Dewei She

A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma

Pre-clinical data demonstrate a pivotal role for interleukin (IL)-13 in the development and maintenance of asthma. This study assessed the effects of tralokinumab, an investigational human IL-13-neutralising immunoglobulin G4 monoclonal antibody, in adults with moderate-to-severe uncontrolled asthma despite controller therapies. 194 subjects were randomised to receive tralokinumab (150, 300 or 600 mg) or placebo subcutaneously every 2 weeks. Primary end-point was change from baseline in mean Asthma Control Questionnaire score (ACQ-6; ACQ mean of six individual item scores) at week 13 comparing placebo and combined tralokinumab dose groups. Secondary end-points included pre-bronchodilator lung function, rescue &bgr;2-agonist use and safety. Numerical end-points are reported as mean±sd. At week 13, change from baseline in ACQ-6 was -0.76±1.04 for tralokinumab versus -0.61±0.90 for placebo (p=0.375). Increases from baseline in forced expiratory volume in 1 s (FEV1) were 0.21±0.38 L versus 0.06±0.48 L (p=0.072), with a dose-response observed across the tralokinumab doses tested. &bgr;2-agonist use (puffs per day) was decreased for tralokinumab -0.68±1.45 versus placebo -0.10±1.49 (p=0.020). The increase in FEV1 following tralokinumab treatment remained evident 12 weeks after the final dose. Safety profile was acceptable with no serious adverse events related to tralokinumab. No improvement in ACQ-6 was observed, although tralokinumab treatment was associated with improved lung function.

Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial

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. FINDINGS 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). INTERPRETATION 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. FUNDING MedImmune.

Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study

BACKGROUND Chronic obstructive pulmonary disease (COPD) is associated with eosinophilic airway inflammation in 10-20% of patients. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, depletes blood and sputum eosinophils. We aimed to establish whether benralizumab reduces acute exacerbations of COPD in patients with eosinophilia and COPD. METHODS We did this randomised, double-blind, placebo-controlled, phase 2a study between Nov 18, 2010, and July 13, 2013, at 26 sites in the UK, Poland, Germany, Canada, the USA, Denmark, and Spain. Adults aged 40-85 years, with moderate-to-severe COPD, at least one acute exacerbation of COPD, and a sputum eosinophil count of 3·0% or more within the previous year, were randomly assigned (1:1) via computer-generated permuted block randomisation (block size of four), with an interactive voice or web-response system, to receive placebo or 100 mg benralizumab subcutaneously, every 4 weeks (three doses), then every 8 weeks (five doses) over 48 weeks. Study site personnel included in study assessments, participants, and data analysts, were masked to treatment allocation. The primary endpoint was the annualised rate of acute exacerbations of COPD at week 56, defined as the number of acute exacerbations divided by total duration of person-year follow-up. Secondary and exploratory endpoints included COPD-specific Saint Georges Respiratory Questionnaire (SGRQ-C), Chronic Respiratory Questionnaire self-administered standardised format (CRQ-SAS), pre-bronchodilator forced expiratory volume in 1 second (FEV1), and safety. We did a prespecified subgroup analysis by baseline blood eosinophil count. Analyses were by intention to treat and per-protocol. This trial is registered with ClinicalTrials.gov, number NCT01227278. FINDINGS We randomly assigned 101 patients to receive placebo (n=50) or benralizumab (n=51), of whom 88 (87%) patients completed the study. Six patients who completed the study were excluded from the per-protocol population because of major protocol violations; the per-protocol population thus included 82 patients. Benralizumab did not reduce the annualised rate of acute exacerbations of COPD compared with placebo in the per-protocol population, with rates of 0·95 (0·68-1·29; n=40) versus 0·92 (0·67-1·25; n=42). Mean pre-bronchodilator FEV1 change from baseline to week 56 was -0·06 L (SD 0·24) with placebo, and 0·13 L (0·41) with benralizumab (p=0·014). Numerical, albeit non-significant, improvement in acute exacerbations of COPD, SGRQ-C, CRQ-SAS, and FEV1 were greater in benralizumab-treated patients with baseline blood eosinophil concentrations of 200 cells per μL or more or 300 cells per μL or more. Incidence of treatment-emergent adverse events was similar between the two groups, with the most common events being respiratory disorders (31 [62%] of 50 patients given placebo vs 32 [63%] of 51 given benralizumab) and infections (28 [56%] vs 27 [53%]). A higher incidence of serious treatment-emergent adverse events were recorded in patients in the benralizumab group than in those in the placebo group (14 vs nine patients), although none of these events were considered by the investigator to be benralizumab related. INTERPRETATION Compared with placebo, benralizumab did not reduce the rate of acute exacerbations of COPD. However, the results of prespecified subgroup analysis support further investigation of benralizumab in patients with COPD and eosinophilia. FUNDING MedImmune.

