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Setipiprant, a selective CRTH2 antagonist, reduces allergen-induced airway responses in allergic asthmatics.
Clin Exp Allergy. 2014 Aug; 44(8):1044-52.CE

Abstract

BACKGROUND

CRTH2 is a G-protein-coupled receptor on T helper2 cells that mediates pro-inflammatory effects of prostaglandin D2 in allergic responses.

OBJECTIVE

To investigate the tolerability and pharmacokinetics of setipiprant (ACT-129968), a selective orally active CRTH2 antagonist, in allergic asthmatics and to assess the protective effects of multiple doses of this drug against allergen-induced airway responses.

METHODS

In this 3-centre, double-blinded, placebo-controlled, cross-over study, 18 allergic asthmatic males were randomized to setipiprant 1000 mg or matching placebo b.i.d. for 5 consecutive days. Study periods were separated by a washout of ≥ 3 weeks. On study day 4, subjects underwent a standardized allergen challenge and airway response was recorded by FEV1 until 10 h post-allergen. Airway responsiveness to methacholine and exhaled nitric oxide (eNO) were measured pre- and post-dosing. The effects of both treatments on the allergen-induced airway responses were compared by a paired Student's t-test.

RESULTS

Fifteen subjects completed the study per-protocol and were included in the analysis. Overall, setipiprant was well tolerated and no clinically relevant adverse events occurred. Trough plasma concentrations showed a high inter-subject variability. Compared with placebo, setipiprant significantly reduced the allergen-induced late asthmatic response (LAR), inhibiting the area under the response vs. time curve (AUC(3-10 h)) by on average 25.6% (P = 0.006) and significantly protected against the allergen-induced airway hyperresponsiveness (AHR) to methacholine (P = 0.0029). There was no difference in the early asthmatic response (EAR) or in allergen-induced changes in eNO between treatments.

CONCLUSION AND CLINICAL RELEVANCE

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.

Authors+Show Affiliations

Centre for Human Drug Research, Leiden, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial, Phase II
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24964348

Citation

Diamant, Z, et al. "Setipiprant, a Selective CRTH2 Antagonist, Reduces Allergen-induced Airway Responses in Allergic Asthmatics." Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology, vol. 44, no. 8, 2014, pp. 1044-52.
Diamant Z, Sidharta PN, Singh D, et al. Setipiprant, a selective CRTH2 antagonist, reduces allergen-induced airway responses in allergic asthmatics. Clin Exp Allergy. 2014;44(8):1044-52.
Diamant, Z., Sidharta, P. N., Singh, D., O'Connor, B. J., Zuiker, R., Leaker, B. R., Silkey, M., & Dingemanse, J. (2014). Setipiprant, a selective CRTH2 antagonist, reduces allergen-induced airway responses in allergic asthmatics. Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology, 44(8), 1044-52. https://doi.org/10.1111/cea.12357
Diamant Z, et al. Setipiprant, a Selective CRTH2 Antagonist, Reduces Allergen-induced Airway Responses in Allergic Asthmatics. Clin Exp Allergy. 2014;44(8):1044-52. PubMed PMID: 24964348.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Setipiprant, a selective CRTH2 antagonist, reduces allergen-induced airway responses in allergic asthmatics. AU - Diamant,Z, AU - Sidharta,P N, AU - Singh,D, AU - O'Connor,B J, AU - Zuiker,R, AU - Leaker,B R, AU - Silkey,M, AU - Dingemanse,J, PY - 2014/01/22/received PY - 2014/06/10/revised PY - 2014/06/13/accepted PY - 2014/6/26/entrez PY - 2014/6/26/pubmed PY - 2015/4/7/medline KW - CRTH2 antagonist KW - allergen bronchoprovocation test KW - asthma KW - setipiprant SP - 1044 EP - 52 JF - Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology JO - Clin Exp Allergy VL - 44 IS - 8 N2 - BACKGROUND: CRTH2 is a G-protein-coupled receptor on T helper2 cells that mediates pro-inflammatory effects of prostaglandin D2 in allergic responses. OBJECTIVE: To investigate the tolerability and pharmacokinetics of setipiprant (ACT-129968), a selective orally active CRTH2 antagonist, in allergic asthmatics and to assess the protective effects of multiple doses of this drug against allergen-induced airway responses. METHODS: In this 3-centre, double-blinded, placebo-controlled, cross-over study, 18 allergic asthmatic males were randomized to setipiprant 1000 mg or matching placebo b.i.d. for 5 consecutive days. Study periods were separated by a washout of ≥ 3 weeks. On study day 4, subjects underwent a standardized allergen challenge and airway response was recorded by FEV1 until 10 h post-allergen. Airway responsiveness to methacholine and exhaled nitric oxide (eNO) were measured pre- and post-dosing. The effects of both treatments on the allergen-induced airway responses were compared by a paired Student's t-test. RESULTS: Fifteen subjects completed the study per-protocol and were included in the analysis. Overall, setipiprant was well tolerated and no clinically relevant adverse events occurred. Trough plasma concentrations showed a high inter-subject variability. Compared with placebo, setipiprant significantly reduced the allergen-induced late asthmatic response (LAR), inhibiting the area under the response vs. time curve (AUC(3-10 h)) by on average 25.6% (P = 0.006) and significantly protected against the allergen-induced airway hyperresponsiveness (AHR) to methacholine (P = 0.0029). There was no difference in the early asthmatic response (EAR) or in allergen-induced changes in eNO between treatments. CONCLUSION AND CLINICAL RELEVANCE: 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. SN - 1365-2222 UR - https://www.unboundmedicine.com/medline/citation/24964348/Setipiprant_a_selective_CRTH2_antagonist_reduces_allergen_induced_airway_responses_in_allergic_asthmatics_ L2 - https://doi.org/10.1111/cea.12357 DB - PRIME DP - Unbound Medicine ER -