Randomized, Subject and Investigator Blinded, Placebo-controlled Study to Demonstrate the Anti-inflammatory Effect of Fevipiprant (QAW039) in Moderate to Severe Asthma Patients With High Sputum and Blood Eosinophils.

This is an exploratory, randomized, subject- and investigator-blinded, placebo-controlled mode-of-action study to demonstrate the anti-inflammatory effects of fevipiprant compared to placebo after 12 weeks of treatment in 48 moderate to severe asthma patients with sputum and blood eosinophilia.

Start Date15 Oct 2019

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

EUCTR2018-004381-33-BE

/ Not yet recruitingPhase 2

Randomized, subject and investigator blinded, placebo-controlled study to demonstrate the anti-inflammatory effect of fevipiprant (QAW039) in moderate-severe asthma patients with high sputum and blood eosinophils

Start Date09 Aug 2019

Sponsor / Collaborator

Novartis Pharma AG

EUCTR2018-003548-22-BG

/ Not yet recruitingPhase 3

A 52 week, randomised, double blind, multinational, multicentre, 4-arm parallel group trial to assess the efficacy and safety of 3 doses of CHF 6532 (10, 25 or 50 mg BID) compared to placebo on top of standard of care in subjects with uncontrolled severe eosinophilic asthma.

Start Date17 Jul 2019

Sponsor / Collaborator

CHIESI Farmaceutici SpA

100 Clinical Results associated with PGD2 receptor x CRTH2

100 Translational Medicine associated with PGD2 receptor x CRTH2

0 Patents (Medical) associated with PGD2 receptor x CRTH2

Literatures (Medical) associated with PGD2 receptor x CRTH2

01 Jan 2024·International Archives of Allergy and Immunology

The Prostaglandin D2 Receptor CRTH2 Contributes to Airway Hyperresponsiveness during Airway Inflammation Induced by Sensitization without an Adjuvant in Mice

Article

Author: Masuo, Masahiro ; Matsumoto, Kenji ; Nakae, Susumu ; Nakamura, Masataka ; Takeda, Kazuyoshi ; Sugiura, Makiko ; Okumura, Ko ; Miyazaki, Yasunari ; Morita, Hideaki ; Ohno, Tatsukuni ; Hanzawa, Satoshi

Introduction: Prostaglandin D2 (PGD2), which is produced mainly by Th2 cells and mast cells, promotes a type-2 immune response by activating Th2 cells, mast cells, eosinophils, and group 2 innate lymphoid cells (ILC2s) via its receptor, chemoattractant receptor-homologous molecules on Th2 cells (CRTH2). However, the role of CRTH2 in models of airway inflammation induced by sensitization without adjuvants, in which both IgE and mast cells may play major roles, remain unclear. Methods: Wild-type (WT) and CRTH2-knockout (KO) mice were sensitized with ovalbumin (OVA) without an adjuvant and then challenged intranasally with OVA. Airway inflammation was assessed based on airway hyperresponsiveness (AHR), lung histology, number of leukocytes, and levels of type-2 cytokines in the bronchoalveolar lavage fluid (BALF). Results: AHR was significantly reduced after OVA challenge in CRTH2 KO mice compared to WT mice. The number of eosinophils, levels of type-2 cytokines (IL-4, IL-5, and IL-13) in BALF, and IgE concentration in serum were decreased in CRTH2 KO mice compared to WT mice. However, lung histological changes were comparable between WT and CRTH2 KO mice. Conclusion: CRTH2 is responsible for the development of asthma responses in a mouse model of airway inflammation that features prominent involvement of both IgE and mast cells.

