AZD1981

Preclinical pharmacology

AZD1981 is a potent, fully reversible, functionally non-competitive antagonist of human CRTh2.

AZD1981 blocks agonist-induced human eosinophil CD11b expression, shape change (including in whole blood), chemotaxis, basophil shape change and Th2-cell chemotaxis. AZD1981 is a weak inhibitor (>10μM) of CYP2C9, OATP1B1 and UGT1A1 as well as an inducer of CYP3A4 in vitro. 

Safety and tolerability

AZD1981 has been administered orally in healthy volunteers for 2-weeks (single-dose up to 4000mg; multiple-dose up to 2000mg BID), in asthma or COPD patients (up to 100mg, BID for 4-weeks), and in asthmatics (up to 400mg BID for 12-weeks). A small percentage of patients treated with AZD1981 had ALT/AST elevations without an increase in total bilirubin.  Data suggest a dose-response relationship with 2-3% of subjects in the AZD1981 400mg BID group having LFT abnormalities compared with the placebo group. In all cases, transaminases returned to baseline after cessation of dosing. The possibility that AZD1981 may be associated with an increased risk of liver injury cannot be excluded.

In completed DDI studies, AZD1981 at >400mg 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). These potential DDI effects appear to translate to in vivo at super pharmacologic doses/exposures.

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

Clinical pharmacology

Target engagement was demonstrated in the SAD and MAD Ph1 studies using an ex vivo whole blood PGD2-induced eosinophil shape change assay (A2= 35nM). These data in addition to results from 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, the dosing regimen (level and duration) and inclusion/exclusion criteria should be selected carefully to support a favourable risk-benefit. There are currently no clinical data to support use in paediatric 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 will not be considered at this time.

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Mechanism of Action

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

Original Therapeutic Area

Other

CNS Penetrant

Low

Route of administration

Oral

Modality

Small Molecule

Additional Information

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