• Mary N Brown, Rainard Fuhr, Jutta Beier, Hong-Lin Su, Yingxue Chen, Henrik Forsman, Hamrén Ulrika Wählby UW Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca, SE-43183, Gothenburg, Mölndal, Sweden., Helen Jackson, and Ajay Aggarwal.
• Respiratory, Inflammation and Autoimmunity Translational Medicine Unit, Early Clinical Development, IMED Biotech Unit, AstraZeneca, 35 Gatehouse Drive, Waltham, MA, 02451, USA. mary.brown@astrazeneca.com.
• Resp Res. 2019 Feb 18; 20 (1): 37.

BackgroundInhaled corticosteroids reduce inflammation in asthma but chronic use may cause adverse effects. AZD7594, an inhaled non-steroidal selective glucocorticoid receptor modulator, has the potential of an improved risk-benefit profile. We investigated the safety and efficacy of AZD7594 in asthma.MethodsThis phase 2a multi-center, randomized, double-blind, placebo-controlled crossover study enrolled adults with asthma aged 18 to 75 years. Patients were treated with budesonide 200 μg twice daily for 2-3 3 weeks (run in part one). If controlled, as demonstrated by an asthma control questionnaire-5 score of < 1.5, patients entered a three-week run-in (part two) where they received a short acting bronchodilator alone. Thereafter, patients with a fractional exhaled nitric oxide (FENO) ≥25 ppb and pre-dose FEV1 40 to 90% predicted were randomized to one of nine treatment sequences. Each patient received placebo and two of three dose levels of AZD7594 (58, 250, 800 μg) once daily via inhalation, in 14-day treatment periods, separated by three-week washout periods. The primary endpoint was the change from baseline in morning trough FEV1 versus placebo on day 15. Secondary endpoints included measures of airway inflammation and asthma control.ResultsFifty-four patients were randomized and received at least 1 dose of treatment, 48 patients completed the study. Overall 52 patients received placebo, 34 received AZD7594 58 μg, 34 received AZD7594 250 μg, and 34 received AZD7594 800 μg. AZD7594 800 μg demonstrated a significant improvement in Day 15 morning trough FEV1versus placebo (LS means difference 0.148 L 95% CI 0.035-0.261, p = 0.011), with a dose-dependent response seen in the 250 μg (0.076 L -0·036-0·188, p = 0.183) and 58 μg (0·027 L -0·086-0·140, p = 0.683). All secondary endpoints showed statistically significant improvement at the 800 μg dose. All doses demonstrated a significant reduction in FENO at day 15 p < 0.01. No statistically significant difference in plasma cortisol level was observed between AZD7594 and placebo at any dose. AZD7594 was considered safe and well tolerated.ConclusionsTwo-week treatment with AZD7594 demonstrated a favorable risk-benefit profile in patients with mild to moderate asthma. Further clinical studies are needed to fully characterize AZD7594.Trial RegistrationClinicalTrials.gov number NCT02479412 .

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