Discovery and characterization of NVP-QAV680, a potent and selective CRTh2 receptor antagonist suitable for clinical testing in allergic diseases

Sandham, David A.; Arnold, Nicola; Aschauer, Heinrich; Bala, Kamlesh; Barker, Lucy; Brown, Lyndon; Brown, Zarin; Budd, David C.; Cox, Brian J.; Docx, Cerys; Dubois, Gerald; Duggan, Nicholas; England, Karen; Everatt, Brian; Furegati, Marcus; Hall, Edward; Kalthoff, Frank; King, Anna; Leblanc, Catherine; Manini, Jodie; Meingassner, Josef G.; Profit, Rachael; Schmidt, Alfred; Simmons, Jennifer; Sohal, Bindi; Stringer, Rowan; Thomas, M.; Turner, Katharine L.; Walker, Christoph; Watson, Simon J.; Westwick, John; Willis, Jennifer; Williams, Gareth; Wilson, Caroline

doi:10.1016/j.bmc.2013.08.025

Cited by 22 publications

(23 citation statements)

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“…1. QAW039 is a triuoromethyl derivative of the previously described 7-azaindole-3-acetic acid QAV680 (Sandham et al, 2013). The measured lipophilicity (logD 7.4 ) of these compounds is lower than other described CRTh2 antagonists (Table 3), which likely contributes to their lower plasma-protein binding.…”

Section: Qaw039 and Related Crth2mentioning

confidence: 99%

“…QAW039 was prepared using procedures reported for QAV680 (Sandham et al, 2013), and all reference CRTh2 antagonists were prepared according to patent procedures referenced in Lamers et al, (2013). The preparation of [ 3 H]-QAW039 has been previously described (see Luu et al, 2015 All radioligand experiments were conducted in 96 deep-well plates in assay binding buffer (Hanks' balanced salt solution containing 10 mM HEPES, 1% dimethylsufoxide (DMSO), and 0.02% pluronic acid, pH 7.4) at 37°C.…”

Section: Compoundsmentioning

confidence: 99%

“…We recently reported the discovery of QAV680, a potent selective CRTh2 receptor antagonist, suitable for clinical testing in allergic diseases (Sandham et al, 2013). QAV680 dosed twice or four times daily was shown to reduce nasal symptom scores after allergen challenge in patients with allergic rhinitis (Erpenbeck et al, 2014a,b).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Qaw039 and Related Crth2mentioning

confidence: 99%

Section: Compoundsmentioning

confidence: 99%

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

et al. 2016

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“…This has led to considerable interest and research on the clinical use of CRTH2 antagonists as a novel treatment approach in chronic allergic inflammatory conditions such as AR, allergic dermatitis, and asthma [14, 16, 17, 23–26]. A number of lines of experimental data suggest that CRTH2 antagonists can selectively counteract the pro-inflammatory effects of PGD 2 , which are thought to underlie the allergic response in AR [16, 17, 21, 27–32]. …”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of setipiprant in seasonal allergic rhinitis: results from Phase 2 and Phase 3 randomized, double-blind, placebo- and active-referenced studies

