Phase 3 Study of Reslizumab in Patients With Poorly Controlled Asthma: Effects Across a Broad Range of Eosinophil Counts. Lebrikizumab treatment in adults with asthma. Predictors of enhanced response with benralizumab for patients with severe asthma: pooled analysis of the SIROCCO and CALIMA studies. Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial. Benralizumab for patients with mild to moderate, persistent asthma (BISE): a randomised, double-blind, placebo-controlled, phase 3 trial. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. A randomized, controlled trial to evaluate the effect of an anti-interleukin-9 monoclonal antibody in adults with uncontrolled asthma Effect of ligustrazine injection on levels of interleukin-4 and interferon-γ in patients with bronchial asthma 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. Daclizumab improves asthma control in patients with moderate to severe persistent asthma: a randomized, controlled trial. Mepolizumab treatment in patients with severe eosinophilic asthma. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Long-term Safety and Efficacy of Reslizumab in Patients with Eosinophilic Asthma. 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 Phase 2, randomised placebo-controlled trial to evaluate the efficacy and safety of an anti-GM-CSF antibody (KB003) in patients with inadequately controlled asthma Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Reslizumab for Inadequately Controlled Asthma With Elevated Blood Eosinophil Levels: A Randomized Phase 3 Study. Efficacy and safety of an anti-IL-13 mAb in patients with severe asthma: a randomized trial. A Phase 2a Study of Benralizumab for Patients with Eosinophilic Asthma in South Korea and Japan Safety and efficacy of an oral CCR3 antagonist in patients with asthma and eosinophilic bronchitis: a randomized, placebo‐controlled clinical trial Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial The prevalence of severe refractory asthma. A randomized trial of benralizumab, an antiinterleukin 5 receptor α monoclonal antibody, after acute asthma. Tralokinumab for severe, uncontrolled asthma (STRATOS 1 and STRATOS 2): two randomised, double-blind, placebo-controlled, phase 3 clinical trials. Effect of tralokinumab, an interleukin-13 neutralising monoclonal antibody, on eosinophilic airway inflammation in uncontrolled moderate-to-severe asthma (MESOS): a multicentre, double-blind, randomised, placebo-controlled phase 2 trial. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled 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. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. Dupilumab Efficacy and Safety in Moderate‐to‐Severe Uncontrolled Asthma
BACKGROUND IL-5 , a mediator of eosinophil activity , is an important potential treatment target in patients with uncontrolled asthma . The efficacy of reslizumab , a humanized anti-human IL-5 monoclonal antibody , has been characterized in patients with blood eosinophils ≥ 400 cells/μL. This study further characterizes the efficacy and safety of reslizumab in patients with poorly-controlled asthma , particularly those with eosinophils < 400 cells/μL. METHODS Patients were r and omly assigned to intravenous reslizumab 3.0 mg/kg or placebo once every 4 weeks for 16 weeks . The primary end point was the change in FEV1 from baseline to week 16 . Secondary measures included Asthma Control Question naire-7 ( ACQ-7 ) scores , use of short-acting β-agonists ( SABAs ) , and FVC . RESULTS Four hundred ninety-two patients received ≥ 1 dose of placebo ( n = 97 ) or reslizumab ( n = 395 ) . In the overall population , mean FEV1 change from baseline to week 16 was not significantly different between reslizumab and placebo , and no significant relationship was detected between treatment , baseline blood eosinophils and change in FEV1 . In the subgroup of patients with baseline eosinophils < 400 cells/μL , patients treated with reslizumab showed no significant improvement in FEV1 compared with those receiving placebo . In the subgroup with eosinophils ≥ 400 cells/μL , however , treatment with reslizumab was associated with much larger improvements in FEV1 , ACQ-7 , rescue SABA use , and FVC compared with the placebo group . Reslizumab was well tolerated , with fewer overall adverse events compared with placebo ( 55 % vs 73 % ) . CONCLUSIONS Reslizumab was well tolerated in patients with inadequately controlled asthma . Clinical ly meaningful effects on lung function and symptom control were not seen in patients unselected for baseline eosinophils . TRIAL REGISTRY Clinical Trials.gov ; No. : NCT01508936 ; URL : www . clinical trials.gov 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 Benralizumab is an anti-eosinophilic , anti-interleukin-5 receptor α monoclonal antibody that has been shown to significantly reduce asthma exacerbations and improve lung function for patients with severe , uncontrolled asthma . We further explored the efficacy of benralizumab for patients with different baseline blood eosinophil thresholds and exacerbation histories . METHODS This study is a pooled analysis of the results from the r and omised , double-blind , placebo-controlled SIROCCO ( NCT01928771 ) and CALIMA ( NCT01914757 ) phase 3 studies . In these studies , patients with severe , uncontrolled asthma were r and omly assigned ( 1:1:1 ) to receive subcutaneous benralizumab 30 mg , either every 4 weeks or every 8 weeks ( with first three doses given every 4 weeks ) , or placebo every 4 weeks . The primary endpoint was annual exacerbation rate ( AER ) ratio versus placebo , analysed by baseline eosinophil counts ( ≥0 , ≥150 , ≥300 , or ≥450 cells per μL ) and by number of exacerbations ( two vs three or more ) during the year before enrolment . The analyses were done in accordance with the intention-to-treat principle . FINDINGS Of 2295 patients , 756 received benralizumab every 4 weeks , 762 received benralizumab every 8 weeks , and 777 patients received placebo . AER among patients with baseline blood eosinophil counts of at least 0 cells per μL was 1·16 ( 95 % CI 1·05 - 1·28 ) in patients who received placebo versus 0·75 ( 0·66 - 0·84 ) in patients who received benralizumab every 8 weeks ( rate ratio 0·64 , 0·55 - 0·75 ; p<0·0001 ) . In patients who received benralizumab every 4 weeks who had eosinophil counts of 0 or more cells per μL , AER was 0·73 ( 0·65 - 0·82 ) ; rate ratio versus placebo was 0·63 ( 0·54 - 0·74 ; p<0·0001 ) . The extent to which exacerbation rates were reduced increased with increasing blood eosinophil thresholds and with greater exacerbation history in patients in the 4-weekly and 8-weekly benralizumab groups . Greater improvements in AER were seen with benralizumab compared with placebo for patients with a combination of high blood eosinophil thresholds and a history of more frequent exacerbations . INTERPRETATION These results will help to guide clinicians when they are deciding whether to use benralizumab to treat patients with severe , uncontrolled , eosinophilic asthma . FUNDING AstraZeneca BACKGROUND Mepolizumab , an anti-interleukin-5 monoclonal antibody approved as add-on therapy to st and ard of care for patients with severe eosinophilic asthma , has been shown in previous studies to reduce exacerbations and dependency on oral corticosteroids compared with placebo . We aim ed to further assess mepolizumab in patients with severe eosinophilic asthma by examining its effect on health-related quality of life ( HRQOL ) . METHODS We did a r and omised , double-blind , placebo-controlled , parallel-group , multicentre , phase 3b trial ( MUSCA ) in 146 hospitals or research centres in 19 countries worldwide . Eligible participants were patients aged 12 years or older with severe eosinophilic asthma and a history of at least two exacerbations requiring treatment in the previous 12 months before screening despite regular use of high-dose inhaled corticosteroids plus other controller medicines . Exclusion criteria included current smokers or