AZD9567 versus prednisolone in patients with active rheumatoid arthritis: A phase IIa, randomized, double-blind, efficacy, and safety study

Abstract

Oral corticosteroid use is limited by side effects, some caused by off-target actions on the mineralocorticoid receptor that disrupt electrolyte balance. AZD9567 is a selective, nonsteroidal glucocorticoid receptor modulator. The efficacy, safety, and tolerability of AZD9567 and prednisolone were assessed in a phase IIa study. Anti-inflammatory mechanism of action was also evaluated in vitro in monocytes from healthy donors. In this randomized, double-blind, parallel-group, multicenter study, patients with active rheumatoid arthritis were randomized 1:1 to AZD9567 40 mg or prednisolone 20 mg once daily orally for 14 days. The primary end point was change from baseline in DAS28-CRP at day 15. Secondary end points included components of DAS28-CRP, American College of Rheumatology (ACR) response criteria (ACR20, ACR50, and ACR70), and safety end points, including serum electrolytes. Overall, 21 patients were randomized to AZD9567 (n = 11) or prednisolone (n = 10), and all completed the study. As anticipated, AZD9567 had a similar efficacy profile to prednisolone, with no clinically meaningful (i.e., >1.0) difference in change from baseline to day 15 in DAS28-CRP between AZD9567 and prednisolone (least-squares mean difference: 0.47, 95% confidence interval: -0.49 to 1.43). Similar results were observed for the secondary efficacy end points. In vitro transcriptomic analysis showed that anti-inflammatory responses were similar for AZD9567, prednisolone, and dexamethasone. Unlike prednisolone, AZD9567 had no effect on the serum sodium:potassium ratio. The safety profile was not different from that of prednisolone. Larger studies of longer duration are required to determine whether AZD9567 40 mg may in the future be an alternative to prednisolone in patients with inflammatory disease.

FIGURE 1

DAS28‐CRP and components. Change from baseline in: (a) DAS28‐CRP (primary endpoint); (b) absolute DAS28‐CRP; and individual components of DAS28‐CRP: (c) TJC28; (d) SJC28; (e) global health; and (f) CRP. Data are LS means with 95% CIs. Comparisons are LS mean differences for AZD9567 − prednisolone, with 95% CIs. Supporting data are shown in Table S4. CI, confidence interval; CRP, C‐reactive protein; DAS28‐CRP, disease activity score in 28 joints with C‐reactive protein; LS, least‐squares; SJC28, 28 swollen joint count; TJC28, 28 tender joint count.

FIGURE 2

Morning serum sodium and potassium levels. Change from baseline in: (a) sodium:potassium ratio; (b) serum sodium; and (c) serum potassium. Data are least‐squares means with 95% confidence intervals.

FIGURE 3

Overall AZD9567 treatment effects on gene transcription in primary monocytes stimulated with tumor necrosis factor α at 4 h (preclinical study). (a) Venn diagrams of protein‐coding genes induced or repressed by AZD9567, prednisolone, and dexamethasone at their highest concentrations (949, 3162, and 316 nM, respectively; false discovery rate < 0.05); (b) predicted upstream regulator analysis and pathway analyses of differentially expressed genes. A full list of protein‐coding genes induced or repressed by AZD9567, prednisolone, and dexamethasone at their highest concentrations is included in Table S6. Color by z‐score: blue for predicted inhibition (negative z‐score) and orange for predicted activation (positive z‐score).

FIGURE 4

Log₂ fold‐change of AZD9567 or prednisolone versus dexamethasone for differentially expressed genes common to prednisolone and dexamethasone (preclinical study). AZD9567 (blue) or prednisolone (red) effects compared with dexamethasone (highest concentration, respectively) for all differentially expressed genes (false discovery rate < 0.05) common to prednisolone and dexamethasone treatments in primary human monocytes stimulated with TNFα, at 4 h. DMSO, dimethyl sulfoxide; TNFα, tumor necrosis factor α.