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Aims: This 3‐part, randomised, phase 1 first‐in‐human study (NCT03436316) investigated the safety, tolerability and pharmacokinetics (PK) of AZD8154, a dual phosphoinositide 3‐kinase (PI3K) γδ inhibitor developed as a novel inhaled anti‐inflammatory treatment for respiratory disease. Methods: Healthy men, and women of nonchildbearing potential, were enrolled to receive single and multiple ascending inhaled doses of AZD8154 in parts 1 and 3 of the study, respectively, while part 2 characterised the systemic PK after a single intravenous (IV) dose. In part 1, participants received 0.1–7.7 mg AZD8154 in 6 cohorts. In part 2, participants were given 0.15 mg AZD8154 as an IV infusion. In part 3, AZD8154 was given in 3 cohorts of 0.6, 1.8 and 3.1 mg, with a single dose on Day 1 followed by repeated once‐daily doses on Days 4–12. Results: In total, 78 volunteers were randomised. All single inhaled, single IV and multiple inhaled doses were shown to be well tolerated without any safety concerns. A population PK model, using nonlinear mixed‐effect modelling, was developed to describe the PK of AZD8154. The terminal mean half‐life of AZD8154 was 18.0–32.0 hours. The geometric mean of the absolute pulmonary bioavailability of AZD8154 via the inhaled route was 94.1%. Conclusion: AZD8154 demonstrated an acceptable safety profile, with no reports of serious adverse events and no clinically significant drug‐associated safety concerns reported in healthy volunteers. AZD8154 demonstrated prolonged lung retention and a half‐life supporting once‐daily dosing. [ABSTRACT FROM AUTHOR]

BACKGROUND Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by eosinophilic inflammation. Benralizumab, a monoclonal antibody against the interleukin-5α receptor expressed on eosinophils, may be an option for treating EGPA. METHODS We conducted a multicenter, double-blind, phase 3, randomized, active-controlled noninferiority trial to evaluate the efficacy and safety of benralizumab as compared with mepolizumab. Adults with relapsing or refractory EGPA who were receiving standard care were randomly assigned in a 1:1 ratio to receive benralizumab (30 mg) or mepolizumab (300 mg) subcutaneously every 4 weeks for 52 weeks. The primary end point was remission at weeks 36 and 48 (prespecifled noninferiority margin, -25 percentage points). Secondary end points included the accrued duration of remission, time to first relapse, oral glucocorticoid use, eosinophil count, and safety. RESULTS A total of 140 patients underwent randomization (70 assigned to each group). The adjusted percentage of patients with remission at weeks 36 and 48 was 59% in the benralizumab group and 56% in the mepolizumab group (difference, 3 percentage points; 95% confidence interval [CI], -13 to 18; P=0.73 for superiority), showing noninferiority but not superiority of benralizumab to mepolizumab. The accrued duration of remission and the time to first relapse were similar in the two groups. Complete withdrawal of oral glucocorticoids during weeks 48 through 52 was achieved in 41% of the patients who received benralizumab and 26% of those who received mepolizumab. The mean (±SD) blood eosinophil count at baseline was 306.0±225.0 per microliter in the benralizumab group and 384.9±563.6 per micro-liter in the mepolizumab group, decreasing to 32.4±40.8 and 71.8±54.4 per micro-liter, respectively, at week 52. Adverse events were reported in 90% of the patients in the benralizumab group and 96% of those in the mepolizumab group; serious adverse events were reported in 6% and 13%, respectively. CONCLUSIONS Benralizumab was noninferior to mepolizumab for the induction of remission in patients with relapsing or refractory EGPA. (Funded by AstraZeneca; MANDARA ClinicalTrials.gov number, NCT04157348.) [ABSTRACT FROM AUTHOR]

Background: Navafenterol (AZD8871) belongs to a new class of bronchodilator, the single-molecule muscarinic antagonist and β-agonist, developed for the treatment of COPD. This study aimed to evaluate the efficacy, pharmacokinetics and safety of navafenterol versus placebo and an active comparator treatment for moderate-to-severe COPD., Methods: This phase 2a, randomised, multicentre (Germany and UK), double-blind, double-dummy, three-way complete crossover study (ClinicalTrials.gov identifier: NCT03645434) compared 2 weeks' treatment of once-daily navafenterol 600 µg via inhalation with placebo and a fixed-dose combination bronchodilator (umeclidinium/vilanterol (UMEC/VI); 62.5 µg/25 µg) in participants with moderate-to-severe COPD. The primary outcome was change from baseline in trough forced expiratory volume in 1 s (FEV 1 ) on day 15. Secondary end-points included change from baseline in peak FEV 1 ; change from baseline in Breathlessness, Cough and Sputum Scale (BCSS); change from baseline in COPD Assessment Tool (CAT); adverse events; and pharmacokinetics., Results: 73 participants were randomised. After 14 days, trough FEV 1 was significantly improved with navafenterol compared with placebo (least-squares (LS) mean difference 0.202 L; p<0.0001). There was no significant difference in FEV 1 between navafenterol and UMEC/VI (LS mean difference -0.046 L; p=0.075). COPD symptoms (CAT and BCSS) showed significantly greater improvements with both active treatments versus placebo (all p<0.005). Novel objective monitoring (VitaloJAK) showed that cough was reduced with both active treatments compared with placebo. Safety profiles were similar across the treatment groups and no serious adverse events were reported in the navafenterol treatment period., Conclusion: Once-daily navafenterol was well tolerated, improved lung function and reduced COPD-related symptoms, similar to an established once-daily fixed-dose combination bronchodilator., Competing Interests: Conflict of interest: D. Singh has received grants and personal fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, Epiendo, GlaxoSmithKline, Glenmark, Gossamerbio, Kinaset, Menarini, Mundipharma, Novartis, Pfizer, Pulmatrix, Sanofi, Teva, Theravance and Verona, and personal fees from Cipla, Genentech and Peptinnovate. J. Beier has received consultation fees from AstraZeneca, Berlin Chemie/Menarini, Chiesi and Pohl-Boskamp, and participated in scientific advisory boards that were funded by AstraZeneca and Chiesi. C. Astbury, M.G. Belvisi, C.A. Da Silva, A. Jauhiainen, E. Jimenez, A. Lei, S. Necander, U. Wählby Hamrén, W. Xin and I. Psallidas are employees of AstraZeneca and may hold stock or stock options. The VitaloJAK algorithm has been licensed by Manchester University Foundation Trust (MFT) and the University of Manchester to Vitalograph Ltd and Vitalograph Ireland (Ltd); MFT receives royalties which may be shared with the clinical division in which J.A. Smith works, and J.A. Smith has received personal fees from AstraZeneca., (Copyright ©The authors 2022.)