POS0089 AZD9567 VERSUS PREDNISOLONE IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS: A PHASE 2A, RANDOMISED, DOUBLE-BLIND, PARALLEL-GROUP EFFICACY AND SAFETY STUDY

Abstract

Background:Oral corticosteroids such as prednisolone are potent anti-inflammatory drugs but their use is limited by side effects caused by unwanted actions on the glucocorticoid receptor (GR), such as increased insulin resistance, and off-target actions on the mineralocorticoid receptor (MR) that disrupt electrolyte balance and increase water retention. AZD9567 is an oral, selective, non-steroidal glucocorticoid receptor modulator being developed to treat inflammatory diseases. Pre-clinical and phase 1 clinical data indicate that AZD9567 is the first GR modulator with an improved efficacy–dysglycaemic side effect profile versus prednisolone.Objectives:To compare the efficacy, safety and tolerability of AZD9567 with prednisolone in patients with active rheumatoid arthritis (RA), at doses with predicted equivalent anti-inflammatory activity.Methods:In this phase 2a, randomised, double-blind, parallel-group, multicentre study in RA patients with DAS28-CRP ≥ 3.2 despite stable treatment with conventional disease-modifying anti-rheumatic therapies (NCT03368235), patients were randomised 1:1 to AZD9567 40 mg or prednisolone 20 mg orally once daily for 14 days. The primary endpoint was change from baseline in DAS28-CRP at day 15. Secondary outcomes included components of DAS28-CRP, TJC68, SJC66, ACR response (ACR20, ACR50, ACR70) and safety outcomes, including serum electrolytes.Results:All 21 randomised patients (AZD9567, n = 11; prednisolone, n = 10) completed the study. There was a slight imbalance between the treatment groups at baseline, with higher age (mean ± SD: 64.5 ± 8.4 vs 55.5 ± 13.6 years), more women (8 vs 5) and greater disease severity (DAS28-CRP, mean ± SD: 5.26 ± 0.98 vs 4.90 ± 0.74) in the AZD9567 group versus the prednisolone group. There was no statistically significant or clinically meaningful (i.e. > 1.2) difference in change from baseline to day 15 in DAS28-CRP between AZD9567 and prednisolone, although this was numerically lower with AZD9567 (Table 1). Similar results were observed for TJC68, SJC66, CRP and GH (Table 1). The proportions of patients achieving ACR20, 50 and 70 response criteria were similar in both groups, albeit numerically lower with AZD9567. Similar numbers of patients in each group reported treatment-emergent adverse events (AZD9567, n = 10, prednisolone, n = 9); most were mild in severity. One serious adverse event, suicidal depression, was reported after completing AZD9567 treatment. Morning fasting serum sodium/potassium ratio at day 15 was not altered with AZD9567 but was increased from baseline with prednisolone (Figure 1).Conclusion:AZD9567 40 mg had a similar efficacy profile to prednisolone 20 mg in patients with active RA. Both drugs were well tolerated, with no new safety signals. Unlike prednisolone, AZD9567 had no effect on serum sodium/potassium ratio, suggesting selectivity of AZD9567 for the GR over the MR. These results support further trials of AZD9567 in patients with inflammatory disease.Table 1.Change from baseline to day 15 in clinical disease activity measures.AZD9567 (n = 11)Prednisolone (n = 10)Comparison(AZD9567 – prednisolone)LSM CFB (SE)95% CILSM CFB (SE)95% CILSMD (SE)95% CIp valueDAS28−CRP score−1.93 (0.35)−2.66, −1.21−2.40 (0.34)−3.11, −1.700.47 (0.46)−0.49, 1.430.315TJC28 score−6.12 (1.25)−8.76, −3.49−6.07 (1.21)−8.61, −3.52−0.05 (1.60)−3.43, 3.320.973SJC28 score−5.14 (0.65)−6.51, −3.76−5.40 (0.63)−6.73, −4.080.26 (0.84)−1.50, 2.030.757GH score−27.7 (7.3)−42.8, −12.5−37.4 (7.1)−52.3, −22.69.8 (9.7)−10.5, 30.10.325CRP, mg/L−10.8 (2.4)−15.9, −5.8−15.6 (2.5)−20.9, −10.34.8 (3.5)−2.5, 12.00.187TJC68 score−9.02 (2.46)−14.21, −3.82−7.90 (2.36)−12.88, −2.91−1.12 (3.12)−7.69, 5.460.724SJC66 score−6.24 (0.89)−8.13, −4.36−6.66 (0.86)−8.48, −4.850.42 (1.14)−1.98, 2.810.717CFB, change from baseline; CRP, C-reactive protein; DAS28, 28-joint disease activity score; GH, global health; LSM(D), least-squares mean (difference); SJC, swollen joint count; TJC, tender joint count.Acknowledgements:Medical writing support was provided by Richard Claes PhD of PharmaGenesis London, London, UK, funded by AstraZeneca, Gothenburg, Sweden in accordance with Good Publication Practice 3 (GPP3) guidelines (http://www.ismpp.org/gpp3).This study was funded by AstraZeneca. AZD9567 is an investigational medical product with no approved indication.Disclosure of Interests:Jacob M. van Laar Consultant of: Honoraria from - Abbvie, Arxx Tx, Galapagos, Gesyntha, Leadiant, Magenta, Roche, Sanofi Genzyme, Grant/research support from: AstraZeneca, Pfizer, Roche, Alejhandra Lei Shareholder of: AstraZeneca., Grant/research support from: Boehringer Ingelheim in 1998, Bristol-Myers Squibb in 1999, Employee of: AstraZeneca. Past employee of Almirall, Grünenthal, Boehringer Ingelheim, CESIF Pharma, Mary Safy-Khan Grant/research support from: Student grant from AstraZeneca 2015-2018., Joachim Almquist Shareholder of: AstraZeneca, Consultant of: AstraZeneca., Employee of: AstraZeneca., Carol Astbury Shareholder of: AstraZeneca., Employee of: AstraZeneca., Maria Belvisi Shareholder of: AstraZeneca., Grant/research support from: AstraZeneca and Chiesi, Employee of: AstraZeneca., Adam Platt Shareholder of: AstraZeneca., Employee of: AstraZeneca., Susanne Prothon Shareholder of: AstraZeneca., Employee of: AstaZeneca., Sara Samuelsson Shareholder of: AstraZeneca, Employee of: AstraZeneca, Petter Svanberg Employee of: AstraZeneca, Christina Keen Shareholder of: AstraZeneca., Employee of: AstraZeneca.