Lebrikizumab treatment in adults with asthma. Anrukinzumab, an anti-interleukin 13 monoclonal antibody, in active UC: efficacy and safety from a phase IIa randomised multicentre study Tralokinumab for moderate-to-severe UC: a randomised, double-blind, placebo-controlled, phase IIa study 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. A phase 1 study evaluating the pharmacokinetics, safety and tolerability of repeat dosing with a human IL-13 antibody (CAT-354) in subjects with asthma Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies Omalizumab and the risk of malignancy: results from a pooled analysis. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma The effects of lebrikizumab in patients with mild asthma following whole lung allergen challenge Efficacy and safety of an anti-IL-13 mAb in patients with severe asthma: a randomized trial. A phase 1, randomized, placebo-controlled, dose-escalation study of an anti-IL-13 monoclonal antibody in healthy subjects and mild asthmatics. A randomized, controlled, phase 2 study of AMG 317, an IL-4Ralpha antagonist, in patients with asthma. Incidence of malignancy in patients with moderate-to-severe asthma treated with or without omalizumab. Pharmacokinetics of tralokinumab in adolescents with asthma: implications for future dosing. Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial. Dose-ranging study of lebrikizumab in asthmatic patients not receiving inhaled steroids. Effect of Subcutaneous Dupilumab on Nasal Polyp Burden in Patients With Chronic Sinusitis and Nasal Polyposis: A Randomized Clinical Trial. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies
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 . ) Objective Interleukin 13 ( IL-13 ) is thought to play a key role as an effector cytokine in UC . Anrukinzumab , a humanised antibody that inhibits human IL-13 , was evaluated for the treatment of UC . Design In a multicentre , r and omised , double-blind , placebo-controlled study , patients with active UC ( Mayo score ≥4 and < 10 ) were r and omised to anrukinzumab 200 , 400 or 600 mg or placebo . Patients received five intravenous administrations over 14 weeks . The primary endpoint was fold change from baseline in faecal calprotectin ( FC ) at Week 14 . Secondary endpoints included safety , pharmacokinetics and IL-13 levels . Results The modified intention-to-treat population included 84 patients ( 21 patients /arm ) . Fold change of FC from baseline at Week 14 was not significantly different for any treatment groups compared with the placebo . The study had a high dropout rate , in part , related to lack of efficacy . The exploratory comparisons of each dose were not significantly different from placebo in terms of change from baseline in total Mayo score , clinical response , clinical remission and proportion of subjects with mucosal healing . An increase in serum total IL-13 ( free and bound to anrukinzumab ) was observed for all anrukinzumab groups but not with placebo . This suggests significant binding of anrukinzumab to IL-13 . The safety profile was not different between the anrukinzumab and placebo groups . Conclusions A statistically significant therapeutic effect of anrukinzumab could not be demonstrated in patients with active UC in spite of binding of anrukinzumab to IL-13 . Trial registration number Clinical Trials.gov number NCT01284062 Objective Interleukin-13 ( IL-13 ) has been implicated as a key driver of UC . This trial evaluates the efficacy and safety of tralokinumab , an IL-13-neutralising antibody , as add-on therapy in adults with moderate-to-severe UC despite st and ard treatments . Design Non-hospitalised adults with UC ( total Mayo score ≥6 ) were r and omised to receive tralokinumab 300 mg or placebo subcutaneously every 2 weeks for 12 weeks . The primary end point was the rate of clinical response at week 8 . Secondary efficacy end points included clinical remission and mucosal healing rates at week 8 and changes in total Mayo score , total modified Riley score , partial Mayo score and disease activity markers . Results Clinical response rate was 38 % ( 21/56 ) for tralokinumab vs 33 % ( 18/55 ) for placebo ( p=0.406 ) . Clinical remission rate was 18 % ( 10/56 ) vs 6 % ( 3/55 ) ( p=0.033 ) and mucosal healing rate was 32 % ( 18/56 ) vs 20 % ( 11/55 ) ( p=0.104 ) for