Lebrikizumab treatment in adults with asthma. Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): replicate, phase 3, randomised, double-blind, placebo-controlled trials. An open-label, single-dose bioavailability study of the pharmacokinetics of CAT-354 after subcutaneous and intravenous administration in healthy males. Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies T-helper type 2-driven inflammation defines major subphenotypes of asthma. Interleukin 13 and the evolution of asthma therapy. A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma Predicting episodes of poor asthma control in treated patients with asthma. A pharmacokinetic comparison of anrukinzumab, an anti- IL-13 monoclonal antibody, among healthy volunteers, asthma and ulcerative colitis patients. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial.
BACKGROUND Many patients with asthma have uncontrolled disease despite treatment with inhaled glucocorticoids . One potential cause of the variability in response to treatment is heterogeneity in the role of interleukin-13 expression in the clinical asthma phenotype . We hypothesized that anti-interleukin-13 therapy would benefit patients with asthma who had a pretreatment profile consistent with interleukin-13 activity . METHODS We conducted a r and omized , double-blind , placebo-controlled study of lebrikizumab , a monoclonal antibody to interleukin-13 , in 219 adults who had asthma that was inadequately controlled despite inhaled glucocorticoid therapy .  The primary efficacy outcome was the relative change in prebronchodilator forced expiratory volume in 1 second ( FEV(1 ) ) from baseline to week 12 . Among the secondary outcomes was the rate of asthma exacerbations through 24 weeks . Patient subgroups were prespecified according to baseline type 2 helper T-cell ( Th2 ) status ( assessed on the basis of total IgE level and blood eosinophil count ) and serum periostin level . RESULTS At baseline , patients had a mean FEV(1 )  that was 65 % of the predicted value and were taking a mean dose of inhaled glucocorticoids of 580 μg per day ; 80 % were also taking a long-acting beta-agonist . At week 12 , the mean increase in FEV(1 ) was 5.5 percentage points higher in the lebrikizumab group than in the placebo group ( P = 0.02 ) . Among patients in the high-periostin subgroup , the increase from baseline FEV(1 ) was 8.2 percentage points higher in the lebrikizumab group than in the placebo group ( P = 0.03 ) . Among patients in the low-periostin subgroup , the increase from baseline FEV(1 ) was 1.6 percentage points higher in the lebrikizumab group than in the placebo group ( P = 0.61 ) . Musculoskeletal side effects were more common with lebrikizumab than with placebo ( 13.2 % vs. 5.4 % , P = 0.045 ) . CONCLUSIONS Lebrikizumab treatment was associated with improved lung function . Patients with high pretreatment levels of serum periostin had greater improvement in lung function with lebrikizumab than did patients with low periostin levels . ( Funded by Genentech ; Clinical Trials.gov number , NCT00930163 . ) 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 r and omly 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 . R and omisation 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 Clinical Trials.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 evidence d by the effect on interleukin-13-related pharmacodynamic biomarkers , and clinical ly relevant changes could not be ruled out . FUNDING F Hoffmann-La Roche AIM To assess the bioavailability and pharmacokinetics of CAT-354 , an anti-IL-13 human monoclonal IgG4 antibody , following subcutaneous ( s.c . ) and intravenous ( i.v . ) administration . METHODS This was a single-dose , r and omized , open-label , parallel-group bioavailability study . Healthy male subjects aged 20 - 54 years were r and omly assigned to one of three dose groups ( n= 10/group ) to receive CAT-354 : 150 mg i.v . ; 150 mg s.c . or 300 mg s.c . ( two 150 mg injections ) . Serum pharmacokinetics , adverse events ( AEs ) , vital signs , electrocardiograms and laboratory parameters were assessed . RESULTS CAT-354 showed bioavailability of 62 % and 60 % after 150 mg and 300 mg s.c . doses , respectively , and linear pharmacokinetics over the dose range tested . Peak serum concentrations in the s.c . groups occurred after 3 - 9 ( median 5 ) days , with a mean elimination half-life of 19.2 + /- 3.1 days ( 150 mg ) and 19.4 + /- 3.59 days ( 300 mg ) after s.c . and 21.4 + /- 2.46 days after i.v . administration . Volume of distribution at steady state ( V(ss ) ) was 4960 + /- 1440 ml kg(-1 ) after i.v . ( slightly greater than plasma volume ) . Average apparent clearances ( CL/F ) were 292 + /- 82.3 and 307 + /- 109 ml day(-1 ) after 150 and 300 mg s.c . , respectively ; systemic CL of 188 + /- 84.0 ml day(-1 ) after i.v . dosing was consistent with endogenous IgG and reticuloendothelial elimination . No severe or serious AEs occurred . Among 40 reported AEs , 25 were headache , sinus disorders/respiratory symptoms and changes in body temperature perception . CONCLUSIONS CAT-354 exhibited bioavailability of approximately 60 % when given s.c . to healthy male subjects Introduction In a subset of patients with asthma , st and ard-of-care treatment does not achieve disease control , highlighting the need for novel therapeutic approaches . Lebrikizumab is a humanised , monoclonal antibody that binds to and blocks interleukin-13 activity . Methods LUTE and VERSE were replicate , r and omised , double-blind , placebo-controlled studies , evaluating multiple doses of lebrikizumab in