former smokers with a history of at least ten pack-years . We r and omly assigned participants ( 1:1 ) by country to receive a subcutaneous injection of either mepolizumab 100 mg or placebo , plus st and ard of care , every 4 weeks for 24 weeks ( the final dose was given at week 20 ) . We did the r and omisation using an interactive voice response system and a central ised , computer-generated , permuted-block design of block size six . The two treatments were identical in appearance and administered in a masked manner ; patients , investigators , other site staff and the entire study team including those assessing outcomes data were also masked to group assignment . The primary endpoint was the mean change from baseline in the St George 's Respiratory Question naire ( SGRQ ) total score at week 24 in the modified intention-to-treat ( modified ITT ) population ( analysed according to their r and omly assigned treatment ) . Safety was assessed in all patients who received at least one dose of trial medication ( analysed according to the actual treatment received ) . This trial is registered with Clinical Trials.gov , number NCT02281318 . FINDINGS We recruited patients between Dec 11 , 2014 , and Nov 20 , 2015 , and the study was undertaken between Dec 11 , 2014 , and June 10 , 2016 . The modified ITT population comprised 274 patients assigned to mepolizumab 100 mg and 277 assigned to placebo . Mepolizumab versus placebo showed significant improvements at week 24 from baseline in SGRQ total score ( least squares mean [ SE ] change from baseline -15·6 ( 1·0 ) vs -7·9 ( 1·0 ) , a treatment difference of -7·7 ( 95 % CI -10·5 to -4·9 ; p<0·0001 ) . No deaths occurred during the study . 192 ( 70 % ) of 273 patients who received mepolizumab and 207 ( 74 % ) of 278 who received placebo reported at least one on-treatment adverse event , the most common of which were headache ( in 45 [ 16 % ] given mepolizumab vs 59 [ 21 % ] given placebo ) and nasopharyngitis ( in 31 [ 11 % ] given mepolizumab vs 46 [ 17 % ] given placebo ) . 15 ( 5 % ) and 22 ( 8 % ) patients had an on-treatment serious adverse event in the mepolizumab and placebo groups , respectively ; the most common was asthma in both groups ( in three [ 1 % ] given mepolizumab vs nine [ 3 % ] given placebo ) . INTERPRETATION Mepolizumab was associated with significant improvements in HRQOL in patients with severe eosinophilic asthma , and had a safety profile similar to that of placebo . These results add to and support the use of mepolizumab as a favourable add-on treatment option to st and ard of care in patients with severe eosinophilic asthma . FUNDING GlaxoSmithKline BACKGROUND Benralizumab is a humanised , anti-interleukin 5 receptor α monoclonal antibody that directly and rapidly depletes eosinophils , reduces asthma exacerbations , and improves lung function for patients with severe eosinophilic asthma . The objective of this trial was to assess the safety and efficacy of benralizumab for patients with mild to moderate , persistent asthma . METHODS In this r and omised , double-blind , placebo-controlled , phase 3 trial , we recruited patients aged 18 - 75 years , weighing at least 40 kg , and with a postbronchodilator reversibility in forced expiratory volume in 1 s ( FEV1 ) of at least 12 % at screening , from 52 clinical research centres in six countries . Patients must have been receiving either low- to medium-dosage inhaled corticosteroids ( ICS ) or low-dosage ICS plus long-acting β2 agonist fixed-combination therapy at screening , had a morning prebronchodilator FEV1 of more than 50 % to 90 % predicted at screening , and had one or more of the following symptoms within the 7 days before r and omisation : a daytime or night-time asthma symptom score of at least 1 for at least 2 days , rescue short-acting β2 agonist use for at least 2 days , or night-time awakenings due to asthma for at least one night . We converted patients ' ICS treatments to 180 μg or 200 μg budesonide dry powder inhaler twice daily for the entire duration of the study using the approved dosages in the patients ' respective countries and r and omly allocated them ( 1:1 ; stratified by blood eosinophil count [ < 300 cells per μL vs ≥300 cells per μL ] and region [ USA vs the rest of the world ] ) with an interactive web-based voice response system to receive subcutaneous placebo or benralizumab 30 mg injections every 4 weeks for 12 weeks . All patients and investigators involved in patient treatment or clinical assessment and those assessing outcomes were masked to treatment allocation . The primary endpoint was change from baseline prebronchodilator FEV1 at week 12 . Efficacy analyses used an intention to treat approach . This trial is registered with Clinical Trials.gov , number NCT02322775 . FINDINGS Between Feb 2 , 2015 , and April 24 , 2015 , we enrolled 351 patients , with 211 ( 60 % ) r and omly assigned ( 105 [ 50 % ] to placebo and 106 [ 50 % ] to benralizumab ) . Benralizumab result ed in an 80 mL ( 95 % CI 0 - 150 ; p=0·04 ) greater improvement ( least-squares mean difference ) in prebronchodilator FEV1 after 12 weeks than did placebo ( placebo group : 2246 mL [ SD 768 ] at baseline vs 2261 mL [ 796 ] at week 12 , change from baseline of 0 mL ; benralizumab group : 2248 mL [ 606 ] vs 2310 mL [ 670 ] , 70 mL ) . 44 ( 42 % ) patients in the benralizumab group had adverse events compared with 49 ( 47 % ) in the placebo group . The most common adverse events for both groups were nasopharyngitis ( eight [ 8 % ] patients in each group ) and upper respiratory tract infections ( five [ 5 % ] patients in each group ) . Serious adverse events occurred in two ( 2 % ) patients each in the benralizumab ( pancytopenia and a suicide attempt , both considered unrelated to treatment ) and placebo ( cervix carcinoma and colon adenoma ) groups . INTERPRETATION This study suggests that active and modifiable disease processes might be ongoing in patients with mild to moderate , persistent asthma receiving ICS . Although the lung function improvement observed does not warrant use of benralizumab in this population because it did not reach the minimum clinical ly important difference of 10 % , further studies to assess this finding should be considered . FUNDING AstraZeneca BACKGROUND Eosinophilic inflammation , which may be a consequence of interleukin-5 action , is a characteristic feature of some forms of asthma . However , in three previous clinical trials involving patients with asthma , blockade of this cytokine did not result in a significant improvement in outcomes . We studied the prednisone-sparing effect of mepolizumab , a monoclonal antibody against interleukin-5 , in a rare subgroup of patients who have sputum eosinophilia and airway symptoms despite continued treatment with prednisone . Secondary objectives were to examine its effect on the number of eosinophils in sputum and blood , symptoms , and airflow limitation . METHODS In this r and omized , double-blind , parallel-group trial involving patients with persistent sputum eosinophilia and symptoms despite prednisone treatment , we assigned 9 patients to receive mepolizumab ( administered in five monthly infusions of 750 mg each ) and 11 patients to receive  placebo . RESULTS There were 12 asthma exacerbations in 10 patients who received placebo , 9 of whom had sputum eosinophilia at the time of exacerbation . In comparison , only one patient who received mepolizumab had an asthma exacerbation , and this episode was not associated with sputum eosinophilia ( P=0.002 ) . Patients who received mepolizumab were able to reduce their prednisone dose by a mean ( + /-SD ) of 83.8+/-33.4 % of their maximum possible dose , as compared with 47.7+/-40.5 % in the placebo group ( P=0.04 ) . The use of mepolizumab was associated with a significant decrease in the number of sputum and blood eosinophils . Improvements in eosinophil numbers , asthma control , and forced expiratory volume in 1 second were maintained for 8 weeks after the last