Treatment with Lebrikizumab Improves Lung Function in Adults with Asthma

Asthma in adults is often treated with inhaled glucocorticoids, yet the disease often remains uncontrolled, requiring more intensive therapy. One factor thought to contribute to many of the key features of asthma is interleukin-13, a pleiotropic cytokine of type 2 helper T cells (Th2). Inhaled glucocorticoids inhibit production of interleukin-13, but the agents also have other effects on the airways. Patients treated with both systemic and inhaled glucocorticoids may have elevated levels of interleukin-13 in the sputum, leading researchers to hypothesize that interleukin-13 can contribute to resistance to glucocorticoids. To determine whether anti–interleukin-13 therapy would benefit patients with asthma who had a pretreatment profile consistent with interleukin-13 activity, researchers recently conducted a randomized, double-blind, placebo-controlled study of lebrikizumab. Lebrikizumab is an IgG4 humanized monoclonal antibody that specifically binds to interleukin-13 and inhibits its function. They reported study results in the New England Journal of Medicine [2011;365(12):1088-1098]. The main outcome efficacy measure was the relative change in prebronchodilator forced expiratory volume in 1 second (FEV1) from baseline to week 12. Secondary outcomes included the rate of asthma exacerbations through 24 weeks. Patients were randomly assigned in a 1:1 ratio to receive lebrikizumab or placebo on the basis of a dynamic randomization scheme. Randomization was balanced through stratification according to the following hierarchy: Th2 status (high vs low), use or no use of long-acting beta-agonists, and study site. Subgroups were defined according to baseline Th2 status and serum periostin level. Inclusion criteria included physician-diagnosed asthma, at least a 12% decrease in FEV1 following inhalation of a short-acting bronchodilator, and prebronchodilator FEV1 between 40% and 80% (inclusive) of the predicted value at the time of randomization. Patients also had to have used inhaled glucocorticoids (≥200 and ≥1000 mcg of inhaled fluticasone propionate daily, administered via a dry-powder inhaler, or a nominal equivalent) for at least 6 months, and present with evidence of uncontrolled asthma on the day of randomization. The researchers defined uncontrolled asthma as a score on the symptom-only version of the Asthma Control Questionnaire (ACQ-5) of ≥1.5 on a scale of 0 to 6 (higher scores indicate poorer control). At week 12, in the lebrikizumab group the mean increase from baseline in prebronchodilator FEV1 was greater by 5.5 percentage points (95% confidence interval [CI], 0.8-10.2) than in the placebo group (9.8 vs 4.3; P=.02). There was a significant interaction between treatment and baseline periostin level (P=.03). In the high-periostin subgroup, the relative increase from baseline FEV1 was higher by 8.2 percentage points (95% CI, 1.0-15.4) among patients in the lebrikizumab group compared with those in the placebo group (14.0 vs 5.2; P=.03). In the low-periostin subgroup, among patients in the intervention group, the relative increase from baseline FEV1 was higher by 1.6 percentage points (95% CI, ¬4.5-7.7) than among patients in the placebo group (5.1 vs 3.5; P=.61). Relative changes in FEV1 were evident after 1 week of treatment and were sustained throughout the study. There were no significant effects on the ACQ-5 score or on the daily diary measures (asthma symptom score, change in use of rescue medication, or change in the frequency of nocturnal awakening) associated with treatment with lebrikizumab, nor were there any significant changes in the rates of protocol-defined exacerbations. Serious adverse events occurred in 4 patients in the lebrikizumab group: 2 had asthma exacerbations that required hospitalization, 1 had community-acquired pneumonia, and 1 had traumatic pneumothorax related to an automobile accident. In the placebo group, 6 patients had a serious adverse event. Overall, the frequency of adverse events in the 2 groups was similar. In summary, the researchers commented, “Lebrikizumab treatment was associated with improved lung function. Patients with high pretreatment levels of serum periostin had greater improvement in lung function with lebrikizumab than did patients with low periostin levels.”