patients with uncontrolled asthma despite the use of medium-to-high-dose inhaled corticosteroid and a second controller . Patients received lebrikizumab 37.5  , 125 , 250 mg or placebo subcutaneously every four weeks . The primary endpoint was the rate of asthma exacerbations during the placebo-controlled period . Analyses were performed on prespecified subgroups based on baseline serum periostin levels . Following the discovery of a host-cell impurity in the study drug material , protocol s were amended to convert from phase III to phase IIb . Subsequently , dosing of study medication was discontinued early as a pre caution ary measure . The data collected for analysis were from a placebo-controlled period of variable duration and pooled across both studies . Results The median duration of treatment was approximately 24 weeks . Treatment with lebrikizumab reduced the rate of asthma exacerbations , which was more pronounced in the periostin-high patients ( all doses : 60 % reduction ) than in the periostin-low patients ( all doses : 5 % reduction ) ; no dose – response was evident . Lung function also improved following lebrikizumab treatment , with greatest increase in FEV1 in periostin-high patients ( all doses : 9.1 % placebo-adjusted improvement ) compared with periostin-low patients ( all doses : 2.6 % placebo-adjusted improvement ) . Lebrikizumab was well tolerated and no clinical ly important safety signals were observed . Conclusions These data are consistent with , and extend , previously published results demonstrating the efficacy of lebrikizumab in improving rate of asthma exacerbations and lung function in patients with moderate-to-severe asthma who remain uncontrolled despite current st and ard-of-care treatment . Trial registration numbers The LUTE study was registered under NCT01545440 and the VERSE study under NCT01545453 at http://www . clinical RATIONALE T-helper type 2 ( Th2 ) inflammation , mediated by IL-4 , IL-5 , and IL-13 , is considered the central molecular mechanism underlying asthma , and Th2 cytokines are emerging therapeutic targets . However , clinical studies increasingly suggest that asthma is heterogeneous . OBJECTIVES To determine whether this clinical heterogeneity reflects heterogeneity in underlying molecular mechanisms related to Th2 inflammation . METHODS Using microarray and polymerase chain reaction analyses of airway epithelial brushings from 42 patients with mild-to-moderate asthma and 28 healthy control subjects , we classified subjects with asthma based on high or low expression of IL-13-inducible genes . We then vali date d this classification and investigated its clinical implication s through analyses of cytokine expression in bronchial biopsies , markers of inflammation and remodeling , responsiveness to inhaled corticosteroids , and reproducibility on repeat examination . MEASUREMENTS AND MAIN RESULTS Gene expression analyses identified two evenly sized and distinct subgroups , " Th2-high " and " Th2-low " asthma ( the latter indistinguishable from control subjects ) . These subgroups differed significantly in expression of IL-5 and IL-13 in bronchial biopsies and in airway hyperresponsiveness , serum IgE , blood and airway eosinophilia , subepithelial fibrosis , and airway mucin gene expression ( all P < 0.03 ) . The lung function improvements expected with inhaled corticosteroids were restricted to Th2-high asthma , and Th2 markers were reproducible on repeat evaluation . CONCLUSIONS Asthma can be divided into at least two distinct molecular phenotypes defined by degree of Th2 inflammation . Th2 cytokines are likely to be a relevant therapeutic target in only a subset of patients with asthma . Furthermore , current models do not adequately explain non-Th2-driven asthma , which represents a significant proportion of patients and responds poorly to current therapies This is a concise review on Interleukin (IL)-13 and the evolution of asthma therapy , from discovery of the molecule , the identification of its pathogenic role in animal models of asthma , to the development of clinical ly successful neutralizing agents . The translational path from basic research to clinical application was not sequential as expected but r and om with respect to the tools ( molecular & cell biology , animal models , human studies ) used and to the application of academic versus industry research . The experiences with the development of neutralizing  anti-IL-13  reagents emphasize the need for inclusion of a biomarker assay in the clinical trials that both identifies individuals that actually have aberrant expression of the pathway of interest and allows determining whether the target of interest is neutralized 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 r and omised 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 Question naire 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 BACKGROUND Asthma exacerbations are dangerous , expensive , and difficult to anticipate . OBJECTIVE To characterize patients with asthma who had asthma episodes and exacerbations during 4 weeks of observation . METHODS A total of 2032 volunteers with asthma ( age , 3 - 64 years ; 62 % female subjects ) were studied over two 2-week intervals after flu vaccine and placebo . Baseline data , including several asthma question naires , were analyzed for prediction of subsequent asthma events as recorded on diaries detailing peak flow , medication use , and health care use . RESULTS During 28 days of diary collection , 43.2 % of participants had at least 1 episode of poor asthma control . Most episodes were characterized by