Ratner

Andrews

Hampel

et al. 2017

Allergy Asthma Clin Immunol

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BackgroundAntagonism of chemoattractant receptor-homologous molecule on T-helper type-2 cells (CRTH2), a G-protein coupled receptor for prostaglandin D2, could be beneficial for treating allergic disorders. We present findings on the efficacy and safety/tolerability of a CRTH2 antagonist (setipiprant) in participants with seasonal allergic rhinitis (AR) in a real-life setting over 2 weeks.MethodsA Phase 2 trial and a Phase 3 trial were conducted at seven centers in Texas, USA during the Mountain Cedar pollen season. Both were prospective, randomized, double-blind, placebo- and active-referenced (cetirizine) studies. The Phase 2 trial assessed setipiprant 100–1000 mg b.i.d. and 1000 mg o.d. versus placebo in adult and elderly participants. The Phase 3 trial assessed setipiprant 1000 mg b.i.d. in adolescent, adult, and elderly participants. Efficacy was assessed using daytime nasal symptom scores (DNSS), night-time nasal symptom scores (NNSS) and daytime eye symptom scores (DESS).Results579 participants were randomized in the Phase 2 trial (mean age 41.6–43.4 years); 630 were randomized in the Phase 3 trial (mean age 37.5–40.7 years). A statistically significant, dose-related improvement in mean change from baseline DNSS was observed over 2 weeks with setipiprant 1000 mg b.i.d. versus placebo in the Phase 2 trial (−0.15 [95% CI −0.29, −0.01]; p = 0.030). Setipiprant 1000 mg b.i.d. had no significant effect on this endpoint in the Phase 3 trial (−0.02 [95% CI −0.12, 0.07]; p = 0.652). Total and individual NNSS and DESS symptom scores were significantly improved with setipiprant 1000 mg b.i.d. versus placebo in the Phase 2 but not the Phase 3 trial. Setipiprant showed a favorable safety/tolerability profile.ConclusionsThe Phase 2 trial was the first large clinical study to assess a CRTH2 antagonist in seasonal AR in a real-life setting. Setipiprant dose-related efficacy in the Phase 2 trial was not confirmed during Phase 3. Setipiprant was well tolerated in both studies. Trial registration NCT01241214 and NCT01484119Electronic supplementary materialThe online version of this article (doi:10.1186/s13223-017-0183-z) contains supplementary material, which is available to authorized users.

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“…To the date of reporting, three CRTH2 antagonists have been tested in phase II trials, i.e. NAV-QAV680, which showed good bioavailability in rats and rodents [87], setipiprant [2-(2-[1-naphthoyl]-8-fluoro-3,4-dihydro-1H-pyrido(4, 3-b)indol-5[2H]-yl)acetic acid] [88], and ARRY-502.…”

Section: Drugs Targeting Crth2 and Crth2/dprmentioning

confidence: 99%

Pharmacological Therapy of Bronchial Asthma: The Role of Biologicals

Heck¹,

Nguyen

Le³

et al. 2015

Int Arch Allergy Immunol

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Bronchial asthma is a heterogeneous, complex, chronic inflammatory and obstructive pulmonary disease driven by various pathways to present with different phenotypes. A small proportion of asthmatics (5-10%) suffer from severe asthma with symptoms that cannot be controlled by guideline therapy with high doses of inhaled steroids plus a second controller, such as long-acting β₂ agonists (LABA) or leukotriene receptor antagonists, or even systemic steroids. The discovery and characterization of the pathways that drive different asthma phenotypes have opened up new therapeutic avenues for asthma treatment. The approval of the humanized anti-IgE antibody omalizumab for the treatment of severe allergic asthma has paved the way for other cytokine-targeting therapies, particularly those targeting interleukin (IL)-4, IL-5, IL-9, IL-13, IL-17, and IL-23 and the epithelium-derived cytokines IL-25, IL-33, and thymic stromal lymphopoietin. Knowledge of the molecular basis of asthma phenotypes has helped, and continues to help, the development of novel biologicals that target a diverse array of phenotype-specific molecular targets in patients suffering from severe asthma. This review summarizes potential therapeutic approaches that are likely to show clinical efficacy in the near future, focusing on biologicals as promising novel therapies for severe asthma.

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Discovery and characterization of NVP-QAV680, a potent and selective CRTh2 receptor antagonist suitable for clinical testing in allergic diseases

Cited by 22 publications

References 23 publications

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

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

Efficacy and safety of setipiprant in seasonal allergic rhinitis: results from Phase 2 and Phase 3 randomized, double-blind, placebo- and active-referenced studies

Pharmacological Therapy of Bronchial Asthma: The Role of Biologicals

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