Asthma exacerbation profile of benralizumab for severe eosinophilic asthma (the BenRex study): a multicentre, prospective cohort study

Benralizumab, an interleukin-5 receptor α antagonist, depletes blood eosinophils, reducing exacerbations of severe asthma by approximately 50% versus placebo. In this study, we aimed to characterise mechanisms underlying exacerbations occurring on benralizumab. BenRex, a multicentre, prospective cohort study, recruited participants meeting national licensing criteria for benralizumab for asthma. The study was conducted in 15 UK severe asthma centres. After collecting baseline data, open-label benralizumab was administered for 12-18 months. At exacerbation, participants attended for medical review before initiating treatment, fractional exhaled nitric oxide (FeNO), spirometry, asthma control questionnaire, and blood and sputum sampling. Between Sept 30, 2019, and April 23, 2024, 121 exacerbation events were assessed in 156 individuals. 90 participants (58%) were female and 66 (42%) were male; 147 (94%) of participants identified as White. Median blood eosinophil counts at exacerbation were 0 (IQR 0-0) cells per μL. Airway neutrophilia was present in 55% of exacerbations where sputum was available (27/49). Median C-reactive protein (CRP) increased from 3·00 mg/L (1·00-6·00) at baseline to 9·00 mg/L (3·00-17·00) at exacerbation (p=0·0067). Clinically relevant viral pathogens were seen in eight (20·5%) of 39 sputum samples; although viruses were detected in 22 (56·4%) of 39 samples. Influenza A, metapneumovirus, and rhinovirus were the most common viral pathogens (each found in 2 [5·1%] of 39 samples). New acquisition of Moraxella catarrhalis (3 [13·6%] of 22), Haemophilus influenzae (4 [18·2%] of 22), and Streptococcus pneumoniae (2 [9·1%] of 22) occurred. DNA-neutrophil elastase complexes (p=0·0080) and azurocidin-1 (p=0·012) concentrations rose from baseline to exacerbation. FeNO was ≥50 parts per billion in 56 (50·5%) of 111 assessed exacerbations and was associated with reduced odds of bacterial detection. FeNO did not correlate with CRP or sputum neutrophils. Our findings suggested that eosinophilic inflammation is not involved in exacerbations when a patient is being treated with benralizumab. Airway neutrophilia, viral pathogens, and alteration of the sputum microbiome point to infection as the most prominent causes of exacerbations. This observation should improve precision management of asthma exacerbations occurring despite treatment with benralizumab. AstraZeneca.