Development of a decision-making biomarker for CRTH2 antagonism in clinical studies

Strasser, Daniel S.; Farine, Hervé; Holdener, Martin; Zisowsky, Jochen; Roscher, René; Hoerner, Julie; Géhin, Martine; Sidharta, Patricia N.; Dingemanse, Jasper; Groenen, Peter M.A.

doi:10.1016/j.nhtm.2015.05.001

Cited by 7 publications

(9 citation statements)

References 27 publications

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“…IL‐13 was measured using the Erenna ® (Merck KGaA, Darmstadt, Germany) system from Singulex, capable of quantifying subtle changes of IL‐13 concentrations in blood . The Erenna ® (Merck KGaA) system employs antibody‐based single molecule counting that allows to reliably quantify IL‐13 concentrations in the fg/ml range in human serum samples.…”

Section: Methodsmentioning

confidence: 99%

Serum IL‐5 and IL‐13 consistently serve as the best predictors for the blood eosinophilia phenotype in adult asthmatics

Agache

Strasser

Klenk

et al. 2016

Allergy

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Section: Methodsmentioning

confidence: 99%

Serum IL‐5 and IL‐13 consistently serve as the best predictors for the blood eosinophilia phenotype in adult asthmatics

Agache

Strasser

Klenk

et al. 2016

Allergy

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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%

“…Preclinical studies have shown that setipiprant blocks the activation of eosinophils and basophils, and reduces the secretion of cytokines (IL-4, IL-5, and IL-13) by Th2 cells [33]. In clinical studies, setipiprant has been shown to be well tolerated at both single and multiple doses in healthy subjects [27, 34–36]. A multicenter, double-blind, placebo-controlled, proof-of-mechanism Phase 2 study in 18 adult male participants with mild allergic asthma (forced expiratory volume in 1 s [FEV 1 ] ≥70% predicted) demonstrated that setipiprant 1000 mg b.i.d.…”

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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“…In vitro, ACT-453859 is 15-fold more effective in blocking PGD 2 -mediated internalization of CRTH2 on eosinophils (IC 50 ¼ 45 nM) 1 than setipiprant (IC 50 ¼ 684 nM). 2 As deduced by Dr Srinivas, preliminary in vitro experiments suggested that ACT-453859 is metabolized by a CYP enzyme. CYP2C9 is thought to be the primary driver of M1 formation.…”

mentioning

confidence: 98%

“…However, we respectfully disagree with Dr Srinivas that removing the PD contribution of M1 from the overall PD profile would transform ACT‐453859 into a compound similar to setipiprant. In vitro, ACT‐453859 is 15‐fold more effective in blocking PGD 2 ‐mediated internalization of CRTH2 on eosinophils (IC 50 = 45 nM) than setipiprant (IC 50 = 684 nM) …”

mentioning

confidence: 99%

CYP2C9 involvement in ACT‐453859 metabolism

Géhin

Dingemanse

Sidharta

2015

The Journal of Clinical Pharma

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We thank Dr Srinivas for reading our paper carefully, for his positive general comments, and for raising some interesting discussion points. He indicated that the data described in our paper suggested a reduced metabolism after an 800-mg single dose of ACT-453859. The metabolite-to-parent exposure ratios in the Multiple Ascending Dose (MAD) part are 0.48, 0.36, and 0.41 for the 10-, 100-, and 800-mg once daily dosing regimen, respectively, and, therefore, independent of dose. In the Single Ascending Dose (SAD) part, this ratio for the highest dose of 800 mg is 0.38, which is within the range observed in the MAD part. Therefore, no apparent saturation of metabolism after single-or multipledose administration of ACT-453859 up to high dose levels was observed in this study.We acknowledge that the pharmacodynamics (PD) contribution of M1 is substantial, especially at trough (predose), at which M1 might be responsible for up to one-fourth of the overall PD effect. However, we respectfully disagree with Dr Srinivas that removing the PD contribution of M1 from the overall PD profile would transform ACT-453859 into a compound similar to setipiprant. In vitro, ACT-453859 is 15-fold more effective in blocking PGD 2 -mediated internalization of CRTH2 on eosinophils (IC 50 ¼ 45 nM) 1 than setipiprant (IC 50 ¼ 684 nM). 2As deduced by Dr Srinivas, preliminary in vitro experiments suggested that ACT-453859 is metabolized by a CYP enzyme. CYP2C9 is thought to be the primary driver of M1 formation. In the SAD/MAD study, the enrolled subjects were genotyped for cyp2c9. All of them had at least one wild-type cyp2c9 allele which resulted in apparent normal cyp2c9 gene activity. The impact of cyp2c9 slow metabolizer phenotypes on M1 formation will need to be further assessed in a dedicated study. As mentioned above, we agree that M1 contributes in vivo to ACT-453859 PD, but an interaction with a CYP2C9 inhibitor would not be of concern in terms of PD activity, as it would lead to a more pronounced presence of the parent compound, which is 4.5-fold more potent than M1 (IC 50 ¼ 205 nM).1 However, the relevance and extent of drug-drug interactions should be further assessed during the clinical development of ACT-453859.

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Development of a decision-making biomarker for CRTH2 antagonism in clinical studies

Cited by 7 publications

References 27 publications

Serum IL‐5 and IL‐13 consistently serve as the best predictors for the blood eosinophilia phenotype in adult asthmatics

Serum IL‐5 and IL‐13 consistently serve as the best predictors for the blood eosinophilia phenotype in adult asthmatics

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

CYP2C9 involvement in ACT‐453859 metabolism

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