tralokinumab vs placebo . Changes to week 8 in total Mayo score and total modified Riley score were similar for tralokinumab and placebo ( least-squares mean difference between groups : −0.49 ( p=0.394 ) and 0.25 ( p=0.449 ) , respectively ) . Partial Mayo score at week 4 was lower with tralokinumab than placebo ( least-squares mean difference between groups : −0.90 ( p=0.041 ) ) . No consistent patterns were observed for disease activity markers . Tralokinumab had an acceptable safety profile . Conclusions Add-on therapy with tralokinumab did not significantly improve clinical response . However , the higher clinical remission rate with tralokinumab than placebo suggests that tralokinumab may benefit some patients with UC .  Tralokinumab was well tolerated . Trial registration number Clinical Trials.gov number : NCT01482884 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 Background IL-13 has been implicated in the development of airway inflammation and hyperresponsiveness . This study investigated the multiple-dose pharmacokinetics and safety profile of human anti-IL-13 antibody ( CAT-354 ) in adults with asthma . Methods This was a multiple-dose , r and omised , double-blind , placebo-controlled phase 1 study in asthmatics ( forced expiratory volume in 1 second [ FEV1 ] ≥ 80 % predicted ) . Subjects were r and omised to receive three intravenous infusions of CAT-354 ( 1 mg/kg , 5 mg/kg or 10 mg/kg ) or placebo at 28-day intervals . Blood sample s were taken for pharmacokinetic measurements . Safety was assessed by adverse events , vital signs , ECGs , laboratory and pulmonary function parameters . Results Twenty-three subjects ( aged 21 - 60 years , FEV1 88 - 95 % predicted ) received ≥ 1 dose of study medication . The half-life of CAT-354 was 12 - 17 days and was dose-independent . The maximum serum concentration and area under the curve were dose-dependent . Clearance ( 2.2 - 2.6 mL/day/kg ) and volume of distribution ( 44 - 57 mL/kg ) were both low and dose-independent . The observed maximum serum concentration after each dose increased slightly from dose 1 through dose 3 at all dose levels , consistent with an accumulation ratio of 1.4 to 1.7 for area under the curve . Most adverse events were deemed mild to moderate and unrelated to study medication . One SAE was reported and deemed unrelated to study drug . There were no effects of clinical concern for vital signs , ECG , laboratory or pulmonary parameters . Conclusions CAT-354 exhibited linear pharmacokinetics and an acceptable safety profile . These findings suggest that at the doses tested , CAT-354 can be safely administered in multiple doses to patients with asthma . Trial registration NCT00974675 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 BACKGROUND Since initial registration , the omalizumab clinical trial data base has exp and ed considerably , with a doubling of patients exposed in the clinical trial environment . Previous pooled data ( 2003 ) from phase I to III studies of omalizumab showed a numeric imbalance in malignancies arising in  omalizumab recipients ( 0.5 % ) compared with control subjects ( 0.2 % ) . The previous analysis was based on limited available data , warranting further investigation . OBJECTIVE We sought to examine the incidence of malignancy using comprehensive pooled data from clinical trials of omalizumab-treated patients . METHODS This pooled analysis included data from 67 phase I to IV clinical trials . The prespecified primary analysis assessed the incidence of primary malignancy in 32 r and omized , double-blind , placebo-controlled ( RDBPC ) trials . RESULTS There were 11,459 unique patients in all clinical trials ( 7,789 received omalizumab ) . The primary analysis identified  malignancies in 25 patients ( RDBPC trials ) : 14 in 4,254 omalizumab-treated patients and 11 in 3,178 placebo-treated patients .  