Setipiprant, a selective <scp>CRTH</scp>2 antagonist, reduces allergen‐induced airway responses in allergic asthmatics

Diamant, Zuzana; Sidharta, Patricia N.; Singh, Dave; O’Connor, Brian; Zuiker, Rob; Leaker, Brian; Silkey, Mariabeth; Dingemanse, Jasper

doi:10.1111/cea.12357

Cited by 79 publications

(67 citation statements)

References 30 publications

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“…CRTH2 also designated as Prostaglandin D 2 receptor 2 (DP 2 ), and cluster of differentiation 294 (CD294) is encoded by the PTGDR2 gene in human. Several pieces of evidence indicate that CRTH2 receptor may play an important role in the allergic diseases, since the blockade of this receptor reduces the allergic airway inflammation [42, 43]. Further, the previous findings have highlighted the role of Prostaglandin D2 (PGD2) and CRTH2 receptor interaction in the pathogenesis of allergic diseases [44].…”

Section: General Characteristics Of Vasoactive Intestinal Peptide mentioning

confidence: 99%

Neuroendocrine cells derived chemokine vasoactive intestinal polypeptide (VIP) in allergic diseases

Verma

Manohar

Venkateshaiah

et al. 2017

Cytokine & Growth Factor Reviews

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Worldwide increase incidences of allergic diseases have heightened the interest of clinicians and researchers to understand the role of neuroendocrine cells in the recruitment and activation of inflammatory cells. Several pieces of evidence revealed the association of neuropeptides in the pathogenesis of allergic diseases. Importantly, one such peptide that is secreted by neuronal cells and immune cells exerts a wide spectrum of immunological functions as cytokine/chemokine is termed as Vasoactive Intestinal Peptide (VIP). VIP mediates immunological function through interaction with specific receptors namely VPAC-1, VPAC-2, CRTH2 and PAC1 that are expressed on several immune cells such as eosinophils, mast cells, neutrophils, and lymphocytes; therefore, provide the basis for the action of VIP on the immune system. Additionally, VIP mediated action varies according to target organ depending upon the presence of specific VIP associated receptor, involved immune cells and the microenvironment of the organ. Herein, we present an integrative review of the current understanding on the role of VIP and associated receptors in allergic diseases, the presence of VIP receptors on various immune cells with particular emphasis on the role of VIP in the pathogenesis of allergic diseases such as asthma, allergic rhinitis, and atopic dermatitis. Being crucial signal molecule of the neuroendocrine-immune network, the development of stable VIP analogue and/or antagonist may provide the future therapeutic drug alternative for the better treatment of these allergic diseases. Taken together, our current review summarizes the current understandings of VIP biology and further explore the significance of neuroendocrine cells derived VIP in the recruitment of inflammatory cells in allergic diseases that may be helpful to the investigators for planning the experiments and accordingly predicting new therapeutic strategies for combating allergic diseases. Summarized graphical abstract will help the readers to understand the significance of VIP in allergic diseases.

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Section: General Characteristics Of Vasoactive Intestinal Peptide mentioning

confidence: 99%

Neuroendocrine cells derived chemokine vasoactive intestinal polypeptide (VIP) in allergic diseases

Verma

Manohar

Venkateshaiah

et al. 2017

Cytokine & Growth Factor Reviews

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“…This accumulating evidence suggests that the CRTh2 receptor may play an important role in respiratory disease, since the blockade of the CRTh2 receptor significantly reduces experimental allergic airway inflammation 20–22. Evidence for the potential clinical efficacy of CRTh2 antagonists in patients with asthma or grass pollen allergies has also been provided by recent in vivo human studies 23–25…”

Section: Introductionmentioning

confidence: 99%

Two Phase II randomized trials on the CRTh2 antagonist AZD1981 in adults with asthma