infusion . There were no serious adverse events . CONCLUSIONS Mepolizumab reduced the number of blood and sputum eosinophils and allowed prednisone sparing in patients who had asthma with sputum eosinophilia despite prednisone treatment . ( Clinical Trials.gov number , NCT00292877 . RATIONALE Eosinophilic asthma is a phenotype of asthma characterized by the persistence of eosinophils in the airways . IL-5 is involved in the activation and survival of eosinophils . OBJECTIVES To evaluate the effect of the antibody to IL-5 , reslizumab , in patients with eosinophilic asthma that is poorly controlled with high-dose inhaled corticosteroid . METHODS Patients were r and omly assigned to receive infusions of reslizumab at 3.0 mg/kg ( n = 53 ) or  placebo  ( n = 53 ) at baseline and at Weeks 4 , 8 , and 12 , with stratification by baseline Asthma Control Question naire ( ACQ ) score less than or equal to 2 or greater than 2 . The primary efficacy measure was the difference between the reslizumab and placebo groups in the change in ACQ score from baseline to end of therapy ( Week 15 or early withdrawal ) . MEASUREMENTS AND MAIN RESULTS Mean changes from baseline to end of therapy in ACQ score were -0.7 in the reslizumab group and -0.3 in the placebo group ( P = 0.054 ) and in FEV(1 ) were 0.18 and -0.08 L , respectively ( P = 0.002 ) . In those patients with nasal polyps , the changes in ACQ score were -1.0 and -0.1 , respectively ( P = 0.012 ) . Median percentage reductions from baseline in sputum eosinophils were 95.4 and 38.7 % , respectively ( P = 0.007 ) . Eight percent of patients in the reslizumab group and 19 % of patients in the placebo group had an asthma exacerbation ( P = 0.083 ) . The most common adverse events with reslizumab were nasopharyngitis , fatigue , and pharyngolaryngeal pain . CONCLUSIONS Patients receiving reslizumab showed significantly greater reductions in sputum eosinophils , improvements in airway function , and a trend toward greater asthma control than those receiving placebo . Reslizumab was generally well tolerated Background Pre clinical studies suggest that interleukin-9 may be a central mediator in the development and maintenance of airway inflammation in asthma . The aim of this study was therefore to evaluate the effects of MEDI-528 , an anti-interleukin-9 monoclonal antibody , in adults with confirmed uncontrolled moderate-to-severe asthma . Methods In this prospect i ve double-blind , multicenter , parallel-group study , 329 subjects were r and omized ( 1:1:1:1 ) to subcutaneous placebo or MEDI-528 ( 30 , 100 , 300 mg ) every 2 weeks for 24 weeks , in addition to their usual asthma medications . The primary endpoint was change in mean Asthma Control Question naire-6 ( ACQ-6 ) score at week 13 . Secondary endpoints included weighted asthma exacerbation rates and pre-bronchodilator forced expiratory volume in 1 second ( FEV1 ) at weeks 13 and 25 , as well as Asthma Quality of Life Question naire scores at weeks 12 and 25 and the safety of MEDI-528 throughout the study period . The primary endpoint was analyzed using analysis of covariance . Results The study population ( n = 327 ) was predominantly female ( 69 % ) with a mean age of 43 years ( range 18–65 ) . The mean ( SD ) baseline ACQ-6 score  for placebo ( n = 82 ) and combined MEDI-528 ( n = 245 ) was 2.8 ( 0.7 ) and 2.8 ( 0.8 ) ; FEV1 % predicted was 70.7 % ( 15.9 ) and 71.5 % ( 16.7 ) . Mean ( SD ) change from baseline to week 13 in ACQ-6 scores for placebo vs combined MEDI-528 groups was −1.2 ( 1.0 ) vs −1.2 ( 1.1 ) ( p = 0.86 ) . Asthma exacerbation rates ( 95 % CI ) at week 25 for placebo vs MEDI-528 were 0.58 ( 0.36–0.88 ) vs 0.49 ( 0.37–0.64 ) exacerbations/subject/year ( p = 0.52 ) . No significant improvements in FEV1 % predicted were observed between the placebo and MEDI-528 groups . Adverse events were comparable for placebo ( 82.9 % ) and MEDI-528 groups ( 30 mg , 76.5 % ; 100 mg , 81.9 % ; 300 mg , 85.2 % ) . The most frequent were asthma ( placebo vs MEDI-528 , 30.5 % vs 33.5 % ) , upper respiratory tract infection ( 14.6 % vs 17.1 % ) , and headache ( 9.8 % vs 9.8 % ) . Conclusions The addition of MEDI-528 to existing asthma controller medications was not associated with any improvement in ACQ-6 scores , asthma exacerbation rates , or FEV1 values , nor was it associated with any major safety concerns . Trial registration Clinical Trials.gov : NCT00968669 Objective To explore the effect of ligustrazine injection ( LI ) on serum levels of interleukin-4 ( IL-4 ) and interferon-γ ( IFN-γ ) in patients with bronchial asthma and determine the mechanism of action of LI in preventing and treating asthma . Methods Sixty-eight patients with mild or moderate bronchial asthma were assigned to two groups equally according to their sequence number , odd or even . The conventional treatment was administered to both groups , and LI was given to the treatment group by ultrasonic spray inhalation twice a day but not to the control group . The therapeutic course for all was 2 weeks . Further , 30 healthy subjects who had no history of smoking were enrolled as the normal control group .  The clinical condition scores , frequency of attacks and dosage of Terbutaline inhaled were scored and recorded on the first day of hospitalization ( before treatment ) and after treatment . At the same time , the indexes of lung function , including forced expiratory volume in one second ( FEV1 ) , forced expiratory volume in one second to forced vital capacity ratio ( FEV1 % ) and the peak expiratory flow ( PEF ) were determined before treatment . The levels of IL-4 and IFN-γ in peripheral blood were detected by ELISA before and after treatment , and compared with that of the healthy control group . Results After treatment , the clinical condition scores were found to be lower , indexes of lung function were elevated , but serum level of IL-4 and ratio of IL-4/IFN-γ were reduced in both groups , showing significant differences as compared to those before treatment ( P<0.05 ) . However , the changes in all the indexes were more significant in the treatment group than in the control group , also showing statistical significance ( P<0.05 ) . No significant difference was revealed when IFN-γ levels were compared before and after treatment in both groups , though a lowering trend could be seen , significant difference could not be found in the comparison of IFN-γ levels between groups after treatment ( P>0.05 ) . Conclusion LI shows good clinical effect in treating bronchial asthma , and its mechanism might be related to the suppression of the synthesis of IL-4 , thus leading to the inhibition of TH2 cell subset preponderant response and immune equilibrium regulation 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 RATIONALE Airway inflammation in asthma is associated with increased activated CD25(+ ) T cells , IL-2 , and soluble IL-2 receptors ( IL-2Rs ) . OBJECTIVES A r and omized , double-blinded , placebo-controlled study was used to evaluate the safety and efficacy of daclizumab , a humanized IgG1 monoclonal antibody against the IL-2R alpha chain ( CD25 ) of activated lymphocytes , in adults with moderate to severe persistent asthma . METHODS Patients with obstructive pulmonary functions , despite inhaled corticosteroids ( ICS ) , were switched to equivalent dose inhaled triamcinolone acetate acetonide ( TAA ) .  Patients dependent on ICS were r and omized ( 3:1 ) to daclizumab ( intravenous loading dose , 2 mg/kg , then 1 mg/kg ) or placebo every 2 weeks , added to stable-dose TAA through Week 12 ( Treatment Period 1 ) . Over Weeks 12 - 20 ( Treatment Period 2 ) , patients tapered TAA while on the study drug , and were followed for 16 weeks off the study drug . MEASUREMENTS AND MAIN RESULTS Among 115 evaluable patients ( 88 daclizumab , 27 placebo ) , groups had similar age , disease duration , and length of ICS use .  