Incidence rates per 1,000 patient-years of observation time for omalizumab- and placebo-treated patients were 4.14 ( 95 % CI , 2.26 - 6.94 ) and 4.45 ( 95 % CI , 2.22 - 7.94 ) , respectively ; the corresponding rate ratio was 0.93 ( 95 % CI , 0.39 - 2.27 ) . Primary malignancies were of varying histologic type and occurred in a number of different organ systems ; no cluster of histologies was identified . CONCLUSIONS In this pooled analysis no association was observed between omalizumab treatment and risk of malignancy in RDBPC trials ; the rate ratio was below unity . The data suggest that a causal relationship between omalizumab therapy and malignancy is unlikely BACKGROUND Dupilumab , a fully human monoclonal antibody that blocks interleukin-4 and interleukin-13 , has shown efficacy in patients with asthma and elevated eosinophil levels . The blockade by dupilumab of these key drivers of type 2 helper T-cell (Th2)-mediated inflammation could help in the treatment of related diseases , including atopic dermatitis . METHODS We performed r and omized , double-blind , placebo-controlled trials involving adults who had moderate-to-severe atopic dermatitis despite treatment with topical glucocorticoids and calcineurin inhibitors . Dupilumab was evaluated as monotherapy in two 4-week trials and in one 12-week trial and in combination with topical glucocorticoids in another 4-week study . End points included the Eczema Area and Severity Index ( EASI ) score , the investigator 's global assessment score , pruritus , safety assessment s , serum biomarker levels , and disease transcriptome . RESULTS In the 4-week monotherapy studies , dupilumab result ed in rapid and dose-dependent improvements in clinical indexes , biomarker levels , and the transcriptome . The results of the 12-week study of dupilumab monotherapy reproduced and extended the 4-week findings : 85 % of patients in the dupilumab group , as compared with 35 % of those in the placebo group , had a 50 % reduction in the EASI score ( EASI-50 , with higher scores in the EASI indicating greater severity of eczema ) ( P<0.001 ) ; 40 % of patients in the dupilumab group , as compared with 7 % in the placebo group , had a score of 0 to 1 ( indicating clearing or near-clearing of skin lesions ) on the investigator 's global assessment ( P<0.001 ) ; and pruritus scores decreased ( indicating a reduction in itch ) by 55.7 % in the dupilumab group versus 15.1 % in the placebo group ( P<0.001 ) . In the combination study , 100 % of the patients in the dupilumab group , as compared with 50 % of those who received topical glucocorticoids with placebo injection , met the criterion for EASI-50 ( P=0.002 ) , despite the fact that patients who received dupilumab plus glucocorticoids used less than half the amount of  topical glucocorticoids  used by those who received placebo plus the topical medication ( P=0.16 ) . Adverse events , such as skin infection , occurred more frequently with placebo ;  nasopharyngitis and headache were the most frequent adverse events with dupilumab . CONCLUSIONS Patients treated with dupilumab had marked and rapid improvement in all the evaluated measures of atopic dermatitis disease activity . Side-effect profiles were not dose-limiting . ( Funded by Regeneron Pharmaceuticals and Sanofi ; Clinical Trials.gov numbers , NCT01259323 , NCT01385657 , NCT01639040 , and NCT01548404 . ) BACKGROUND Dupilumab , a fully human anti-interleukin-4 receptor α monoclonal antibody , inhibits interleukin-4 and interleukin-13 signalling , key drivers of type-2-mediated inflammation . Adults with uncontrolled persistent asthma who are receiving medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist require additional treatment options as add-on therapy . We aim ed to assess the efficacy and safety of dupilumab as add-on therapy in patients with uncontrolled persistent asthma on medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist , irrespective of baseline eosinophil count . METHODS We did this r and omised , double-blind , placebo-controlled , parallel-group , pivotal phase 2b clinical trial at 174 study sites across 16 countries or regions . Adults ( aged ≥18 years ) with an asthma diagnosis for 12 months or more based on the Global Initiative for Asthma 2009 Guidelines receiving treatment with medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist were eligible for participation . Patients were r and omly assigned ( 1:1:1:1:1 ) to receive subcutaneous dupilumab 200 mg or 300 mg every 2 weeks or every 4 weeks , or placebo , over a 24-week period . The primary endpoint was change from baseline at week 12 in forced expiratory volume in 1 s ( FEV1 in L ) in patients with baseline blood eosinophil counts of at least 300 eosinophils per μL assessed in the intention-to-treat population . Safety outcomes were assessed in all patients that received at least one dose or part of a dose of study drug . This trial is registered at Clinical Trials.gov , number NCT01854047 , and with the EU Clinical Trials Register , EudraCT number 2013 - 000856 - 16 . FINDINGS 769 patients ( 158 in the placebo group and 611 in the dupilumab groups ) received at least one dose of study drug . In the subgroup with at least 300 eosinophils per μL , the greatest increases ( 200 mg every 2 weeks , p=0·0008 ; 300 mg every 2 weeks , p=0·0063 ) in FEV1 compared with placebo were observed at week 12 with doses every 2 weeks in the 300 mg group ( mean change 0·39 L [ SE 0·05 ] ; mean difference 0·21 [ 95 % CI 0·06 - 0·36 ; p=0·0063 ] ) and in the 200 mg group ( mean change 0·43 L [ SE 0·05 ] ; mean difference 0·26 [ 0·11 - 0·40 ; p=0·0008 ] ) compared with placebo ( 0·18 L [ SE 0·05 ] ) . Similar significant increases were observed in the overall population and in the fewer than 300 eosinophils per μL subgroup ( overall population : 200 mg every 2 weeks , p<0·0001 ; 300 mg every 2 weeks , p<0·0001 ; < 300 eosinophils per μL : 200 mg every 2 weeks , p=0·0034 ; 300 mg every 2 weeks , p=0·0086 ) , and were maintained to week 24 . Likewise , dupilumab every 2 weeks produced the greatest reductions in annualised rates of exacerbation in the overall population ( 70 - 70·5 % ) , the subgroup with at least 300 eosinophils per μL ( 71·2 - 80·7 % ) , and the subgroup with fewer than 300 eosinophils per μL ( 59·9 - 67·6 % ) . The most common adverse events with dupilumab compared with placebo were upper respiratory tract infections ( 33 - 41 % vs 35 % ) and injection-site reactions ( 13 - 26 % vs 13 % ) . INTERPRETATION Dupilumab increased lung function and reduced severe exacerbations in patients with uncontrolled persistent asthma irrespective of baseline eosinophil count and had a favourable safety profile , and hence in addition to inhaled corticosteroids plus long-acting β2-agonist therapy could improve the lives of patients with uncontrolled persistent asthma compared with st and ard therapy alone . FUNDING Sanofi-Genzyme and Regeneron Pharmaceuticals 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 Interleukin 13 ( IL13 ) is a T‐helper type 2 ( Th2 ) cytokine associated with inflammation and pathology in allergic diseases such as bronchial asthma . We have shown that treatment with lebrikizumab , an anti‐IL13 monoclonal antibody , significantly improves prebronchodilator forced expiratory volume in 1 s ( FEV1 ) in a subset of subjects with uncontrolled asthma BACKGROUND Approximately 5 % to 10 % of asthmatic patients achieve incomplete symptom control on current therapies . The association of IL-13 with asthma pathology and reduced corticosteroid sensitivity suggests a potential benefit of anti-IL-13 therapy in refractory asthma .  GSK679586 , a humanized mAb , inhibits IL-13 binding to both IL-13 receptor α1 and α2 . OBJECTIVES We sought to evaluate the efficacy and safety of GSK679586 in patients with severe asthma refractory to maximally indicated doses of inhaled corticosteroids . METHODS Patients who remained symptomatic ( Asthma Control Question naire score ≥1.5 ) after uptitration to 1000 μg/d fluticasone propionate or greater were r and omized  to 3 once-monthly intravenous infusions of 10 mg/kg GSK679586 ( n = 99 ) or placebo ( n = 99 ) . RESULTS Treatment differences in adjusted mean change from baseline over 12 weeks were nonsignificant for Asthma Control Question naire symptom scores ( the primary end point ; GSK679586 = -0.31 , placebo = -0.17 , P = .058 ) and FEV₁ ( GSK679586 = -0.01 , placebo = 0.03 , P = .276 ) . Similar analyses in patients with increased serum IgE levels , blood eosinophil counts , or both were also negative . Incidence of asthma exacerbations was similar between treatments . Most adverse events were nonserious and unrelated to treatment . Two GSK679586-treated patients had treatment-related serious adverse events ( lethargy and supraventricular extrasystoles ) . CONCLUSIONS Although well tolerated , GSK679586 did not demonstrate clinical ly meaningful improvements in asthma control , pulmonary function , or exacerbations in patients with severe asthma . Further studies are needed to determine whether therapies targeting IL-13 , the functionally related IL-4 