01 Jan 2023·International Archives of Allergy and Immunology

Functional Polymorphisms of the Arachidonic Acid Pathway Associate with Risks and Clinical Outcomes of Allergic Diseases

Article

Author: Fok, Yu Ting Rachel ; Sio, Yang Yie ; Chew, Fook Tim ; Say, Yee-How ; Chiang, Wen Chin ; Shi, Ping ; Matta, Sri Anusha

Introduction: The arachidonic acid (AA) pathway plays a crucial role in allergic inflammatory diseases; however, the functional roles of allergy-associated single nucleotide polymorphisms (SNPs) in this pathway remain incompletely illustrated. Methods: This study belongs to a part of an ongoing Singapore/Malaysia cross-sectional genetics and epidemiological study (SMCSGES). We performed population genotyping on n = 2,880 individuals from the SMCSGES cohort to assess the associations of SNPs in the AA pathway genes with asthma and allergic rhinitis (AR). Spirometry assessments were performed to identify associations between SNPs and lung function among n = 74 pediatric asthmatic patients from the same cohort. Allergy-associated SNPs were functionally characterized using in vitro promoter luciferase assay, along with DNA methylome and transcriptome data of n = 237 peripheral blood mononuclear cell (PBMC) samples collected from a subset of the SMCSGES cohort. Results: Genetic association analysis showed 5 tag-SNPs from 4 AA pathway genes were significantly associated with asthma (rs689466 at COX2, rs35744894 at hematopoietic PGD2 synthase (HPGDS), rs11097414 at HPGDS, rs7167 at CRTH2, and rs5758 at TBXA2R, p < 0.05), whereas 3 tag-SNPs from HPGDS (rs35744894, rs11097414, and rs11097411) and 2 tag-SNPs from PTGDR (rs8019916 and rs41312470) were significantly associated with AR (p < 0.05). The asthma-associated rs689466 regulates COX2 promoter activity and associates with COX2 mRNA expression in PBMC. The allergy-associated rs1344612 was significantly associated with poorer lung function, increased risks of asthma and AR, and increased HPGDS promoter activity. The allergy-associated rs8019916 regulates PTGDR promoter activity and DNA methylation levels of cg23022053 and cg18369034 in PBMC. The asthma-associated rs7167 affects CRTH2 expression by regulating the methylation level of cg19192256 in PBMC. Conclusions: The present study identified multiple allergy-associated SNPs that modulate the transcript expressions of key genes in the AA pathway. The development of a “personalized medicine” approach with consideration of genetic influences on the AA pathway may hopefully result in efficacious strategies to manage and treat allergic diseases.

01 Oct 2022·Biochemical and Biophysical Research Communications

Protective effects of CRTH2 suppression in dry age-related macular degeneration

Article

Author: Xie, Ruotian ; Zuo, Shengkai ; Du, Mei ; Yan, Hua ; Wang, Xiaohong ; Yu, Ying ; Wang, Bei

Age-related macular degeneration (AMD) is the leading cause of central vision loss in the elderly. Oxidative stress-induced retinal pigment epithelium (RPE) cell apoptosis is a crucial pathogenic hallmark in AMD. Chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2), a prostaglandin (PG) D2 receptor, has been implicated in various pathophysiological events, especially inflammation and stress-induced cell apoptosis. However, its specific role in AMD is not fully understood. Here we studied the effect of CRTH2 on AMD. Our results showed that when stimulated by H₂O₂, CRTH2 mRNA expression in cells tended to increase. Flow cytometry revealed that the CRTH2 inhibitor could protect the RPE from apoptosis. After NaIO₃ injection, a larger area of retinal degeneration was observed in wild-type mice than in CRTH2^-/- mice. Optical coherence tomography (OCT) and Hematoxylin and Eosin (H&E) staining of retinal sections showed that sodium iodate-induced loss of photoreceptor cells was reduced in CRTH2^-/- mice after treatment; TUNEL-positive cells were mostly found in the outer nuclear layer. In the control group, NaIO₃ stimulation increased the number of TUNEL-positive cells, whereas the percentage of TUNEL-positive cells was significantly lower in CRTH2^-/- mice. Similarly, the CRTH2 receptor inhibitor CAY10471 similarly inhibited sodium iodate-induced retinal damage. Our results suggest that targeting CRTH2 is a promising therapeutic strategy for the treatment of progressive retinal degeneration in AMD.

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