Jim Kling

May 28, 2014

SAN DIEGO — Benralizumab reduces exacerbations and improves lung function in asthma patients with elevated eosinophil counts, according to a phase 2 trial.

Some patients with severe asthma fail to achieve adequate control, even with high-dose inhaled steroids and long-acting bronchodilators. Such patients are more likely to be hospitalized and to visit the emergency department.

"Drugs like benralizumab could help us manage these patients," said Mario Castro, MD, professor of medicine and pediatrics at Washington University in St. Louis, Missouri.

Benralizumab is an anti-interleukin (IL)-5 receptor-alpha monoclonal antibody that depletes blood and airway eosinophils. These cells play an important role in asthma pathogenesis.

Dr. Castro presented the study results here at the American Thoracic Society 2014 International Conference.

The 52-week, multicenter, double-blind, phase 2 study evaluated 606 subjects who had experienced at least 2 exacerbations of their asthma in the previous year. Mean age of the cohort was 48 years, and 69% of the cohort was female.

All subjects were taking inhaled corticosteroid or long-acting beta-agonist therapy at medium (60%) or high (40%) doses, and 5% of the cohort was using chronic oral corticosteroids.

Mean score on the 7-point Asthma Control Questionnaire, version 6, was 2.58. Predicted forced expiratory volume in 1 second (FEV₁) was 66.5%.

The subjects were categorized by eosinophil status (determined with a blood-count algorithm or the fraction of exhaled nitric oxide above 50 ppb) and baseline inhaled corticosteroid dose (medium or high).

Subjects who were eosinophil-positive were randomized to receive benralizumab 2, 20, or 100 mg or placebo. Those who were eosinophil-negative were randomized to receive benralizumab 100 mg or placebo. Injections were given at 1, 4, 8, 16, 24, 32, and 40 weeks.

The primary end point was exacerbation rate at week 52, but only for eosinophil-positive subjects. One of the secondary end points was FEV₁.

The study was 80% powered to detect a 40% reduction in exacerbations (2-sided alpha = .20). After an interim analysis, the critical alpha for final analysis was adjusted to 0.169.

In the eosinophil-positive group, the improvement in the exacerbation rate was significantly greater in the benralizumab 100 mg group than in the placebo group (rate ratio, 0.59; 80% confidence interval [CI], 0.40 - 0.89; P = .096).

There was no difference in the exacerbation rate between lower doses of benralizumab and placebo, or among eosinophil-negative subjects (rate ratio, 0.78; 80% CI, 0.58 - 1.05; P = .284).

The improvement in FEV₁ was better in the 20 mg group than in the placebo group (P =.069), and was better in the 100 mg group (P = .063).

Improvements in exacerbation rate and FEV₁ were better in subjects with higher eosinophil counts at baseline.

Overall, there were more adverse events in the benralizumab groups than in the placebo group (71.9% vs 64.7%). Specifically, with benralizumab, there was more nasopharyngitis (11.4% vs 5.9%), headache (9.4% vs 7.2%), upper respiratory tract infection (7.5% vs 5.9%), and pharyngitis (6.2% vs 3.6%); however, there was less bronchitis (7.0% vs 7.2%) and influenza (5.7% vs 6.3%).

This study revealed some positive effects of the drug on lung function in eosinophil-negative subjects, which the researchers included because IL-5 is known to have effects other than just eosinophil depletion.

"What we are driving toward in these patients [with severe asthma] is to identify a subset of patients and use targeted therapy," said Dr. Castro.

The results were surprising to Peter Sterk, MD, PhD, professor of medicine at the University of Amsterdam, who attended the session.

"Surprisingly, the anti-IL-5 strategy is doing well. I would have never thought that a single cell [eosinophils] would determine disease outcome," he told Medscape Medical News.

The effect in eosinophil-negative subjects indicates that something else is going on. "I almost suspect that anti-IL-5 is doing more than just wiping out eosinophils, although biologically there's no good reason to say that," he said.

No matter what the mechanism is behind the drug, its effectiveness is encouraging. "We haven't had good news in moderate to severe asthma for a couple of decades, but this is," said Dr. Sterk. The IL-4 blocker dupilumab also looks promising, he added (N Engl J Med. 2013;368:2455-2466).

The study was funded by MedImmune. Dr. Castro and Dr. Sterk have disclosed no relevant financial relationships.

American Thoracic Society (ATS) 2014 International Conference: Abstract A3699. Presented May 20, 2014.

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