cytokine , or both can provide clinical benefit in patients with severe refractory asthma or a sub population of these patients beyond that achievable with high-dose corticosteroids AIMS IL-13 is implicated as an important mediator of the pathology of asthma . This first clinical study with GSK679586 , a novel humanized anti-IL-13 IgG1 monoclonal antibody , evaluated the safety , pharmacokinetics and pharmacodynamics of escalating single and repeat doses of GSK679586 . METHODS In this r and omized , double-blind study , healthy subjects received single intravenous infusions of GSK679586 ( 0.005 , 0.05 , 0.5 , 2.5 , 10 mg kg(-1 ) ) or placebo and mild intermittent asthmatics received two once monthly intravenous infusions of GSK679586 ( 2.5 , 10 , 20 mg kg(-1 ) ) or placebo . RESULTS GSK679586 displayed approximately linear pharmacokinetics ( based on AUC and C(max ) ) with limited accumulation upon repeat administration . In mild intermittent asthmatics , treatment with GSK679586 produced an increase in serum total IL-13 concentrations , indicative of GSK679586-IL-13 complex formation . Additionally , mean levels of exhaled nitric oxide ( FeNO ) , a marker of pulmonary inflammation , were reduced relative to baseline at 2.5 , 10 and 20 mg kg(-1 ) doses of GSK679586 at both 2 weeks ( 19 % , 44 % and 52 % decreases ) and 8 weeks ( 29 % , 55 % and 42 % decreases ) after the second infusion . GSK679586 was well tolerated ; the incidence of AEs was comparable across all presumed biologically active doses and there were no treatment-related SAEs . CONCLUSIONS GSK679586 demonstrated dose-dependent pharmacological activity in the lungs of mild intermittent asthmatics . These findings , together with the favourable safety profile and advantageous PK characteristics of a monoclonal antibody ( e.g. a long half-life supporting less frequent dosing ) , warrant further investigation of GSK679586 in a broader asthma patient population RATIONALE IL-4 and IL-13 share many biological functions important in the development of allergic airway inflammation and are implicated in the pathogenesis of asthma . AMG 317 is a fully human monoclonal antibody to IL-4Ralpha that blocks both IL-4 and IL-13 pathways . OBJECTIVES To evaluate efficacy and safety of AMG 317 in patients with moderate to severe asthma . METHODS In this phase 2 , r and omized , double-blind , placebo-controlled study , patients received weekly subcutaneous injections of  placebo or AMG 317 ( 75 - 300 mg ) for 12 weeks , followed by a 4-week follow-up period . The primary endpoint was change from baseline at Week 12 in Asthma Control Question naire ( ACQ ) symptom score . MEASUREMENTS AND MAIN RESULTS Mean ACQ change ( SE ) was -0.49 ( 0.09 ) in placebo ( n = 74 ) , and -0.43 ( 0.11 ) , -0.58 ( 0.12 ) , and -0.70 ( 0.09 ) in the AMG 317 75 mg ( n = 73 ) , 150 mg ( n = 73 ) , and 300 mg ( n = 74 ) groups , respectively ( treatment effect P = 0.25 ) . No statistically significant differences were observed in the secondary endpoints . Numerical decreases in number of and time to exacerbations were noted in patients receiving AMG 317 150 mg and 300 mg . Preplanned analyses by tertile of baseline ACQ revealed that patients with higher baseline ACQ scores ( > or=2.86 ) were more likely to respond to AMG 317 . Serious adverse events were reported in three patients , each noted as not related to study drug . CONCLUSIONS AMG 317 did not demonstrate clinical efficacy across the overall group of patients . Clinical ly significant improvements were observed in several outcome measures in patients with higher baseline ACQ scores . AMG 317 was safe and well tolerated in this study population . Clinical trial registered with www . clinical trials.gov ( NCT 00436670 ) BACKGROUND The Epidemiologic Study of Xolair ( omalizumab ) : Evaluating Clinical Effectiveness and Long-term Safety in Patients with Moderate-to-Severe Asthma ( EXCELS ) assessed the long-term safety of omalizumab in a clinical practice setting as part of a phase IV US Food and Drug Administration postmarketing commitment . OBJECTIVE We sought to evaluate long-term safety in  omalizumab-treated and nonomalizumab-treated patients . Primary outcome measures focused on assessment of malignancies . METHODS EXCELS was a prospect i ve observational cohort study in patients ( ≥12 years of age ) with moderate-to-severe allergic asthma . There were 2 cohorts : omalizumab ( taking omalizumab at baseline ) and nonomalizumab ( no history of omalizumab treatment ) . Primary outcomes included all confirmed , incident , study -emergent primary malignancies ( malignancies ) , including and excluding nonmelanoma skin cancer ( NMSC ) ; all malignancies were externally adjudicated . RESULTS The  omalizumab cohort had a higher proportion of patients with severe asthma compared with the nonomalizumab cohort ( 50.0 % vs 23.0 % ) .  