AZD0328
Preclinical Pharmacology
AZD9567 is a first-in-class, oral, selective, non-steroidal glucocorticoid receptor modulator designed as an alternative to oral corticosteroids to treat inflammatory disease with a similar efficacy, but differentiated safety profile. AZD9567 binds the glucocorticoid receptor differently from steroids, inducing a unique transcriptomic response.
In vitro, AZD9567 has higher affinity for the glucocorticoid receptor and 104-fold lower affinity for the mineralocorticoid receptor than prednisolone, suggesting that AZD9567 could also be less disruptive to fluid and electrolyte balance.
In preclinical experiments, AZD9567 has similar anti-inflammatory effects to prednisolone, both in vivo in a rat model of joint inflammation and ex vivo by inhibition of lipopolysaccharide-stimulated TNFα release in human whole blood. However, AZD9567 has been shown to have a less deleterious effect than prednisolone on glucose homeostasis. In vitro, unlike prednisolone, AZD9567 does not upregulate the transcription of gluconeogenic enzymes in human hepatocytes and inhibition of glucose-stimulated insulin secretion in human pancreatic islets is twofold lower with AZD9567 than prednisolone2
Safety and tolerability
AZD9567 has been shown to be safe and well tolerated in Phase 1 studies in healthy volunteers and in Phase 2a studies in patients following oral administration once daily, for up to two weeks2,3. Chronic toxicology studies in rodents (6mo) and non-human primates (9mo) have been completed Reproductive and development toxicity assays in rats and rabbits have also been completed. Data on blood brain barrier penetration has not yet been generated, but it is assumed that AZD9567 will penetrate into the CNS.
Clinical pharmacology
Data from Phase 1 studies (NCT02512575) in healthy volunteers support the preclinical findings; ex vivo inhibition of lipopolysaccharide-stimulated inflammatory cytokine release in whole blood and oral glucose tolerance tests indicate that AZD9567 had an improved antiinflammatory–dysglycaemic therapeutic index compared with prednisolone2.
In a Phase 2a study (NCT02512575) in patients with rheumatoid arthritis experiencing a disease flare, after 14-days’ once-daily therapy with equipotent doses of AZD9567 (N=11) and prednisolone (N=10), both compounds demonstrated a similar improvement in the composite disease activity score, DAS28-CRP, and the four individual components of the score. Although there was slight imbalance in the two treatment groups, the overall conclusion from the study was that AZD9567 demonstrated a similar efficacy profile to prednisolone. Furthermore, AZD9567, unlike prednisolone, did not alter serum electrolyte balance3.
Suitable for and exclusions
Suitable for preclinical and clinical studies
Mechanism of Action
Glucocorticoid receptor modulator
Original Therapeutic Area
Respiratory and Immunology
CNS Penetrant
Assumed
Route of administration
Oral
Modality
Small Molecule
Additional Information
1. Ripa L, et al. (2018) Discovery of a novel oral glucocorticoid receptor modulator (AZD9567) with improved side effect profile. J Med Chem; 61: 1785–99.
2. Hegelund-Myrbäck T, et al. (2020) Effects of a selective glucocorticoid receptor modulator (AZD9567) versus prednisolone in healthy volunteers: two phase 1, single-blind, randomised controlled trials. Lancet Rheumatol; 2: 31-41
3. van Laar JM, et al. (2021) AZD9567 versus prednisolone in patients with active rheumatoid arthritis: a phase 2a, randomised, double-blind, parallel-group efficacy and safety study. Ann Rhem Dis; 80 suppl 1: 283