During Treatment Period 1 , daclizumab improved FEV(1 )  ( daclizumab , 4.4 + /- 1.80 % vs. placebo , 1.5 + /- 2.39 % ; P = 0.05 ) , and reduced daytime asthma symptoms ( P = 0.018 ) and short-acting inhaled beta(2)-agonist use ( P = 0.009 ) . Daclizumab treatment prolonged time to exacerbation ( P = 0.024 ) . Adverse events were evenly distributed between groups , although there were more serious adverse events in the patients treated with daclizumab . CONCLUSIONS Daclizumab improved pulmonary function and asthma control in patients with moderate to severe chronic asthma inadequately controlled on ICS . The mechanism of action likely involves inhibition of proinflammatory cytokine generation by IL-2R blockade in activated T cells . Clinical trial registered with www . clinical trials.gov ( NCT00028288 ) BACKGROUND Some patients with severe asthma have frequent exacerbations associated with persistent eosinophilic inflammation despite continuous treatment with high-dose inhaled glucocorticoids with or without oral glucocorticoids . METHODS In this r and omized , double-blind , double-dummy study , we assigned 576 patients with recurrent asthma exacerbations and evidence of eosinophilic inflammation despite high doses of inhaled glucocorticoids to one of three study groups . Patients were assigned to receive mepolizumab , a humanized monoclonal antibody against interleukin-5 , which was administered as either a 75-mg intravenous dose or a 100-mg subcutaneous dose , or placebo every 4 weeks for 32 weeks . The primary outcome was the rate of exacerbations . Other outcomes included the forced expiratory volume in 1 second ( FEV1 ) and scores on the St. George 's Respiratory Question naire ( SGRQ ) and the 5-item Asthma Control Question naire ( ACQ-5 ) . Safety was also assessed . RESULTS The rate of exacerbations was reduced by 47 % ( 95 % confidence interval [ CI ] , 29 to 61 ) among patients receiving intravenous mepolizumab and by 53 % ( 95 % CI , 37 to 65 ) among those receiving subcutaneous mepolizumab , as compared with those receiving placebo ( P<0.001 for both comparisons ) . Exacerbations necessitating an emergency department visit or hospitalization were reduced by 32 % in the group receiving intravenous mepolizumab and by 61 % in the group receiving subcutaneous mepolizumab . At week 32 , the mean increase from baseline in FEV1 was 100 ml greater in patients receiving intravenous mepolizumab than in those receiving placebo ( P=0.02 ) and 98 ml greater in patients receiving subcutaneous mepolizumab than in those receiving placebo ( P=0.03 ) . The improvement from baseline in the SGRQ score was 6.4 points and 7.0 points greater in the intravenous and subcutaneous mepolizumab groups , respectively , than in the placebo group ( minimal clinical ly important change , 4 points ) , and the improvement in the ACQ-5 score was 0.42 points and 0.44 points greater in the two mepolizumab groups , respectively , than in the placebo group ( minimal clinical ly important change , 0.5 points ) ( P<0.001 for all comparisons ) . The safety profile of mepolizumab was similar to that of placebo . CONCLUSIONS Mepolizumab administered either intravenously or subcutaneously significantly reduced asthma exacerbations and was associated with improvements in markers of asthma control . ( Funded by GlaxoSmithKline ; MENSA Clinical Trials.gov number , NCT01691521 . ) RATIONALE Accumulation of eosinophils in the bronchial mucosa of individuals with asthma is considered to be a central event in the pathogenesis of asthma . In animal models , airway eosinophil recruitment and airway hyperresponsiveness in response to allergen challenge are reduced by specific targeting of interleukin-5 . A previous small dose-finding study found that mepolizumab , a humanized anti-interleukin-5 monoclonal antibody , had no effect on allergen challenge in humans . OBJECTIVES To investigate the effect of three intravenous infusions of mepolizumab , 250 or 750 mg at monthly intervals , on clinical outcome measures in 362 patients with asthma experiencing persistent symptoms despite inhaled corticosteroid therapy ( 400 - 1,000 mug of beclomethasone or equivalent ) . METHODS Multicenter , r and omized , double-blind , placebo-controlled study . MEASUREMENTS AND MAIN RESULTS Morning peak expiratory flow , forced expiratory volume in 1 second , daily beta(2)-agonist use , symptom scores , exacerbation rates , and quality of life measures . Sputum eosinophil levels were also measured in a subgroup of 37 individuals . Mepolizumab was associated with a significant reduction in blood and sputum eosinophils in both treatment groups ( blood , P < 0.001 for both doses ; sputum , P = 0.006 for 250 mg and P = 0.004 for 750 mg ) . There were no statistically significant changes in any of the clinical end points measured . There was a nonsignificant trend for decrease in exacerbation rates in the mepolizumab 750-mg treatment group ( P = 0.065 ) . CONCLUSIONS Mepolizumab treatment does not appear to add significant clinical benefit in patients with asthma with persistent symptoms despite inhaled corticosteroid therapy . Further studies are needed to investigate the effect of mepolizumab on exacerbation rates , using protocol s specifically tailored to patients with asthma with persistent airway eosinophilia BACKGROUND In placebo-controlled trials , reslizumab , an anti-IL-5 monoclonal antibody , significantly reduced asthma exacerbations and improved lung function and asthma control in patients with eosinophilic asthma . OBJECTIVE This open-label extension study evaluated safety and efficacy of reslizumab for up to 24 months . METHODS After participation in 1 of 3 placebo-controlled , phase III trials in moderate-to-severe eosinophilic asthma , patients received reslizumab 3.0 mg/kg intravenously every 4 weeks for up to 24 months . Adverse events ( AEs ) , lung function , and patient-reported asthma control were evaluated . RESULTS In the open-label extension , 1,051 patients received ≥1 reslizumab dose ( 480 reslizumab-naïve , 571 reslizumab-experienced ) ; median ( range ) exposure was 319 ( 36 - 840 ) and 343 ( 36 - 863 ) days in reslizumab-naïve and reslizumab-experienced patients , respectively . Continuous exposure , including during the placebo-controlled studies , was ≥12 months for 740 patients and ≥24 months for 249 patients . The most common AEs were worsening of asthma and nasopharyngitis . Serious AEs affected 78 of 1,051 ( 7 % ) patients ; 18 of 1,051 ( 2 % ) discontinued treatment because of AEs ; and there were 3 deaths ( all non-treatment-related ) . Fifteen adult patients ( 15 of 1,023 ; 1 % ) had malignancies of diverse tissue types . Reslizumab-experienced patients maintained improved lung function and asthma control ; reslizumab-naïve patients had improvements in these measures throughout open-label treatment . Blood eosinophil counts appeared to be returning to baseline after reslizumab discontinuation . CONCLUSIONS In patients with moderate-to-severe eosinophilic asthma , intravenous reslizumab 3.0 mg/kg displays favorable long-term safety and sustained long-term efficacy . Initial improvements in lung function and asthma control were maintained for up to 2 years . These findings substantially add to our underst and ing of the long-term safety and efficacy of anti-IL-5 strategies 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 Objectives We wished to evaluate the effects of an antigranulocyte-macrophage colony-stimulating factor monoclonal antibody ( KB003 ) on forced expiratory volume in 1 s ( FEV1 ) , asthma control and asthma exacerbations in adult asthmatics inadequately controlled by long-acting bronchodilators and inhaled/oral corticosteroids . Setting s 47 ambulatory asthma care centres globally . Primary outcome measures Change in FEV1 at week 24 . Participants 311 were screened , 160 were r and omised and 129 completed the study . Interventions 7 intravenous infusions of either 400 mg KB003 or placebo at baseline and weeks 2 , 4 , 8 , 12 , 16 and 20 . Primary and secondary outcome measures FEV1 at week 24 , asthma control , exacerbation rates and safety in all