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Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): replicate, phase 3, randomised, double-blind, placebo-controlled trials

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Summary

Background

In phase 2 trials, lebrikizumab, an anti-interleukin-13 monoclonal antibody, reduced exacerbation rates and improved FEV1 in patients with uncontrolled asthma, particularly in those with high concentrations of type 2 biomarkers (eg, periostin or blood eosinophils). We undertook replicate phase 3 studies to assess the efficacy and safety of lebrikizumab in patients with uncontrolled asthma despite inhaled corticosteroids and at least one second controller medication.

Methods

Adult patients with uncontrolled asthma, pre-bronchodilator FEV1 40–80% predicted, and stable background therapy were randomly assigned (1:1:1) with an interactive voice–web-based response system to receive lebrikizumab 37·5 mg or 125 mg, or placebo subcutaneously, once every 4 weeks. Randomisation was stratified by screening serum periostin concentration, history of asthma exacerbations within the last 12 months, baseline asthma medications, and country. The primary efficacy endpoint was the rate of asthma exacerbations over 52 weeks in biomarker-high patients (periostin ≥50 ng/mL or blood eosinophils ≥300 cells per μL), analysed with a Poisson regression model corrected for overdispersion with Pearson χ2 that included terms for treatment group, number of asthma exacerbations within the 12 months before study entry, baseline asthma medications, geographic region, screening periostin concentration, and blood eosinophil counts as covariates. Both trials are registered at ClinicalTrials.gov, LAVOLTA I, number NCT01867125, and LAVOLTA II, number NCT01868061.

Findings

1081 patients were treated in LAVOLTA I and 1067 patients in LAVOLTA II. Over 52 weeks, lebrikizumab reduced exacerbation rates in biomarker-high patients in the 37·5 mg dose group (rate ratio [RR] 0·49 [95% CI 0·34–0·69], p<0·0001) and in the 125 mg dose group (RR 0·70 [0·51–0·95], p=0·0232) versus placebo in LAVOLTA I. Exacerbation rates were also reduced in biomarker-high patients in both dose groups versus placebo in LAVOLTA II (37·5 mg: RR 0·74 [95% CI 0·54–1·01], p=0·0609; 125 mg: RR 0·74 [0·54–1·02], p=0·0626). Pooling both studies, the proportion of patients who experienced treatment-emergent adverse events (79% [1125 of 1432 patients] for both lebrikizumab doses vs 80% [576 of 716 patients] for placebo), serious adverse events (8% [115 patients] for both lebrikizumab doses vs 9% [65 patients] for placebo), and adverse events leading to study drug discontinuation (3% [49 patients] for both lebrikizumab doses vs 4% [31 patients] for placebo) were similar between lebrikizumab and placebo. The following serious adverse events were reported in the placebo-controlled period: one event of aplastic anaemia and five serious adverse events related to raised concentrations of eosinophils in patients treated with lebrikizumab and one event of eosinophilic pneumonia in the placebo group.

Interpretation

Lebrikizumab did not consistently show significant reduction in asthma exacerbations in biomarker-high patients. However, it blocked interleukin-13 as evidenced by the effect on interleukin-13-related pharmacodynamic biomarkers, and clinically relevant changes could not be ruled out.

Funding

F Hoffmann-La Roche.

Introduction

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.

Section snippets

Study design and participants

LAVOLTA I and LAVOLTA II are replicate phase 3, randomised, multicentre, multinational, double-blind, placebo-controlled trials. The protocol was amended to update the prespecified biomarker subgroup for the primary analysis to include blood eosinophil count, in addition to serum periostin. Biomarker-high patients were defined as patients with screening periostin of at least 50 ng/mL or screening blood eosinophils of at least 300 cells per μL. This amendment did not alter the conduct of the

Results

Enrolment commenced on July 25, 2013, and was completed on Dec 18, 2014. Across both studies, a total of 2149 patients were enrolled at 367 sites in 28 countries (listed in appendix); 1081 patients were randomly assigned in LAVOLTA I and 1068 in LAVOLTA II (one patient in LAVOLTA II, randomly assigned in error, was not treated and not included in the intention-to-treat group); of these patients, 976 (90%) completed treatment in LAVOLTA I and 957 (90%) completed treatment in LAVOLTA II (figure 1

Discussion

In these replicate trials, LAVOLTA I met its primary endpoint and significantly reduced asthma exacerbation rates in biomarker-high (periostin ≥50 ng/mL or blood eosinophils ≥300 cells per μL) patients. Although LAVOLTA II did not achieve statistically significant reductions on the same endpoint, clinically meaningful treatment effects could not be ruled out. Whereas FEV1 showed improvement in biomarker-high patients in both trials, there were no differences between lebrikizumab and placebo in

References (36)

  • EH Bel

    Clinical phenotypes of asthma

    Curr Opin Pulm Med

    (2004)
  • P Haldar et al.

    Cluster analysis and clinical asthma phenotypes

    Am J Respir Crit Care Med

    (2008)
  • Global Strategy for Asthma Management and Prevention

  • TR Bai et al.

    Severe exacerbations predict excess lung function decline in asthma

    Eur Respir J

    (2007)
  • RH Green et al.

    The reclassification of asthma based on subphenotypes

    Curr Opin Allergy Clin Immunol

    (2007)
  • J Agbetile et al.

    New therapies and management strategies in the treatment of asthma: patient-focused developments

    J Asthma Allergy

    (2011)
  • M Wills-Karp et al.

    Interleukin-13: central mediator of allergic asthma

    Science

    (1998)
  • G Grunig et al.

    Requirement for IL-13 independently of IL-4 in experimental asthma

    Science

    (1998)
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