and induces eosinophil shape change [ 40 , 55 , 56 ]. Eosinophil shape change in response to DP 2 activation [ 57 ] is similar to that visualised previously with eotaxin stimulation [ 58 ].…”

G Protein–Coupled Receptors in Asthma Therapy: Pharmacology and Drug Action

“…The activation of eosinophils by DP2 has also been demonstrated in a number of studies. Those studies showed that PGD 2 signaling through DP2 on the surface of eosinophils could lead to shape change and promote degranulation and cytokine production (Gervais et al, 2001; Pharmacology of GPCRs in Asthma Therapy and Drug Action Sykes et al, 2016;Sandham et al, 2017). In addition, type 2 cytokines induced by DP2 signaling can have positive effects on the activation and migration of eosinophils, further contributing to excessive inflammation.…”