participants as well as prespecified subgroups . Main results In the KB003 treated group , FEV1 at week 24 improved to 118 mL compared with 54 mL in the placebo group ( p=0.224 ) . However , FEV1 improved to 253 vs 26 mL at week 24 ( p=0.02 ) in eosinophilic asthmatics ( defined as > 300 peripheral blood eosinophils/mL at baseline ) and comparable improvements were seen at weeks 20 ( p=0.034 ) and 24 ( p=0.077 ) in patients with FEV1 reversibility ≥20 % at baseline and at weeks 4 ( p=0.029 ) , 16 ( p=0.018 ) and 20 ( p=0.006 ) in patients with prebronchodilator FEV1 ≤50 % predicted at baseline . There were no effects on asthma control or exacerbation rates . The most frequent adverse events in the KB003 group were rhinosinusitis and headache . There was no significant difference in antidrug antibody response between placebo and treated groups . There were no excess infections or changes in biomarkers known to be associated with the development of pulmonary alveolar proteinosis . Conclusions Higher doses and /or further asthma phenotyping may be required in future studies with KB003 . Trial registration number NCT01603277 ; Results BACKGROUND Persistent eosinophilic airway inflammation in asthma increases the risk of exacerbations . In a phase 2b dose-ranging study , we aim ed to assess the efficacy and safety of benralizumab , an anti-interleukin 5 receptor α monoclonal antibody that depletes blood and airway eosinophils , in adults with uncontrolled eosinophilic asthma . METHODS We did a r and omised , controlled , double-blind , dose-ranging phase 2b study . Eligible participants were adults aged 18 - 75 years with uncontrolled asthma using medium-dose or high-dose inhaled corticosteroids and longacting β agonists , with two to six exacerbations in the past year . Current or former smokers were excluded . We used the ELEN index ( an algorithm to predict elevated sputum eosinophils ) or baseline fraction of exhaled nitric  oxide to stratify patients by eosinophilic status , and with an interactive web-voice response system r and omly assigned eosinophilic individuals in a 1:1:1:1 ratio to receive placebo , 2 mg benralizumab , 20 mg benralizumab , or 100 mg benralizumab , and non-eosinophilic individuals in a 1:1 ratio to receive placebo or 100 mg benralizumab . Study drugs were given as two subcutaneous injections every 4 weeks for the first three doses , then every 8 weeks , for 1 year . Patients , treating physicians , and study investigators were masked to treatment allocation . The primary endpoint was annual exacerbation rate in eosinophilic individuals after 1 year of follow-up . Analysis was by modified intention to treat . This study was design ed with a two-sided α of 0·2 and powered at 78 % for the primary outcome in the eosinophilic population . This study is registered with Clinical Trials.gov , number NCT01238861 . FINDINGS Between Jan 3 , 2011 , and March 6 , 2012 , we r and omly assigned 324 eosinophilic individuals  to placebo ( n=80 ) or benralizumab 2 mg dose ( n=81 ) , 20 mg dose , ( n=81 ) , or 100 mg dose ( n=82 ) , and 285 non-eosinophilic individuals to 100 mg benralizumab ( n=142 , 140 included in analysis ) or placebo ( n=143 , 142 included in analysis ) . In eosinophilic individuals ,  benralizumab reduced exacerbation rates compared with placebo in the 100 mg group ( 0·34 vs 0·57 , reduction 41 % , 80 % CI 11 to 60 , p=0·096 ) but not in the 2 mg group ( 0·65 vs 0·57 , difference -9 % , 80 % CI -59 to 26 , p=0·781 ) or the 20 mg group ( 0·37 vs 0·57 , reduction 36 % , 80 % CI 3 to 58 , p=0·173 ) . In patients with a baseline blood eosinophil cutoff of at least 300 cells per μL , exacerbation rates in the benralizumab 20 mg group ( n=70 ) and 100 mg group ( n=97 ) were lower than in the placebo group ( n=83 ; 0·30 vs 0·68 , reduction 57 % , 80 % CI 33 to 72 , p=0·015 for 20 mg dose ; 0·38 vs 0·68 , difference 43 % , 80 % CI 18 to 60 , p=0·049 for 100 mg dose ) . Our findings suggested that benralizumab 20 mg and 100 mg resided at the dose-response plateau . Treatment-emergent adverse events occurred in 277 ( 72 % ) of 385 participants receiving any benralizumab dose compared with 143 ( 65 % ) of 221 receiving  placebo . Nasopharyngitis ( 44 [ 11 % ] patients receiving benralizumab vs 13 [ 6 % ] patients receiving placebo ) and injection site reactions ( 60 [ 16 % ] vs eight [ 4 % ] ) occurred more frequently with benralizumab than with placebo . INTERPRETATION Benralizumab at 20 mg and 100 mg doses seemed to reduce asthma exacerbations in adults with uncontrolled eosinophilic asthma and baseline blood eosinophils of at least 300 cells per μL , possibly due to targeting of the interleukin 5 receptor rather than interleukin 5 lig and . Further investigation of benralizumab treatment in phase 3 studies is warranted . FUNDING MedImmune BACKGROUND This phase 3 study further characterizes the efficacy and safety of reslizumab ( a humanized anti-IL-5 monoclonal antibody ) in patients aged 12 to 75 years with asthma inadequately controlled by at least a medium-dose inhaled corticosteroid and with a blood eosinophil count ≥ 400 cells/μL. METHODS Patients were r and omized to receive reslizumab 0.3 or 3.0 mg/kg or placebo administered once every 4 weeks for 16 weeks ( total four doses ) . The primary end point was change from baseline in pre-bronchodilator FEV1 over 16 weeks . Secondary end points included FVC , forced expiratory flow at 25 % to 75 % of FVC ( FEF25%-75 % ) , patient-reported control of asthma symptoms , short-acting β-agonist ( SABA ) use , blood eosinophil levels , and safety . RESULTS Reslizumab significantly improved FEV1 ( difference vs placebo [ reslizumab 0.3 and 3.0 mg/kg ] , 115 mL [ 95 % CI , 16 - 215 ; P = .0237 ] and 160 mL [ 95 % CI , 60 - 259 ; P = .0018 ] ) . Clinical ly meaningful increases in FVC ( 130 mL ) and FEF25%-75 % ( 233 mL/s ) were observed with reslizumab 3.0 mg/kg . Reslizumab improved scores on the Asthma Control Question naire ( ACQ ) and Asthma Quality of Life Question naire ( AQLQ ) vs placebo ( greater effects seen with 3.0 mg/kg ; P < .05 ) . The minimally important difference was reached for the AQLQ  ( reslizumab 3.0 mg/kg ) but not on the ACQ . Scores on the Asthma Symptom Utility Index and SABA use were improved with reslizumab . The most common adverse events were worsening of asthma , headache , and nasopharyngitis ; most events were mild to moderate in severity . CONCLUSIONS Reslizumab improved lung function , asthma control and symptoms , and quality of life . It was well tolerated in patients with inadequately controlled asthma ( despite st and ard therapy ) and elevated blood eosinophil levels . Overall , the 3.0-mg/kg dose of reslizumab provided greater improvements in asthma outcomes vs the 0.3-mg/kg dose , with comparable safety . TRIAL REGISTRY Clinical Trials.gov ; No. : NCT01270464 ; URL : www . clinical trials.gov 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 Background : Airway eosinophils are considered to play an important role in the pathogenesis of asthma . Interleukin-5 is believed to be a key cytokine for the development , proliferation and activation of eosinophils . Benralizumab is an anti-interleukin-5 receptor α monoclonal antibody that depletes blood and airway eosinophils . We conducted a phase 2a study in South Korea and Japan to evaluate the effect of benralizumab in an East Asian population . The primary objective was to evaluate the effect of benralizumab in adults with uncontrolled eosinophilic asthma with 2 - 6 incidences of exacerbations in the past year using a medium/high dose of inhaled corticosteroids and long-acting β2-agonists . Methods : This was a multicenter , r and omized , double-blind , placebo-controlled study . The subjects ( n = 106 ) were r and omized into four groups : placebo ( n = 27 ) or benralizumab 2 mg ( n = 27 ) , 20 mg ( n = 26 ) and 100 mg ( n = 26 ) . Benralizumab or placebo were administered subcutaneously on weeks 0 ( day 1 ) , 4 , 8 , 16 , 24 , 32 and 40 . The primary