Median follow-up was approximately 5 years for both cohorts . Crude malignancy rates were similar in the omalizumab and nonomalizumab cohorts , with a rate ratio of 0.84 ( 95 % CI , 0.62 - 1.13 ) for all malignancies and 0.98 ( 95 % CI , 0.71 - 1.36 ) for all malignancies excluding NMSC . Kaplan-Meier plots of time to first confirmed study -emergent primary malignancy were similar for the 2 treatment cohorts . Cox proportional hazards modeling , adjusting for confounders and risk factors , result ed in a hazard ratio  ( omalizumab vs nonomalizumab ) of 1.09 ( 95 % CI , 0.87 - 1.38 ) for all malignancies and 1.15 ( 95 % CI , 0.83 - 1.59 ) for all malignancies excluding NMSC . CONCLUSION Results from EXCELS suggest that omalizumab therapy is not associated with an increased risk of malignancy 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 clinical ly 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 population s , 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 BACKGROUND Data from early-stage studies suggested that interleukin (IL)-4 and IL-13 are requisite drivers of atopic dermatitis , evidence d by marked improvement after treatment with dupilumab , a fully-human monoclonal antibody that blocks both pathways . We aim ed to assess the efficacy and safety of several dose regimens of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments . METHODS In this r and omised , placebo-controlled , double-blind study , we enrolled patients aged 18 years or older who had an Eczema Area and Severity Index ( EASI ) score of 12 or higher at screening ( ≥16 at baseline ) and inadequate response to topical treatments from 91 study centres , including hospitals , clinics , and academic institutions , in Canada , Czech Republic , Germany , Hungary , Japan , Pol and , and the USA . Patients were r and omly assigned ( 1:1:1:1:1:1 ) , stratified by severity ( moderate or severe , as assessed by Investigator 's Global Assessment ) and region ( Japan vs rest of world ) to receive subcutaneous dupilumab : 300 mg once a week , 300 mg every 2 weeks , 200 mg every 2 weeks , 300 mg every 4 weeks , 100 mg every 4 weeks , or placebo once a week for 16 weeks . We used a central r and omisation scheme , provided by an interactive voice response system . Drug kits were coded , providing masking to treatment assignment , and allocation was concealed . Patients on treatment every 2 weeks and every 4 weeks received volume-matched placebo every week when dupilumab was not given to ensure double blinding . The primary outcome was efficacy  of dupilumab dose regimens based on EASI score least-squares mean percentage change ( SE ) from baseline to week 16 . Analyses included all r and omly assigned patients who received one or more doses of study drug . This trial is registered with Clinical Trials.gov , number NCT01859988 . FINDINGS Between May 15 , 2013 , and Jan 27 , 2014 , 452 patients were assessed for eligibility , and 380 patients were r and omly assigned . 379 patients received one or more doses of study drug ( 300 mg once a week [ n=63 ] , 300 mg every 2 weeks [ n=64 ] , 200 mg every 2 weeks [ n=61 ] , 300 mg every 4 weeks [ n=65 ] , 100 mg every 4 weeks [ n=65 ] ; placebo [ n=61 ] ) . EASI score improvements favoured all dupilumab regimens versus placebo ( p<0·0001 ) : 300 mg once a week ( -74 % [ SE 5·16 ] ) , 300 mg every 2 weeks ( -68 % [ 5·12 ] ) , 200 mg every 2 weeks ( -65 % [ 5·19 ] ) , 300 mg every 4 weeks ( -64 % [ 4·94 ] ) , 100 mg every 4 weeks ( -45 % [ 4·99 ] ) ; placebo ( -18 % [ 5·20 ] ) . 