Lebrikizumab in the personalized management of asthma

Abstract

There is a need for improved therapies for severe asthma. Lebrikizumab, a humanized monoclonal antibody that binds to interleukin (IL)-13, is under development for the treatment of poorly controlled asthma. This article reviews the potential role of IL-13 in the pathogenesis of asthma, the efficacy and safety of lebrikizumab in humans, and progress in patient selection for lebrikizumab therapy. IL-13 is a T-helper (Th2) cell-derived cytokine implicated in inflammatory responses in asthma, including serum immunoglobulin-E synthesis, mucus hypersecretion, and subepithelial fibrosis. Blocking the pro-inflammatory effects of IL-13 with lebrikizumab has the potential to improve asthma control. Published data on the efficacy and safety of lebrikizumab in the treatment of asthma are relatively limited. The late asthmatic response after inhaled allergen challenge is reduced by almost 50%, following treatment with lebrikizumab. In a Phase II study performed in 219 adults with poorly controlled asthma despite inhaled corticosteroids (MILLY trial), lebrikizumab produced an improvement in prebronchodilator forced expiratory volume in 1 second of 5.5% compared with placebo at 12 weeks, but had no effects on other efficacy end points. Adverse effects were similar to placebo, except that musculoskeletal side effects occurred slightly more often with lebrikizumab. Stratifying patients into a high Th2 phenotype using serum periostin, which is upregulated in lung epithelial cells by IL-13, may identify individuals responsive to blockade of IL-13. In the MILLY trial, lebrikizumab treatment was associated with greater improvement in lung function in patients with elevated serum periostin levels compared with those with low periostin levels. Two large Phase III randomized controlled trials in patients with uncontrolled asthma are underway to establish the safety and efficacy of lebrikizumab when administered over a 52-week period. These studies will also help to determine whether identifying patients with a Th2 high inflammatory phenotype using serum periostin allows a personalized approach to the treatment of asthma.

Keywords: asthma; exhaled nitric oxide; interleukin-13; lebrikizumab; periostin; phenotypes.

Figure 1

T helper-2 (Th-2) cells in asthma pathogenesis. Inhaled allergens are thought to be processed by two mechanisms in asthmatic airways. Notes: Allergens either: (1) activate mast cells through cross-linking with IgE on their cell surfaces through the high-affinity type 1 IgE receptor (FcɛR1) to release mediators that induce bronchoconstriction, such as histamine, cysteinyl leukotrienes, and prostaglandin D₂ (PGD₂) or (2) are processed by dendritic cells, which are induced to secrete the CC chemokine ligand (CCL) 17 and CCL22 by thymic stromal lymphopoietin (TSLP). Dendritic cells then attract and activate Th2 cells by the binding of CCL17 and CCL22 with CC chemokine receptor 4 (CCR4) on the Th2 cell surface. IL-33 is produced by airway epithelial cells and activates dendritic cells and Th2 by inducing the release of tumor necrosis factor-alpha from mast cells. Th2 secretes cytokines, including IL-4 and IL-13, which switch B cells to produce IgE, IL-5, which promotes the development and survival of eosinophils, and IL-9, which activates mast cells. Once IL-13 is produced, it can increase the survival and migration of eosinophils, and it promotes activation of macrophages to create an M2, or an allergic cell phenotype. Airway epithelial cells are stimulated, and through mediators such as periostin and transforming growth factor β1 (TGF-β1), they can increase airway inflammation and lead to the increased permeability of airway epithelial cells and mucous hypersecretion. IL-13 also has direct effects on airway smooth muscle, leading to increased contraction to agonists such as acetylcholine and decreased relaxation with beta-agonists. Adapted by permission from Macmillan Publishers Ltd: Nature Medicine, Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med. 2012;18(5):716–725, copyright 2012. Abbreviations: APC, antigen-presenting cells; IgE, immunoglobulin E; IL-, interleukin; iNOS, inducible nitric oxide synthase.

Figure 2

Effect of lebrikizumab treatment on the change in FEV₁ values in adults with asthma. For all patients at week 12 (A), the increase from baseline in mean (±SE) FEV₁ was higher in the lebrikizumab group (9.8% ± 1.9%) than in the placebo group (4.3% ± 1.5%) (P = 0.02). In the subgroup of patients with high serum periostin levels at week 12 (B), the increase from baseline in mean (±SE) FEV₁ was higher in the lebrikizumab group (14.0% ± 3.1%) than in the placebo group (5.8% ± 2.1%) (P = 0.03). In the subgroup of patients with low serum periostin levels at week 12 (C), the increase from baseline in mean (±SE) FEV₁ was similar in the lebrikizumab group (5.1% ± 2.4%) to the placebo group (3.5% ± 2.1%); (P = 0.61). From The New England Journal of Medicine, Corren J, Lemanske RF, Hanania NA, et al, Lebrikizumab treatment in adults with asthma. 12, 1088–1098. Copyright © 2011 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. Abbreviation: FEV₁, forced expiratory volume in 1 second.