endpoint was the asthma exacerbation rate at week 52 . Results : The asthma exacerbation rate was reduced by 33 , 45 or 36 % versus the placebo group when treated with 2 , 20 or 100 mg of benralizumab , respectively . The percent mean change in forced expiratory volume at 1 s increased with each of the three doses in subjects treated with benralizumab . Conclusions : Benralizumab reduced asthma exacerbation and improved lung function and asthma control in adults with uncontrolled eosinophilic asthma Several chemokines , notably eotaxin , mediate the recruitment of eosinophils into tissues via the CCR3 receptor . BACKGROUND Elevated numbers of blood eosinophils are a risk factor for asthma exacerbations . Reslizumab is a humanised anti-interleukin 5 monoclonal antibody that disrupts eosinophil maturation and promotes programmed cell death . We aim ed to assess the efficacy and safety of reslizumab in patients with inadequately controlled , moderate-to-severe asthma . METHODS We did two duplicate , multicentre , double-blind , parallel-group , r and omised , placebo-controlled phase 3 trials . Both trials enrolled patients with asthma aged 12 - 75 years ( from 128 clinical research centres in study 1 and 104 centres in study 2 ) from Asia , Australia , North America , South America , South Africa , and Europe , whose asthma was inadequately controlled by medium-to-high doses of inhaled corticosteroid based therapy and who had blood eosinophils of 400 cells per μL or higher and one or more exacerbations in the previous year . Patients were r and omly assigned ( 1:1 ) to receive either intravenous reslizumab ( 3·0 mg/kg ) or placebo every 4 weeks for 1 year by computerised central r and omisation . Patients and investigators were masked to treatment assignment during the study . Each patient received a specific volume of study drug ( reslizumab or matching placebo ) on the basis of the patient 's body weight and r and omly assigned treatment group . Additionally , the sponsor 's clinical personnel involved in the study were masked to the study drug identity until the data base was locked for analysis and the treatment assignment revealed . The primary outcome was the annual frequency of clinical asthma exacerbations and was analysed by intention to treat . We assessed safety outcomes in the patients who had received one or more dose of the drug . The trials have been completed and are registered with Clinical Trials.gov , numbers NCT01287039 ( study 1 ) and NCT01285323 ( study 2 ) . FINDINGS Study 1 was done between April 12 , 2011 , and March 3 , 2014 and study 2 between March 22 , 2011 , and April 9 , 2014 . Of 2597 patients screened , 953 were r and omly assigned to receive either reslizumab ( n=477 [ 245 in study 1 and 232 in study 2 ] ) or placebo ( n=476 [ 244 and 232 ] ) . In both studies , patients receiving reslizumab had a significant reduction in the frequency of asthma exacerbations ( study 1 : rate ratio [ RR ] 0·50 [ 95 % CI 0·37 - 0·67 ] ; study 2 : 0·41 [ 0·28 - 0·59 ] ; both p<0·0001 ) compared with those receiving placebo . Common adverse events on reslizumab were similar to placebo . The most common adverse events were worsening asthma symptoms ( 127 [ 52 % ] for placebo and 97 [ 40 % ] for reslizumab in study 1 ; 119 [ 51 % ] for placebo and 67 [ 29 % ] for reslizumab for study 2 ) , upper respiratory tract infections ( 32 [ 13 % ] and 39 [ 16 % ] ; 16 [ 7 % ] and eight [ 3 % ] ) , and nasopharyngitis ( 33 [ 14 % ] and 28 [ 11 % ] ; 56 [ 24 % ] and 45 [ 19 % ] ) . Two patients in the reslizumab group had anaphylactic reactions ; both responded to st and ard treatment at the study centre and resolved , and the patients were withdrawn from the study . INTERPRETATION These results support the use of reslizumab in patients with asthma and elevated blood eosinophil counts who are inadequately controlled on inhaled corticosteroid-based therapy . FUNDING Teva Br and ed Pharmaceutical Products BACKGROUND Benralizumab is a humanised , afucosylated , anti-interleukin-5 receptor α monoclonal antibody that induces direct , rapid , and nearly complete depletion of eosinophils . We aim ed to assess the efficacy and safety of benralizumab as add-on therapy for patients with severe , uncontrolled asthma and elevated blood eosinophil counts . METHODS In this r and omised , double-blind , parallel-group , placebo-controlled , phase 3 study ( CALIMA ) undertaken at 303 sites in 11 countries , we enrolled patients aged 12 - 75 years with severe asthma uncontrolled by medium-dosage to high-dosage inhaled corticosteroids plus long-acting β₂-agonists ( ICS plus LABA ) and a history of two or more exacerbations in the previous year . Patients were r and omly assigned ( 1:1:1 ) to receive 56 weeks of benralizumab 30 mg every 4 weeks ( Q4W ) , benralizumab 30 mg every 8 weeks ( Q8W ; first three doses 4 weeks apart ) , or placebo ( all subcutaneous injection ) . Patients were stratified ( 2:1 ) by baseline blood eosinophil counts 300 cells per μL or greater and less than 300 cells per μL , respectively . Patients and study centre staff were masked to treatment allocation . The primary endpoint was annual exacerbation rate ratio versus placebo for patients receiving high-dosage ICS plus LABA with baseline blood eosinophils 300 cells per μL or greater ( intention-to-treat analysis ) . Key secondary endpoints were pre-bronchodilator forced expiratory volume in 1 s ( FEV1 ) and total asthma symptom score . This study is registered with Clinical Trials.gov , number NCT01914757 . FINDINGS Between Aug 21 , 2013 , and March 16 , 2015 , 2505 patients were enrolled , of whom 1306 patients were r and omised ; 425 patients were r and omly assigned to and received benralizumab 30 mg Q4W , 441 to benralizumab 30 mg Q8W , and 440  to  placebo . 728 patients were included in the primary analysis population . Benralizumab result ed in significantly lower annual exacerbation rates with the Q4W regimen ( rate 0·60 [ 95 % CI 0·48 - 0·74 ] , rate ratio 0·64 [ 95 % CI 0·49 - 0·85 ] , p=0·0018 , n=241 ) and Q8W regimen ( rate 0·66 [ 95 % CI 0·54 - 0·82 ] , rate ratio 0·72 [ 95 % CI 0·54 - 0·95 ] , p=0·0188 , n=239 ) compared with placebo ( rate 0·93 [ 95 % CI 0·77 - 1·12 ] , n=248 ) . Benralizumab also significantly improved pre-bronchodilator FEV1 ( Q4W and Q8W ) and total asthma symptom score ( Q8W only ) in these patients . The most common adverse events were nasopharyngitis ( 90 [ 21 % ] in the Q4W group , 79 [ 18 % ] in the Q8W group , and 92 [ 21 % ] in the placebo group ) and worsening asthma ( 61 [ 14 % ] in the Q4W group , 47 [ 11 % ] in the Q8W group , and 68 [ 15 % ] in the group ) . INTERPRETATION Benralizumab significantly reduced annual exacerbation rates and was generally well tolerated for patients with severe , uncontrolled asthma with blood eosinophils 300 cells per μL or greater . Our data further refine the patient population likely to receive the greatest benefit from benralizumab treatment . FUNDING AstraZeneca and Kyowa Hakko Kirin BACKGROUND Severe asthma is characterized by difficulty to achieve disease control despite high-intensity treatment . However , prevalence figures of severe asthma are lacking , whereas longst and ing estimates vary between 5 % and 10 % of all asthmatic patients . Knowing the exact prevalence of severe refractory asthma as opposed to difficult-to-control asthma is important for clinical decision making , drug development , and reimbursement policies by health authorities . OBJECTIVE We sought to estimate the prevalence of severe refractory asthma as defined by the Innovative Medicine Initiative consensus . METHODS Adult patients with a prescription for high-intensity treatment ( high-dose inhaled corticosteroids and long-acting β2-agonists or medium- to high-dose inhaled corticosteroids combined with oral corticosteroids and long-acting β2-agonists ) were extracted from 65 Dutch pharmacy data bases , representing 3 % of the population ( 500,500 inhabitants ) . Question naires were sent to 5,002 