BACKGROUND: Persistent eosinophilic airway inflammation in asthma increases the 
risk of exacerbations. In a phase 2b dose-ranging study, we aimed to assess the 
efficacy and safety of benralizumab, an anti-interleukin 5 receptor α monoclonal 
antibody that depletes blood and airway eosinophils, in adults with uncontrolled 
eosinophilic asthma.
METHODS: We did a randomised, controlled, double-blind, dose-ranging phase 2b 
study. Eligible participants were adults aged 18-75 years with uncontrolled 
asthma using medium-dose or high-dose inhaled corticosteroids and longacting β 
agonists, with two to six exacerbations in the past year. Current or former 
smokers were excluded. We used the ELEN index (an algorithm to predict elevated 
sputum eosinophils) or baseline fraction of exhaled nitric oxide to stratify 
patients by eosinophilic status, and with an interactive web-voice response 
system randomly assigned eosinophilic individuals in a 1:1:1:1 ratio to receive 
placebo, 2 mg benralizumab, 20 mg benralizumab, or 100 mg benralizumab, and 
non-eosinophilic individuals in a 1:1 ratio to receive placebo or 100 mg 
benralizumab. Study drugs were given as two subcutaneous injections every 4 
weeks for the first three doses, then every 8 weeks, for 1 year. Patients, 
treating physicians, and study investigators were masked to treatment 
allocation. The primary endpoint was annual exacerbation rate in eosinophilic 
individuals after 1 year of follow-up. Analysis was by modified intention to 
treat. This study was designed with a two-sided α of 0·2 and powered at 78% for 
the primary outcome in the eosinophilic population. This study is registered 
with ClinicalTrials.gov, number NCT01238861.
FINDINGS: Between Jan 3, 2011, and March 6, 2012, we randomly assigned 324 
eosinophilic individuals to placebo (n=80) or benralizumab 2 mg dose (n=81), 20 
mg dose, (n=81), or 100 mg dose (n=82), and 285 non-eosinophilic individuals to 
100 mg benralizumab (n=142, 140 included in analysis) or placebo (n=143, 142 
included in analysis). In eosinophilic individuals, benralizumab reduced 
exacerbation rates compared with placebo in the 100 mg group (0·34 vs 0·57, 
reduction 41%, 80% CI 11 to 60, p=0·096) but not in the 2 mg group (0·65 vs 
0·57, difference -9%, 80% CI -59 to 26, p=0·781) or the 20 mg group (0·37 vs 
0·57, reduction 36%, 80% CI 3 to 58, p=0·173). In patients with a baseline blood 
eosinophil cutoff of at least 300 cells per μL, exacerbation rates in the 
benralizumab 20 mg group (n=70) and 100 mg group (n=97) were lower than in the 
placebo group (n=83; 0·30 vs 0·68, reduction 57%, 80% CI 33 to 72, p=0·015 for 
20 mg dose; 0·38 vs 0·68, difference 43%, 80% CI 18 to 60, p=0·049 for 100 mg 
dose). Our findings suggested that benralizumab 20 mg and 100 mg resided at the 
dose-response plateau. Treatment-emergent adverse events occurred in 277 (72%) 
of 385 participants receiving any benralizumab dose compared with 143 (65%) of 
221 receiving placebo. Nasopharyngitis (44 [11%] patients receiving benralizumab 
vs 13 [6%] patients receiving placebo) and injection site reactions (60 [16%] vs 
eight [4%]) occurred more frequently with benralizumab than with placebo.
INTERPRETATION: Benralizumab at 20 mg and 100 mg doses seemed to reduce asthma 
exacerbations in adults with uncontrolled eosinophilic asthma and baseline blood 
eosinophils of at least 300 cells per μL, possibly due to targeting of the 
interleukin 5 receptor rather than interleukin 5 ligand. Further investigation 
of benralizumab treatment in phase 3 studies is warranted.
FUNDING: MedImmune.