increased use of rescue medications or reductions in peak flow , but nearly 15 % of participants had exacerbations characterized by use of systemic corticosteroids , unscheduled health care visits , or both . Episode frequency was highest in children < 10 years of age . Additional risk factors were smoking , African American ethnicity , low lung function , and past history of severe asthma . The best predictors were symptom question naires , and a simple question naire concerning the preceding 2 weeks worked as well as more complex question naires or those reflecting longer periods . In regression analyses , question naire results , smoking , lung function , ethnicity , and asthma history all were associated with asthma episodes in people older than 10 years , whereas only asthma history was predictive in those < 10 years . CONCLUSION Symptom question naires are predictive of subsequent asthma episodes in people older than age 10 years , but not in younger people . CLINICAL IMPLICATION S Simple assessment s may be helpful in identifying patients most at risk for future asthma episodes AIMS Anrukinzumab is an anti-IL13 monoclonal antibody . The goals of this study are to characterize the pharmacokinetics of anrukinzumab in healthy volunteers and different disease states and to identify covariates . METHODS A population pharmacokinetic ( PK ) model was developed in NONMEM , using data from five clinical studies including healthy volunteers , asthma and ulcerative colitis ( UC ) patients . Different dosing regimens including different routes of administration were also included in the data . RESULTS The PK of anrukinzumab were described by a two compartment model with first order absorption and elimination . The population estimates ( relative st and ard error ) of the volumes of distribution in the central ( Vc ) and peripheral ( Vp ) compartments were 3.8 ( 4.6 % ) and 2.2 l ( 8.7 % ) , respectively . In non-UC patients , the population estimate of the systemic clearance ( CL ) and inter-compartmental CL was 0.00732 l h(-1 ) ( 4.9 % ) and 0.0224 l h(-1 ) ( 15.4 % ) . For subcutaneous administration , the absorption rate constant was 0.012 h(-1 ) ( 6.6 % ) and bioavailability was nearly 100 % in healthy and mild to moderate asthma patients . Both V and CL increased with body weight . CL ( but not V ) decreased with increasing baseline albumin concentrations . UC patients had an increased CL of 72.3 % ( 10.5 % ) , after correction for differences in body weight and albumin . Moderate to severe asthma patients had decreased bioavailability compared with other population s. CONCLUSIONS Anrukinzumab 's PK behave like a typical antibody . UC patients were identified to have a faster CL of anrukinzumab than healthy volunteers and asthma patients . This finding suggests a higher dose level may be required for this population For most patients , asthma is not controlled as defined by guidelines ; whether this is achievable has not been prospect ively studied . A 1-year , r and omized , stratified , double-blind , parallel-group study of 3,421 patients with uncontrolled asthma compared fluticasone propionate and salmeterol/fluticasone in achieving two rigorous , composite , guideline -based measures of control : totally and well-controlled asthma . Treatment was stepped-up until total control was achieved ( or maximum 500 microg corticosteroid twice a day ) . Significantly more patients in each stratum ( previously corticosteroid-free , low- and moderate-dose corticosteroid users ) achieved control with salmeterol/fluticasone than fluticasone .  Total control was achieved across all strata : 520 ( 31 % ) versus 326 ( 19 % ) patients after dose escalation ( p < 0.001 ) and 690 ( 41 % ) versus 468 ( 28 % ) at 1 year for salmeterol/fluticasone and fluticasone , respectively . Asthma became well controlled in 1,071 ( 63 % ) versus 846 ( 50 % ) after dose escalation ( p < 0.001 ) and 1,204 ( 71 % ) versus 988 ( 59 % ) at 1 year . Control was achieved more rapidly and at a lower corticosteroid dose with salmeterol/fluticasone versus fluticasone . Across all strata , 68 % and 76 % of the patients receiving salmeterol/fluticasone and fluticasone , respectively , were on the highest dose at the end of treatment . Exacerbation rates ( 0.07 - 0.27 per patient per year ) and improvement in health status were significantly better with salmeterol/fluticasone . This study confirms that the goal of guideline -derived asthma control was achieved in a majority of the patients BACKGROUND Interleukin 13 is a central mediator of asthma .  Tralokinumab is a human interleukin-13 neutralising monoclonal antibody . We aim ed to assess the efficacy and safety of two dosing regimens of tralokinumab in patients with severe uncontrolled asthma . METHODS We did a r and omised , 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 r and omly 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 r and omised ( 2:1 ) , via computer-generated permuted-block r and omisation ( 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 Question naire-6 ( ACQ-6 ) , and Asthma Quality of Life Question naire-St and ardised Version ( AQLQ[S ] ) . This trial is registered with Clinical Trials.gov , number NCT01402986 . FINDINGS Between Oct 4 , 2011 , and Feb 22 , 2014 , we r and omly 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
More and more clinical trials have tried to assess the clinical benefit of anti-interleukin (IL)-13 monoclonal antibodies for uncontrolled asthma .
The aim of this study is to evaluate the efficacy and safety of anti-IL-13 monoclonal antibodies for uncontrolled asthma .