258 ( 81 % ) of 318 patients  given dupilumab and 49 ( 80 % ) of 61 patients  given placebo  reported treatment-emergent adverse events ; nasopharyngitis was the most frequent ( 28 % and 26 % , respectively ) . INTERPRETATION Dupilumab improved clinical responses in adults with moderate-to-severe atopic dermatitis in a dose-dependent manner , without significant safety concerns . Our findings show that IL-4 and IL-13 are key drivers of atopic dermatitis . FUNDING Sanofi and Regeneron Pharmaceuticals 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 BACKGROUND Asthma is a disease with marked heterogeneity in its clinical course and response to treatment . IL-13 is central to type 2 inflammation , which contributes to many key features of asthma . Lebrikizumab is an anti-IL-13 mAb previously reported to significantly improve lung function in patients with inadequately controlled asthma despite inhaled corticosteroid therapy , especially in periostin-high patients . OBJECTIVE This phase II study investigated the efficacy and safety of IL-13 blockade with different doses of lebrikizumab in asthmatic patients not receiving inhaled corticosteroids . METHODS Patients were r and omized to receive 125 , 250 , or 500 mg of lebrikizumab or placebo subcutaneously monthly for 12 weeks with an 8-week follow-up period . The primary efficacy end point was the relative change in prebronchodilator FEV1 from baseline to week 12 . RESULTS A total of 212 patients were r and omized . The mean relative change in FEV1 was numerically higher in all lebrikizumab dose groups versus the placebo group , although the difference was neither statistically nor clinical ly significant . There were no meaningful differences in changes in FEV1 between the dose groups and the placebo group by the periostin subgroup . Lebrikizumab treatment was associated with a reduced risk of treatment failure at all doses versus placebo ( P < .001 ) , and results were similar by the periostin subgroup , with no apparent differences between doses of lebrikizumab . Lebrikizumab was generally well tolerated . CONCLUSION Blocking IL-13 , a single cytokine , in this population of asthmatic patients is insufficient to improve lung function . There is evidence that IL-13 blockade may improve disease control , as measured by prevention of protocol -defined treatment failure in these patients IMPORTANCE Dupilumab has demonstrated efficacy in patients with asthma and atopic dermatitis , which are both type 2 helper T-cell-mediated diseases . OBJECTIVE To assess inhibition of interleukins 4 and 13 with dupilumab in patients with chronic sinusitis and nasal polyposis . DESIGN , SETTING , AND PARTICIPANTS A r and omized , double-blind , placebo-controlled parallel-group study conducted at 13 sites in the United States and Europe between August 2013 and August 2014 in 60 adults with chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids with 16 weeks of follow-up . INTERVENTIONS Subcutaneous dupilumab ( a 600 mg loading dose followed by 300 mg weekly ; n = 30 ) or placebo ( n = 30 ) plus mometasone furoate nasal spray for 16 weeks . MAIN OUTCOMES AND MEASURES Change in endoscopic nasal polyp score ( range , 0 - 8 ; higher scores indicate worse status ) at 16 weeks ( primary end point ) . Secondary end points included Lund-Mackay computed tomography ( CT ) score ( range , 0 - 24 ; higher scores indicate worse status ) , 22-item SinoNasal Outcome Test score ( range , 0 - 110 ; higher scores indicating worse quality of life ; minimal clinical ly important difference ≥8.90 ) , sense of smell assessed using the University of Pennsylvania Smell Identification Test ( UPSIT ) score ( range , 0 - 40 ; higher scores indicate better status ) , symptoms , and safety . RESULTS Among the 60 patients who were r and omized ( mean [ SD ] age , 48.4 years [ 9.4 years ] ; 34 men [ 56.7 % ] ; 35 with comorbid asthma ) , 51 completed the study . The least squares ( LS ) mean change in nasal polyp score was -0.3 ( 95 % CI , -1.0 to 0.4 ) with placebo and -1.9 ( 95 % CI , -2.5 to -1.2 ) with dupilumab ( LS mean difference , -1.6 [ 95 % CI , -2.4 to -0.7 ] ; P < .001 ) . The LS mean difference between the 2 groups for the Lund-Mackay CT total score was -8.8 ( 95 % CI , -11.1 to -6.6 ; P < .001 ) . Significant improvements with dupilumab were also observed for the 22-item SinoNasal Outcome Test ( LS mean difference between groups , -18.1 [ 95 % CI , -25.6 to -10.6 ] ; P < .001 ) and sense of smell assessed by UPSIT ( LS mean difference , 14.8 [ 95 % CI , 10.9 to 18.7 ] ; P < .001 ) . The most common adverse events were nasopharyngitis ( 33 % in the placebo group vs 47 % in the dupilumab group ) , injection site reactions ( 7 % vs 40 % , respectively ) , and headache ( 17 % vs 20 % ) . CONCLUSIONS AND RELEVANCE Among adults with symptomatic chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids , the addition of subcutaneous dupilumab to mometasone furoate nasal spray compared with mometasone alone  reduced endoscopic nasal polyp burden after 16 weeks . Further studies are needed to assess longer treatment duration , larger sample s , and direct comparison with other medications . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01920893 BACKGROUND Increases in T helper ( Th ) 2 cytokine concentrations have been seen in atopic asthma , with interleukin 4 and interleukin 13 thought to have a role in the physiological response to allergen challenge . Our aim was to assess the therapeutic effect of pitrakinra , an interleukin-4 variant that targets allergic Th2 inflammation by potently inhibiting the binding of interleukin 4 and interleukin 13 to interleukin-4Ralpha receptor complexes . METHODS In two independent r and omised , double-blind ,  placebo-controlled  , parallel group phase 2a clinical trials , patients with atopic asthma were treated with pitrakinra or placebo via two routes . In study 1 , patients were r and omly assigned to receive either 25 mg pitrakinra ( n=12 ) or placebo ( n=12 ) by subcutaneous injection once daily . In study 2 , patients were r and omly assigned to receive either 60 mg pitrakinra ( n=16 ) or placebo ( n=16 ) by nebulisation twice daily . Inhaled allergen challenge was done before and after 4 weeks of treatment . The primary endpoint for study 1 was maximum percentage decrease in forced expiratory volume in 1 s ( FEV1 ) over 4 - 10 h after allergen challenge , whereas that in study 2 was average percentage decrease in FEV(1 ) over 4 - 10 h after allergen challenge . All patients except those with baseline data only were included in our analyses . These trials are registered with Clinical Trials.gov , numbers NCT00535028 and NCT00535031 . FINDINGS No patients dropped out or were lost to follow-up in study 1 ; in study 2 , two patients in the placebo group and one in the pitrakinra  group dropped out or were lost to follow-up . These individuals had baseline data only , and were excluded from the analyses . In study 1 , there was a 17.1 % maximum percentage decrease in FEV1 in the pitrakinra group ; by contrast , the maximum decrease was 23.1 % in the placebo group ( difference 6 % , 95 % CI -4.37 to 16.32 ; p=0.243 ) . In study 2 , there was a 4.4 % average percentage decrease in FEV1 in the pitrakinra group ; by contrast , the average percentage decrease was 15.9 % in the placebo group ( 3.7 [ 95 % CI 2.08 - 6.25 ] times lower in the pitrakinra group ; p=0.0001 ) . There were fewer asthma-related adverse events ( p=0.069 ) and fewer adverse events requiring beta-agonist rescue ( p=0.031 ) after subcutaneous administration of pitrakinra than with placebo . There were too few asthma-related adverse events in study 2 to assess the effect of inhalation of pitrakinra on adverse events . INTERPRETATION Local treatment , targeted at inhibition of interleukins 4 and 13 in the lung , could substantially diminish the symptoms of asthma
Introduction Interleukin-13 and interleukin-4 are type-II cytokines signalling through the shared type II interleukin-4 receptor .
As a result of their structural similarity , interleukin-13 and interleukin-4 have overlapping functions in the mediation of type-II-driven diseases and are , therefore , promising targets of biologic drugs currently in development for the treatment of such diseases , including asthma and atopic dermatitis .
Objective This systematic review was conducted to assess pre clinical evidence of potential safety concerns related to blockade of interleukin-13 alone or interleukin-13 and interleukin-4 in combination .
Methods We specifically examined risks related to infection , malignancy and the cardiovascular system .
We systematic ally search ed the BIOSIS , MEDLINE and EMBASE data bases to identify pre clinical studies published between January 2006 and October 2016 that addressed the effects of interleukin-13/interleukin-4 blockade and modulation on the risk of infection , malignancy and cardiovascular events .