Pharmacokinetics of tralokinumab in adolescents with asthma: implications for future dosing

AIMS Tralokinumab, an investigational human immunoglobulin G4 monoclonal antibody, potently and specifically neutralizes interleukin-13, a central mediator of asthma. Tralokinumab has shown improvements in clinical endpoints in adults with uncontrolled asthma. The present study explored the pharmacokinetics (PK) and safety of a single tralokinumab dose, and utilized a population PK modelling and simulation approach to evaluate the optimal dosing strategy for adolescents. METHODS Adolescent subjects with asthma, using daily controller medication, received a single subcutaneous dose of tralokinumab 300 mg. Safety, immunogenicity and PK data were collected during a 57-day follow-up. A population PK model was developed using data from the present study and prior studies in adults. Simulations were performed to evaluate dose adjustment requirements for adolescents. RESULTS Twenty adolescents (12-17 years) were enrolled; all completed the study. No clinically relevant safety findings or antidrug antibodies were detected. PK parameters were similar to those observed in adults. PK modelling showed that body weight was a minor predictor of tralokinumab PK; after incorporating body weight into the PK model, a 15% (nonparametric 95% confidence interval 5%, 26%) lower clearance was found in adolescents compared with adults [173 (151, 209) vs. 204 (191, 229) ml day(-1)]. Simulations showed no therapeutically relevant differences in exposures between adolescent and adult populations, and similar PK profiles for weight-based (4 mg kg(-1)) and fixed (300 mg) fortnightly subcutaneous doses of tralokinumab. CONCLUSION Single-dose administration of tralokinumab 300 mg in adolescents was well tolerated, with a PK profile similar to that in adults. Exposure predictions suggest that dose adjustment is not required for adolescents.

A Phase 2 Randomized Controlled Study of Tralokinumab in Subjects with Idiopathic Pulmonary Fibrosis

Rationale: IL‐13 is a potential therapeutic target for idiopathic pulmonary fibrosis (IPF); preclinical data suggest a role in tissue fibrosis, and expression is increased in subjects with rapidly progressing disease. Objectives: Investigate efficacy and safety of tralokinumab, a human anti‐IL‐13 monoclonal antibody, in subjects with mild to moderate IPF. Methods: Subjects received tralokinumab (400 or 800 mg), or placebo, intravenously every 4 weeks for 68 weeks. The primary endpoint was change from baseline to Week 52 in percent predicted FVC in the intention‐to‐treat population. Exploratory analyses included assessment of clinical response in subgroups with baseline serum periostin concentration above/below median. Measurements and Main Results: The study was stopped due to lack of efficacy after interim analysis. Neither tralokinumab 400 mg nor tralokinumab 800 mg met the primary endpoint; least‐squares mean difference (95% confidence interval) percent predicted FVC from baseline to Week 52: −1.77 (−4.13 to 0.59) (P = 0.140) and −1.41 (−3.73 to 0.91) (P = 0.234), respectively. The primary endpoint was also not met in either treatment group in subgroups defined by periostin baseline concentration. The percentage of subjects with decline in percent predicted FVC greater than or equal to 10% at Week 52 was numerically greater for tralokinumab‐treated subjects compared with placebo. The most common treatment‐emergent adverse events for tralokinumab 400 mg, tralokinumab 800 mg, and placebo were cough (17.5, 30.5, 22.8%), IPF progression and exacerbation (21.1, 16.9, 22.8%), and upper respiratory tract infection (17.5, 20.3, 12.3%), respectively. Conclusions: Tralokinumab demonstrated an acceptable safety and tolerability profile but did not achieve key efficacy endpoints. Clinical trial registered with www.clinicaltrials.gov (NCT01629667).

Effect of Anti–IL-13 Treatment on Airway Dimensions in Severe Asthma

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