Mechanism of action: Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) antagonist [prostaglandin D2 (DP2) receptor antagonist]

Preclinical pharmacology

AZD1981 is a potent (binding IC50 of 4nM), fully reversible, functionally non-competitive antagonist of human CRTh2. It blocks agonist-induced human eosinophil CD11b expression, shape change (including in whole blood), and chemotaxis as well as an basophil shape change and Th2-cell chemotaxis at IC50's of 8.5-50nM. Potency is similar across species as is plasma protein binding (~97%). AZD1981 is a weak (10s of μM) inhibitor in vitro of CYP2C9, OATP1B1 and UGT1A1 as well as an inducer of CYP3A4. These potential DDI effects appear to translate to in vivo at super pharmacologic doses/exposures (see below).

Safety and tolerability

AZD1981 has been administered orally in healthy volunteers (single oral dose up to 4000mg; multiple doses up to 2000mg BID for 2 weeks), asthma or COPD patients (up to 100mg, BID for 4 weeks), and asthmatics (up to 400mg BID for 12 weeks). A small percentage of patients treated with AZD1981 had notable elevations of ALT and AST without notable increase in total bilirubin.  Results suggest a dose-response relationship with the highest percentage of subjects having identified LFT abnormalities in the AZD1981 400mg BID group (~2-3% above placebo). In all cases, transaminases returned to baseline after AZD1981 was stopped. However, the possibility that AZD1981 may be associated with an increased risk of liver injury cannot be excluded. In completed DDI studies, AZD1981 at 400 or 500mg BID, but not at 100mg BID, increased the plasma exposure of ethinyl estradiol in female volunteers receiving a combined oral contraceptive (COC), warfarin (CYP2C9 substrate), and pravastatin (OATP1B1 substrate), while decreasing midazolam (CYP3A4 substrate).

Preclinical safety studies of up to 12 months duration have been performed.

Clinical pharmacology

Target engagement was demonstrated in the SAD and MAD Ph 1 studies using an ex vivo whole blood PGD2-induced eosinophil shape change assay (A2 = 35nM). Data from these as well as asthma efficacy studies indicate effective target coverage at doses of 40-80mg BID or TID.

Suitable for and exclusions

Preclinical reprotoxicology data are available and have not identified any specific risks. Women of child-bearing potential using highly effective contraception can be included.  Given the potential for DDI and LFT effects (see above), dosing regimen (level and duration) as well as inclusion/exclusion criteria should be selected carefully to support a favorable risk-benefit. There are currently no clinical data to support use in pediatric populations below 12 years of age, although existing preclinical data would support clinical studies in a paediatric population of > 5 years.

Proposals for studies in dermatology indications are not of interest at this time.

Additional information

Clinical Trials for this compound

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Publications for this compound

Find out more about this compound by reading related Publications:

Efficacy and safety of AZD1981, a CRTH2 receptor antagonist, in patients with moderate to severe COPD

Biochemical and pharmacological characterization of AZD1981, an orally available selective DP2 antagonist in clinical development for asthma

Substituted indole-1-acetic acids as potent and selective CRTh2 antagonists-discovery of AZD1981

Gene information from the NCBi

This compound works on the following genes: