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Background: AZD9567 is a novel oral selective glucocorticoid receptor modulator (SGRM) developed to have an improved safety profile versus prednisolone while maintaining efficacy. Objectives: To show clinical evidence of safety differentiation for AZD9567 compared to prednisolone with respect to glucose homeostasis and to investigate the underlying effects on the glucose metabolism in human cell systems in vitro. Methods: In a dose escalation study (NCT02760316), healthy volunteers were randomized to a 5-day once-daily treatment with AZD9567 (20, 40, 80, 125 mg) or prednisolone (5, 20, 40 mg). We monitored the anti-inflammatory effect by TNFα release from ex vivo LPS stimulated whole blood and modelled the relationship with pharmacokinetics (PKPD). Plasma glucose was measured (AUC0–4h) during an oral glucose tolerance test (OGTT) before and after four days of treatment. We also studied the effects of AZD9567 and prednisolone on mRNA expression of key gluconeogenesis enzymes (tyrosine aminotransferease (TAT), phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase)) in primary human hepatocytes as well as on insulin secretion in human islets microtissues. Results: The inhibition of TNFα release increased with the plasma concentrations of AZD9567. PKPD modeling of TNFα inhibition data showed that 40 mg AZD9567 results in an anti-inflammatory activity similar to that predicted for 20 mg prednisolone. A significantly smaller increase of the glucose AUC was observed following treatment with 20 to 125 mg AZD9567 compared to 20 mg prednisolone (p We found significant induction of TAT, PEPCK, and G6Pase mRNA in hepatocytes after prednisolone treatment. In contrast, AZD9567 did not change the expression of these enzymes and inhibited the effect of prednisolone when co-administered. Furthermore, AZD9567 showed less suppression of insulin secretion in human islets microtissues compared to prednisolone at concentrations with comparable inhibition of TNFα release, resulting in a 12-fold better therapeutic ratio. Conclusions: In healthy individuals, AZD9567 showed significantly reduced effect on glucose homeostasis versus prednisolone at doses with similar anti-inflammatory activity. Thus, AZD9567 shows potential as an anti-inflammatory treatment with an improved metabolic safety profile compared to prednisolone. Disclosure of Interest: T. Hegelund Myrback Employee of: AstraZeneca, S. Prothon Employee of: AstraZeneca, M. Dearman Employee of: AstraZeneca, G. Edenro Employee of: AstraZeneca (former emplyee), J. Leander Employee of: AstraZeneca, M. Hashemi Employee of: AstraZeneca, G. de Miquel Employee of: AstraZeneca (former emplyee), R. Fuhr Employee of: Parexel International GmbH, T. Kornicke Employee of: Parexel International GmbH, Z. Tahib Employee of: AstraZeneca, E.-M. Andersson Employee of: AstraZeneca, P. Svanberg Employee of: AstraZeneca, K. Edman Employee of: AstraZeneca, R. Hendrickx Employee of: AstraZeneca, C. Keen Employee of: AstraZeneca, M. Kraan Employee of: AstraZeneca (former emplyee), K. Johansson Employee of: AstraZeneca (former emplyee), U. Eriksson Employee of: AstraZeneca, B. Carlsson Employee of: AstraZeneca, O. Vaarala Employee of: AstraZeneca

Background: Glucocorticoids (GC) are highly effective in the treatment of inflammatory diseases but chronic treatment is limited by severe adverse effects including hyperglycemia and bone re-modelling. AZD9567 is a novel, orally delivered, non-steroidal Selective Glucocorticoid Receptor Modulator (SGRM) with the potential to demonstrate an improved therapeutic ratio (TR) compared to steroidal GC such as prednisolone. Objectives: To investigate the effects of AZD9567 and prednisolone on biomarkers of inflammation, glucose metabolism and bone re-modelling in pre-clinical models. To confirm the inhibition of inflammatory biomarker production and to evaluate safety and pharmacokinetics (PK) of AZD9567 in a first clinical study. Methods: The effects on biomarkers of gluconeogenesis (tyrosine aminotransferase, TAT mRNA), bone re-modelling (osteoprotegerin, OPG mRNA) and anti-inflammatory activity (TNFα) were evaluated in vitro using human hepatocytes, an osteoblast cell line and whole blood, respectively. In vivo, effects on plasma insulin and osteocalcin levels were compared with inhibition of whole blood TNFα release in rats. Efficacy was evaluated in an adjuvant-induced rat arthritis model. In a human single ascending dose study the effect of AZD9567 on TNFα inhibition was investigated, together with assessment of safety profile and PK. Results: Potent in vitro anti-inflammatory activity (IC50,u6.2 nM, 7-fold more potent than prednisolone) was observed, whilst no effect on TAT mRNA expression in human hepatocytes was detected for AZD9567 (prednisolone EC5092 nM). This resulted in a substantially better TR compared to prednisolone. Furthermore, AZD9567 showed a 7-fold superior TR compared to prednisolone based on OPG mRNA expression in human osteoblasts. An improved profile for AZD9567 was also demonstrated in vivo in the rat (TR of 7.5 for osteocalcin and 3.6 for insulin). Efficacy was demonstrated in the rat arthritis model where an inhibition of joint inflammation was observed (ED500.1 mg/kg). In human, AZD9567 was safe and well tolerated after single doses (2–155 mg). The PK properties showed a fast absorption with a median tmax of 0.50 to 1.25 hour and a dose-dependent increase in exposure, with a mean terminal half-life of 3.9 to 6.4 hours, suitable for a once daily dosing regimen. TNFa release was inhibited in a concentration-dependent manner (IC50,u5.2 nM), consistent with pre-clinical findings. Conclusions: In pre-clinical models, AZD9567 demonstrated anti-inflammatory activity with a reduced effect on gluconeogenesis and biomarkers of bone re-modelling compared to prednisolone. Single oral dosing of AZD9567 was well tolerated and showed good PK properties in healthy subjects. These results support that AZD9567 has the potential to improve the treatment of several inflammatory diseases with a better TR compared to prednisolone. AZD9567 is currently in clinical evaluation in rheumatoid arthritis. Disclosure of Interest: R. Hendrickx Employee of: AstraZeneca, T. Hegelund-Myrback Employee of: AstraZeneca, M. Dearman Employee of: AstraZeneca, S. Prothon Employee of: AstraZeneca, G. Edenro Employee of: AstraZeneca (former employee), J. Leander Employee of: AstraZeneca, R. Fuhr Employee of: Parexel International GmbH, T. Kornicke Employee of: Parexel International GmbH, P. Svanberg Employee of: AstraZeneca, A. Berggren Employee of: AstraZeneca, T. Drmota Employee of: AstraZeneca (former employee), C. Keen Employee of: AstraZeneca, U. Eriksson Employee of: AstraZeneca