title: Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial.
abstract: BACKGROUND
  Interleukin 13 is a central mediator of asthma. Tralokinumab is a human interleukin-13 neutralising monoclonal antibody. We aimed to assess the efficacy and safety of two dosing regimens of tralokinumab in patients with severe uncontrolled asthma.
  
  
  METHODS
  We did a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 2b study at 98 sites in North America, South America, Europe, and Asia. Patients aged 18-75 years with severe asthma and two to six exacerbations in the previous year were randomly assigned (1:1), via an interactive voice-response or web-response system, to one of two dosing regimen groups (every 2 weeks, or every 2 weeks for 12 weeks then every 4 weeks) and further randomised (2:1), via computer-generated permuted-block randomisation (block size of six), to receive tralokinumab 300 mg or placebo for 1 year. All participants received high-dose fluticasone and salmeterol and continued other pre-study controller drugs. Treatment was administered by an unmasked study investigator not involved in the management of patients; all other study site personnel, patients, the study funder, and data analysts were masked to treatment allocation. The primary endpoint was the annual asthma exacerbation rate at week 52 in the intention-to-treat population. Key secondary endpoints included prebronchodilator forced expiratory volume in 1 s (FEV1), Asthma Control Questionnaire-6 (ACQ-6), and Asthma Quality of Life Questionnaire-Standardised Version (AQLQ[S]). This trial is registered with ClinicalTrials.gov, number NCT01402986.
  
  
  RESULTS
  Between Oct 4, 2011, and Feb 22, 2014, we randomly assigned 452 patients to receive placebo (n=151) or tralokinumab every 2 weeks (n=150) or every 4 weeks (n=151), of whom 383 (85%) completed the treatment period up to week 52. The annual asthma exacerbation rate at week 52 was similar between patients receiving tralokinumab every 2 weeks (0.91 per patient per year [95% CI 0.76-1.08]) and every 4 weeks (0.97 [0.81-1.14]), and those receiving placebo (0.90 [0.75-1.08]). At week 52, percentage changes in annual asthma exacerbation rate were not significant with tralokinumab every 2 weeks or every 4 weeks versus placebo (6% [95% CI -31 to 33; p=0.709] and -2% [-46 to 29; p=0.904], respectively), with positive changes showing a decrease in exacerbation rate and negative changes showing an increase. Prebronchodilator FEV1 was significantly increased compared with placebo for tralokinumab every 2 weeks (change from baseline 7.3% [95% CI 2.6-12.0]; p=0.003), but not every 4 weeks (1.8% [-2.9 to 6.6]; p=0.448); however, we did not identify significant changes in the other key secondary endpoints. In a post-hoc subgroup analysis of patients not on long-term oral corticosteroids and with baseline FEV1 reversibility of 12% or greater, we noted a non-significant improvement in asthma exacerbation rate (44% [95% CI -22 to 74]; p=0.147) and significant improvements in key secondary endpoints (FEV1 12.2% [1.7-22.7]; p=0.022; ACQ-6 -0.55 [-1.07 to -0.04]; p=0.036; and AQLQ[S] 0.70 [0.12-1.28]; p=0.019) in patients given tralokinumab every 2 weeks (n=33) compared with placebo (n=48). In patients in this subgroup who also had baseline serum dipeptidyl peptidase-4 (DPP-4) higher than the population baseline median, we noted additional improvements in prebronchodilator FEV1, ACQ-6, and AQLQ(S), and, in those with periostin concentrations higher than the median, we noted improvements in asthma exacerbation rate, prebronchodilator FEV1, and ACQ-6. The incidence of treatment-emergent adverse events was similar between the tralokinumab and placebo groups. Treatment-emergent serious adverse events regarded as related to the study drug were pneumonia (one [1%] patient in the placebo group), pneumococcal pneumonia (one [1%] in the tralokinumab every 2 weeks group), angioedema (one [1%] in the placebo group), and worsening asthma (one [1%] in the tralokinumab every 2 weeks group and two [1%] in the tralokinumab every 4 weeks group).
  
  
  CONCLUSIONS
  In this phase 2b study, both tralokinumab regimens had an acceptable safety and tolerability profile but did not significantly reduce asthma exacerbation rates in patients with severe uncontrolled asthma. Improvement in FEV1 with tralokinumab given every 2 weeks and results of post-hoc subgroup analyses suggested a possible treatment effect in a defined population of patients with severe uncontrolled asthma. This effect is being further investigated in ongoing phase 3 trials, along with the potential utility of DPP-4 and periostin as biomarkers of interleukin-13 pathway activation.
  
  
  BACKGROUND
  MedImmune.
authors.affiliation: University of Leicester, Leicester, UK.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Brightling
authors.affiliation: Département des Maladies Respiratoires, CIC Nord APHM, Laboratoire INSERM CNRS U 1067, UMR7333, Aix-Marseille Université, Marseille, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Chanez
authors.affiliation: University of Calgary, Calgary, AB, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Leigh
authors.affiliation: McMaster University, Hamilton, ON, Canada.
authors.forename: Paul M
authors.initials: PM
authors.lastname: O'Byrne
authors.affiliation: Johannes Gutenberg University Hospital, Mainz, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Korn
authors.affiliation: MedImmune, Gaithersburg, MD, USA.
authors.forename: Dewei
authors.initials: D
authors.lastname: She
authors.affiliation: MedImmune, Cambridge, UK.
authors.forename: Richard D
authors.initials: RD
authors.lastname: May
authors.affiliation: MedImmune, Gaithersburg, MD, USA.
authors.forename: Katie
authors.initials: K
authors.lastname: Streicher
authors.affiliation: MedImmune, Gaithersburg, MD, USA.
authors.forename: Koustubh
authors.initials: K
authors.lastname: Ranade
authors.affiliation: MedImmune, Cambridge, UK. Electronic address: edward.piper@astrazeneca.com.
authors.forename: Edward
authors.initials: E
authors.lastname: Piper
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D001993:Bronchodilator Agents / Q000627:therapeutic use; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D000068298:Fluticasone / Q000627:therapeutic use; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D011788:Quality of Life; D000068299:Salmeterol Xinafoate / Q000627:therapeutic use; D011795:Surveys and Questionnaires; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D018927:Anti-Asthmatic Agents; D000911:Antibodies, Monoclonal; D001993:Bronchodilator Agents; D000068299:Salmeterol Xinafoate; D000068298:Fluticasone; C574065:tralokinumab