patients , of which 2,312 were analyzed . The diagnosis of asthma and degree of asthma control were derived from question naires to identify patients with difficult-to-control asthma . Inhalation technique was assessed in a r and om sample of 60 adherent patients ( prescription filling , ≥80 % ) . Patients with difficult-to-control asthma , adherence to treatment , and a correct inhalation technique were qualified as having severe refractory asthma . Results were mirrored to the Dutch population . RESULTS Of asthmatic adults , 3.6 % ( 95 % CI , 3.0 % to 4.1 % ) qualified for a diagnosis of severe refractory asthma , representing 10.4 patients per 10,000 inhabitants . CONCLUSION The prevalence of severe refractory asthma might be lower than estimated by expert opinion . This implies that currently recognized severe asthma subphenotypes could meet the criteria of rare diseases BACKGROUND Patients with frequent asthma exacerbations result ing in emergency department ( ED ) visits are at increased risk for future exacerbations . We examined the ability of 1 dose of benralizumab , an investigational antiinterleukin 5 receptor α monoclonal antibody , to reduce recurrence after acute asthma exacerbations . METHODS In this r and omized , double-blind , placebo-controlled study , eligible subjects presented to the ED with an asthma exacerbation , had partial response to treatment , and greater than or equal to 1 additional exacerbation within the previous year . Subjects received 1 intravenous infusion of placebo ( n = 38 ) or benralizumab ( 0.3 mg/kg , n = 36 or 1.0 mg/kg , n = 36 ) added to outpatient management . The primary outcome was the proportion of subjects with greater than or equal to 1 exacerbation at 12 weeks in placebo vs the combined benralizumab groups . Other outcomes included the time-weighted rate of exacerbations at week 12 , adverse events , blood eosinophil counts , asthma symptom changes , and health care re source utilization . RESULTS The proportion of subjects with greater than or equal to 1 asthma exacerbation at 12 weeks was not different between placebo and the combined benralizumab groups ( 38.9 % vs 33.3 % ; P = .67 ) . However , compared with placebo , benralizumab reduced asthma exacerbation rates by 49 % ( 3.59 vs 1.82 ; P = .01 ) and exacerbations result ing in hospitalization by 60 % ( 1.62 vs 0.65 ; P = .02 ) in the combined groups . Benralizumab reduced blood eosinophil counts but did not affect other outcomes , while demonstrating an acceptable safety profile . CONCLUSIONS When added to usual care , 1 dose of benralizumab reduced the rate and severity of exacerbations experienced over 12 weeks by subjects who presented to the ED with acute asthma BACKGROUND Tralokinumab is an anti-interleukin-13 human monoclonal antibody developed for the treatment of severe , uncontrolled asthma . These clinical trials aim ed to assess the efficacy and safety of tralokinumab in this population . METHODS STRATOS 1 and STRATOS 2 were r and omised , double-blind , parallel-group , placebo-controlled , phase 3 clinical trials that enrolled participants aged 12 - 75 years with severe asthma that was inadequately controlled despite use of inhaled corticosteroids ( ≥500 μg per day fluticasone or equivalent ) and a long-acting β2 agonist ( but not oral corticosteroids ) . STRATOS 1 was done at 246 sites in 14 countries , and STRATOS 2 was done at 242 sites in 13 countries . In STRATOS 1 , participants were r and omly assigned ( 2:1 ) to receive tralokinumab 300 mg or matching placebo subcutaneously every 2 weeks or every 4 weeks for 52 weeks . In STRATOS 2 , participants were r and omly assigned ( 1:1 ) to receive tralokinumab 300 mg or matching placebo subcutaneously every 2 weeks for 52 weeks . STRATOS 1 attempted to identify a biomarker-positive population with enhanced tralokinumab benefit , which was then tested in STRATOS 2 . The primary endpoint was the annualised asthma exacerbation rate ( AAER ) reduction at week 52 in the all-comers population for STRATOS 1 and in the biomarker-positive population for STRATOS 2 . All efficacy analyses for both trials were done on the full analysis set by an intention-to-treat approach . The safety analysis set comprised any participant who received the investigational drug and was categorised by treatment received . These trials are registered with Clinical Trials.gov , numbers NCT02161757 ( STRATOS 1 ) and NCT02194699 ( STRATOS 2 ) , and with the EU Clinical Trials Register , EudraCT 2013 - 005614 - 35 ( STRATOS 1 ) and EudraCT 2013 - 005615 - 27 ( STRATOS 2 ) . FINDINGS STRATOS 1 was done between June 13 , 2014 , and Feb 28 , 2017 . 1207 participants were r and omly assigned and 1202 treated as follows : tralokinumab every 2 weeks ( n=398 ) , tralokinumab every 4 weeks ( n=404 ) , or placebo ( n=400 ) . STRATOS 2 was done between Oct 30 , 2014 , and Sept 21 , 2017 . 856 participants were r and omly assigned and 849 treated as follows : tralokinumab every 2 weeks ( n=427 ) and placebo every 2 weeks ( n=422 ) . In the STRATOS 1 all-comers population , tralokinumab every 2 weeks did not significantly reduce AAER compared with placebo ( 7·0 % reduction [ 95 % CI -20·8 to 28·4 ] ; rate ratio 0·93 [ 95 % CI 0·72 to 1·21 ] ; p=0·59 ) . Baseline fractional exhaled nitric oxide ( FENO ) 37 ppb or greater was identified as the preferred biomarker in STRATOS 1 ; in FENO-high participants , tralokinumab every 2 weeks ( n=97 ) reduced AAER by 44·0 % ( 95 % CI 6·0 to 66·0 ; rate ratio 0·56 [ 95 % CI 0·34 to 0·94 ] ; p=0·028 ) compared with placebo ( n=102 ) . In the STRATOS 2 FENO-high population , tralokinumab every 2 weeks ( n=108 ) did not significantly improve AAER ( 15·8 % reduction [ 95 % CI -33·7 to 47·0 ] ; rate ratio 0·84 [ 95 % CI 0·53 to 1·34 ] ; p=0·47 ) compared with placebo ( n=121 ) . The safety profile was consistent with that of previous tralokinumab trials .  INTERPRETATION  Tralokinumab reduced AAER in participants with severe asthma with baseline FENO 37 ppb or higher in STRATOS 1 , but not in STRATOS 2 . These inconsistent effects on AAER do not support a key role for interleukin 13 in severe asthma exacerbations . FUNDING AstraZeneca BACKGROUND The role of interleukin 13 in airway inflammation and remodelling in asthma is unclear . Tralokinumab is a human monoclonal antibody that neutralises interleukin 13 . We aim ed to evaluate whether tralokinumab would have an effect on airway eosinophilic infiltration , blood and sputum eosinophil concentrations , eosinophil activation , and airway remodelling . METHODS We did a multicentre , double-blind , r and omised , placebo-controlled phase 2 trial at 15 centres across the UK , Denmark , and Canada . We enrolled participants of either sex aged 18 - 75 years with inadequately controlled moderate-to-severe asthma for 12 months or more , requiring treatment with inhaled corticosteroids at a stable dose . We r and omly assigned participants ( 1:1 ) to receive tralokinumab ( 300 mg ) or placebo by an interactive web-based system or voice response system . Participants and study personnel were masked to treatment allocation . Both tralokinumab and placebo were administered subcutaneously every 2 weeks . The primary outcome measure was change from baseline to week 12 in bronchial biopsy eosinophil count . Secondary outcome measures included change in blood and sputum eosinophil counts . Exploratory outcomes included fractional exhaled nitric oxide ( FENO ) and blood IgE concentrations . Safety analyses were carried out in all participants who received study drug . This trial is registered with Clinical Trials.gov , number NCT02449473 , and with the European Clinical Trials Data base , EudraCT 2015 - 000857 - 19 . FINDINGS Between Sept 25 , 2015 , and June 21 , 2017 , 224 participants were enrolled and screened . Of these participants , 79 were r and omly assigned to receive tralokinumab ( n=39 ) or placebo ( n=40 ) . Tralokinumab did not significantly affect bronchial eosinophil count compared with placebo at week 12 ( treatment effect ratio 1·43 , 95 % CI 0·63 - 3·27 ; p=0·39 ) . Compared with placebo , tralokinumab did not significantly affect blood eosinophil count ( treatment effect ratio 1·21 , 95 % CI 1·00 - 1·48 ; p=0·055 ) or sputum eosinophil count ( 0·57 , 0·06 - 6·00 ; p=0·63 ) , but FENO concentration ( 0·78 , 0·63 - 0·96 ; p=0·023 ) and total blood IgE concentration ( 0·86 , 0·77 - 0·97 ; p=0·014 ) were significantly reduced . 