Kuna¹,

Bjermer²,

Tornling³

2016

DDDT

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BackgroundChemoattractant receptor-homologous molecule expressed on T helper type 2 (Th2) cell (CRTh2) receptor antagonists is being investigated for asthma.ObjectivesThe aim of this study was to assess the effects of the CRTh2 receptor antagonist, AZD1981 (with/without inhaled corticosteroids [ICSs]), on lung function and asthma control.Patients and methodsAdults aged 18–60 years were enrolled in two randomized, placebo-controlled, parallel-group trials (protocol number: D9830C00003 [study 1, n=209] and protocol number: D9830C00004 [study 2, n=510]). In study 1, patients with stable asthma (forced expiratory volume in 1 second [FEV1]: 65%−110%) were withdrawn from ICS (<400 µg/d) and randomized to AZD1981 1,000 mg twice daily (bid) or placebo. In study 2, patients with uncontrolled asthma (FEV1: 40%−85%) despite ICS therapy (≥500 µg/d) were randomized to 50 mg, 400 mg, or 1,000 mg bid AZD1981 or placebo. The primary efficacy variable for both trials was the change in morning peak expiratory flow after 4 weeks of treatment. Secondary variables included Asthma Control Questionnaire (ACQ-5) scores, FEV1 assessments, safety, and tolerability. In study 2, efficacy was also assessed according to atopic status.ResultsFollowing 4 weeks of treatment, there was a nonsignificant increase in morning peak expiratory flow on AZD1981 1,000 mg bid (9.5 L/min vs placebo, P=0.086 [study 1] and 12 L/min vs placebo, P=0.16 [study 2]). In study 2, all doses of AZD1981 provided significant improvements in ACQ-5 scores (0.26–0.3 units vs placebo, P=0.010–0.022); however, there was no dose–response relationship. Improved ACQ-5 scores and FEV1 were observed in the majority of atopic patients treated with AZD1981. AZD1981 was well tolerated across treatment groups.ConclusionFurther research may be warranted in atopic patients to fully evaluate the clinical efficacy of AZD1981.

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“…In animal models of acute allergen challenge PGD 2 -mediated effects are blocked by CRTh2 antagonists acting on CRTh2 receptors on Th2 cells and inflammatory effector cells downstream of the allergic cascade (Uller et al, 2007). Several selective orally available antagonists have been since described in the literature, with compounds such as setipiprant (Diamant et al, 2014), BI-671800 (Krug et al, 2014), and OC-459 (Barnes et al, 2012) providing clinical proof of concept in asthma and allergic rhinitis. A comprehensive review of the current status of these and other compounds, including the dual CRTh2/thromboxane A 2 receptor (TP) antagonist ramatroban (Sugimoto et al, 2003), is available (Norman 2014).…”

Section: Introductionmentioning

confidence: 99%

Fevipiprant (QAW039), a Slowly Dissociating CRTh2 Antagonist with the Potential for Improved Clinical Efficacy

et al. 2016

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Here we describe the pharmacologic properties of a series of clinically relevant chemoattractant receptor-homologous molecules expressed on T-helper type 2 (CRTh2) receptor antagonists, including fevipiprant (NVP-QAW039 or QAW039), which is currently in development for the treatment of allergic diseases. min 21 and 0.048 minute 21 , respectively. Importantly, the k off of QAW039 (half-life 5 14.4 minutes) was .7-fold slower than the slowest reference compound tested, AZD-1981. In functional studies, QAW039 behaved as an insurmountable antagonist of PGD 2 -stimulated [35 S]-GTPgS activation, and its effects were not fully reversed by increasing concentrations of PGD 2 after an initial 15-minute incubation period. This behavior is consistent with its relatively slow dissociation from the human CRTh2 receptor.In contrast for the other ligands tested this time-dependent effect on maximal stimulation was fully reversed by the 15-minute time point, whereas QAW039's effects persisted for .180 minutes. All CRTh2 antagonists tested inhibited PGD 2 -stimulated human eosinophil shape change, but importantly QAW039 retained its potency in the whole-blood shape-change assay relative to the isolated shape change assay, potentially reflective of its relatively slower off rate from the CRTh2 receptor. QAW039 was also a potent inhibitor of PGD 2 -induced cytokine release in human Th2 cells. Slow CRTh2 antagonist dissociation could provide increased receptor coverage in the face of pathologic PGD 2 concentrations, which may be clinically relevant.

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Setipiprant, a selective CRTH2 antagonist, reduces allergen‐induced airway responses in allergic asthmatics

Abstract: Setipiprant at multiple oral doses was well tolerated and reduced both the allergen-induced LAR and the associated AHR in allergic asthmatics. Our findings confirm that CRTH2 may be a promising target for the treatment of allergic disorders.

Cited by 79 publications

References 30 publications

Neuroendocrine cells derived chemokine vasoactive intestinal polypeptide (VIP) in allergic diseases

Neuroendocrine cells derived chemokine vasoactive intestinal polypeptide (VIP) in allergic diseases

Two Phase II randomized trials on the CRTh2 antagonist AZD1981 in adults with asthma

Fevipiprant (QAW039), a Slowly Dissociating CRTh2 Antagonist with the Potential for Improved Clinical Efficacy

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