Mechanism of action: AZD9567 is an orally-administered, non-steroidal, selective glucocorticoid receptor modulator (oSGRM), with a different binding mode to classic corticosteroids.
Preclinical pharmacology and pharmacokinetics
AZD9567 binds potently to the human glucocorticoid receptor with an IC50 of 3.8 nM in a radioligand binding assay and is selective over other steroidal nuclear hormone receptors (MR, PR, AR and ER). Efficacy was demonstrated in functional reporter gene assays for trans-repression (7 nM) and trans-activation (11 nM) with either full or partial effects demonstrated respectively. In vitro anti-inflammatory efficacy was confirmed by inhibition of TNFα release following LPS stimulation in human whole blood (680 nM). In vivo, AZD9567 was able to attenuate joint inflammation in two rodent models of arthritis when delivered either in a prophylactic or therapeutic manner with efficacy similar to prednisolone. Furthermore, when compared to its anti-inflammatory potency, AZD9567 had a reduced effect on induction of key enzymes involved in gluconeogenesis and bone formation/resorption compared to prednisolone.
Safety and tolerability
In healthy volunteers both single (2-155 mg) and multiple ascending (10-125 mg) oral doses of AZD9567 given for 5 days were safe and well tolerated. Adverse events were mild to moderate in intensity, and no severe nor serious AEs were reported. Headache was the most commonly reported AE. No dose limiting adverse effects have been identified.
Results from two studies in healthy volunteers provide early evidence that AZD9567 is the first glucocorticoid receptor modulator to show an improved efficacy/dysglycaemic side effect profile over prednisolone. In ex vivo assessments of anti-inflammatory biomarkers after up to 5 days of once-daily oral treatment, it was indicated that 40 mg of AZD9567 is equipotent to 20 mg prednisolone and 80 mg AZD9567 is equipotent to 45 mg prednisolone. However, the effects of AZD9567, at doses up to 80 mg, on plasma glucose levels after an oral glucose tolerance test were comparable to those observed with 5 mg prednisolone. AZD9567 displays PK properties that support once-daily dosing. Slightly less than dose proportional PK has been observed to show no evidence of accumulation or time-dependent kinetics.
Suitable for and exclusions
Suitable for administration to adult men using an approved method of contraception, and postmenopausal women in clinical trials of up to 1 month duration. Can be administered to up to 150 women of child-bearing potential with sufficient control over pregnancy risk using AstraZeneca approved methods of birth control. We would exclude new proposals in areas of overlap with any ongoing trials.
Clinical Trials for this compound
Three clinical trials have been conducted with AZD9567. In healthy volunteers, a single ascending dose (SAD) study SAD (NCT02512575) and a multiple ascending dose (MAD) study MAD (NCT02760316) have completed. A Ph2a study in patients with active rheumatoid arthritis is ongoing comparing AZD9567 40mg vs prednisolone 20mg once-daily for 14 days. Ph2a RA study (NCT03368235)
Publications for this compound
Find out more about this compound by reading related publications:
Lena Ripa et al. Discovery of a Novel Oral Glucocorticoid Receptor Modulator (AZD9567) with Improved Side Effect Profile, Journal of Medicinal Chemistry 2018 61 (5), 1785-1799. DOI: 10.1021/acs.jmedchem.7b01690