human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 
    Output:
    
agent
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 
    Output:
    