Asthma is a heterogeneous disease with notable variation in its clinical course and response to treatment.1, 2, 3 Despite management with standard-of-care therapies,4 a proportion of patients remain uncontrolled and at risk of life-threatening exacerbations and disease worsening.5, 6 Advances in understanding of the heterogeneity of asthma have helped identify patients who will benefit from a personalised management approach.7, 8
Interleukin-13 is a pleiotropic effector cytokine central to type 2 inflammation in severe asthma. It contributes to many of the characteristic features of asthma, including mucus production, eosinophilic airway inflammation, IgE synthesis, bronchial fibrosis, and airway hyper-responsiveness.9, 10, 11, 12 Interleukin-13 is, therefore, recognised as a potential therapeutic target in patients with uncontrolled asthma and higher concentrations of type 2 biomarkers.13, 14
Type 2 biomarkers that can be measured in the circulation include blood eosinophils and serum periostin. Blood eosinophil counts tend to be higher in a proportion of patients with asthma (although the size of the population with high eosinophil counts depends on the cutoff used to define those counts),15, 16 and have been used to identify patients suitable for treatment with recently approved biological asthma therapies targeting interleukin-5.17, 18 Interleukin-5 plays a crucial role in maturation of eosinophils in the bone marrow, whereas both interleukin-5 and interleukin-13 have been reported to be implicated in promoting eosinophil survival, activation, and recruitment,19, 20, 21, 22 and therefore blood eosinophils might also be predictive for benefit from anti-interleukin-13 treatment. Periostin is an interleukin-13-induced matricellular protein basally secreted from the bronchial epithelial cells and can be detected in serum. Some patients with asthma have higher concentrations of serum periostin23, 24, 25 and it has been shown that these patients benefit most from anti-interleukin-13 treatment in previous studies with lebrikizumab.13, 14
Research in context
Evidence before this study
Interleukin-13 is thought to play an important role in the effector phase of the inflammatory response and induces the main manifestations of allergic disease including airway hyper-responsiveness, mucus production, airway smooth muscle alterations, and subepithelial fibrosis. In completed phase 2 trials with lebrikizumab, an anti-interleukin-13 antibody in patients with uncontrolled asthma, it reduced the rate of asthma exacerbations and improved lung function (FEV1) to a greater extent in patients with biomarker evidence of type 2 asthma (eg, higher concentrations of periostin). Additionally, results of phase 2 clinical trials with another anti-interleukin-13 monoclonal antibody, tralokinumab, and the anti-interleukin-4Rα monoclonal antibody, dupilumab (which inhibits both interleukin-4 and interleukin-13 signalling), have also been reported. Phase 2a and phase 2b trials of tralokinumab have shown improvement in FEV1 but no significant effect on exacerbations in patients with severe uncontrolled asthma. A phase 2b trial of dupilumab demonstrated a reduction in severe exacerbations and improved lung function in patients with uncontrolled persistent asthma. Other molecules targeting interleukin-13 in asthma have not advanced beyond early-stage trials. The trials described here are the first reported phase 3 trials of a therapy targeting interleukin-13 in patients with uncontrolled asthma.
Added value of this study
Here we report findings from replicate phase 3 randomised controlled trials designed to further assess the efficacy and safety of lebrikizumab in patients with uncontrolled asthma despite treatment with standard-of-care medications. The studies failed to provide consistently significant results for the primary endpoint or a clear dose response. The overall efficacy of lebrikizumab in these trials did not meet the clinically meaningful exacerbation rate reduction or FEV1 improvement expected from phase 2 results in this patient population. Furthermore, the biomarker strategy, which focused on patients who were in the high groups for either eosinophils or periostin, did not consistently identify those who achieved benefit from lebrikizumab treatment.
Implications of all the available evidence
These studies suggest that blocking interleukin-13 in this patient population using lebrikizumab might not be sufficient to provide clinically meaningful improvements in asthma endpoints.
Lebrikizumab is a humanised monoclonal antibody that binds to soluble interleukin-13 with high affinity and blocks signalling through the active interleukin-4 receptor (R)α/interleukin-13Rα1 heterodimer.13, 26, 27 Results from phase 2 studies suggest that in patients with uncontrolled asthma, lebrikizumab can reduce the rate of exacerbations14 and improve lung function to a greater extent in patients with higher concentrations of periostin.13, 14 Here we report findings from replicate phase 3 randomised controlled trials designed to further assess the efficacy and safety of lebrikizumab in patients with uncontrolled asthma despite treatment with standard-of-care medications, and also to assess serum periostin concentration and blood eosinophil count as biomarkers for identifying patients who are most likely to benefit from lebrikizumab treatment.