33 ( 85 % ) of 39 patients receiving tralokinumab and 32 ( 80 % ) of 40 receiving placebo reported at least one adverse event during the treatment period . No deaths in either treatment group were observed . Treatment-related adverse events occurred more frequently in the tralokinumab group than in the placebo group ( 11 [ 28 % ] of 39 vs seven [ 18 % ] of 40 ) . INTERPRETATION Tralokinumab did not significantly affect eosinophilic inflammation in bronchial submucosa , blood , or sputum compared with placebo , but did reduce FENO and IgE concentrations . These results suggest interleukin 13 is not crucial for eosinophilic airway inflammation control in moderate-to-severe asthma . FUNDING AstraZeneca BACKGROUND Some patients with severe asthma have recurrent asthma exacerbations associated with eosinophilic airway inflammation . Early studies suggest that inhibition of eosinophilic airway inflammation with mepolizumab-a monoclonal antibody against interleukin 5-is associated with a reduced risk of exacerbations . We aim ed to establish efficacy , safety , and patient characteristics associated with the response to mepolizumab . METHODS We undertook a multicentre , double-blind , placebo-controlled trial at 81 centres in 13 countries between Nov 9 , 2009 , and Dec 5 , 2011 . Eligible patients were aged 12 - 74 years , had a history of recurrent severe asthma exacerbations , and had signs of eosinophilic inflammation . They were r and omly assigned ( in a 1:1:1:1 ratio ) to receive one of three doses of intravenous mepolizumab ( 75 mg , 250 mg , or 750 mg ) or matched placebo ( 100 mL 0·9 % NaCl ) with a central telephone-based system and computer-generated r and omly permuted block schedule stratified by whether treatment with oral corticosteroids was required . Patients received 13 infusions at 4-week intervals . The primary outcome was the rate of clinical ly significant asthma exacerbations , which were defined as vali date d episodes of acute asthma requiring treatment with oral corticosteroids , admission , or a visit to an emergency department . Patients , clinicians , and data analysts were masked to treatment assignment . Analyses were by intention to treat . This trial is registered with Clinical Trials.gov , number NCT01000506 . FINDINGS 621 patients were r and omised : 159 were assigned to placebo , 154 to 75 mg mepolizumab , 152 to 250 mg mepolizumab , and 156 to 750 mg mepolizumab . 776 exacerbations were deemed to be clinical ly significant . The rate of clinical ly significant exacerbations was 2·40 per patient per year in the placebo group , 1·24 in the 75 mg mepolizumab group ( 48 % reduction , 95 % CI 31 - 61 % ; p<0·0001 ) , 1·46 in the 250 mg mepolizumab group ( 39 % reduction , 19 - 54 % ; p=0·0005 ) , and 1·15 in the 750 mg mepolizumab group ( 52 % reduction , 36 - 64 % ; p<0·0001 ) . Three patients died during the study , but the deaths were not deemed to be related to treatment . INTERPRETATION Mepolizumab is an effective and well tolerated treatment that reduces the risk of asthma exacerbations in patients with severe eosinophilic asthma . FUNDING GlaxoSmithKline 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 BACKGROUND Many patients with severe asthma require regular treatment with oral glucocorticoids despite the use of high-dose inhaled therapy . However , the regular use of systemic glucocorticoids can result in serious and often irreversible adverse effects . Mepolizumab , a humanized monoclonal antibody that binds to and inactivates interleukin-5 , has been shown to reduce asthma exacerbations in patients with severe eosinophilic asthma . METHODS In a r and omized , double-blind trial involving 135 patients with severe eosinophilic asthma , we compared the glucocorticoid-sparing effect of mepolizumab ( at a dose of 100 mg ) with that of placebo administered subcutaneously every 4 weeks for 20 weeks . The primary outcome was the degree of reduction in the glucocorticoid dose ( 90 to 100 % reduction , 75 to less than 90 % reduction , 50 to less than 75 % reduction , more than 0 to less than 50 % reduction , or no decrease in oral glucocorticoid dose , a lack of asthma control during weeks 20 to 24 , or withdrawal from treatment ) . Other outcomes included the rate of asthma exacerbations , asthma control , and safety . RESULTS The likelihood of a reduction in the glucocorticoid-dose stratum was 2.39 times greater in the mepolizumab group than in the placebo group ( 95 % confidence interval , 1.25 to 4.56 ; P=0.008 ) . The median percentage reduction from baseline in the glucocorticoid dose was 50 % in the mepolizumab group , as compared with no reduction in the placebo group ( P=0.007 ) . Despite receiving a reduced glucocorticoid dose , patients in the mepolizumab group , as compared with those in the placebo group , had a relative reduction of 32 % in the annualized rate of exacerbations ( 1.44 vs. 2.12 , P=0.04 ) and a reduction of 0.52 points with respect to asthma symptoms ( P=0.004 ) , as measured on the Asthma Control Question naire 5 ( in which the minimal clinical ly important difference is 0.5 points ) . The safety profile of mepolizumab was similar to that of placebo . CONCLUSIONS In patients requiring daily oral glucocorticoid therapy to maintain asthma control , mepolizumab had a significant glucocorticoid-sparing effect , reduced exacerbations , and improved control of asthma symptoms . ( Funded by GlaxoSmithKline ; SIRIUS Clinical Trials.gov number , NCT01691508 . ) BACKGROUND Dupilumab is a fully human anti – interleukin‐4 receptor α monoclonal antibody that blocks both interleukin‐4 and interleukin‐13 signaling . We assessed its efficacy and safety in patients with uncontrolled asthma . METHODS We r and omly assigned 1902 patients 12 years of age or older with uncontrolled asthma in a 2:2:1:1 ratio to receive add‐on subcutaneous dupilumab at a dose of 200 or 300 mg every 2 weeks or matched‐volume placebos for 52 weeks . The primary end points were the annualized rate of severe asthma exacerbations and the absolute change from baseline to week 12 in the forced expiratory volume in 1 second ( FEV1 ) before bronchodilator use in the overall trial population . Secondary end points included the exacerbation rate and FEV1 in patients with a blood eosinophil count of 300 or more per cubic millimeter . Asthma control and dupilumab safety were also assessed . RESULTS The annualized rate of severe asthma exacerbations was 0.46 ( 95 % confidence interval [ CI ] , 0.39 to 0.53 ) among patients assigned to 200 mg of dupilumab every 2 weeks and 0.87 ( 95 % CI , 0.72 to 1.05 ) among those assigned to a matched placebo , for a 47.7 % lower rate with dupilumab than with placebo ( P<0.001 ) ; similar results were seen with the dupilumab dose of 300 mg every 2 weeks . At week 12 , the FEV1 had increased by 0.32 liters in patients assigned to the lower dose of dupilumab ( difference vs. matched placebo , 0.14 liters ; P<0.001 ) ; similar results were seen with the higher dose . Among patients with a blood eosinophil count of 300 or more per cubic millimeter , the annualized rate of severe asthma exacerbations was 0.37 ( 95 % CI , 0.29 to 0.48 ) among those receiving lower‐dose dupilumab and 1.08 ( 95 % CI , 0.85 to 1.38 ) among those receiving a matched placebo ( 65.8 % lower rate with dupilumab than with placebo ; 95 % CI , 52.0 to 75.6 ) ; similar results were observed with the higher dose . Blood eosinophilia occurred after the start of the intervention in 52 patients ( 4.1 % ) who received dupilumab as compared with 4 patients ( 0.6 % ) who received placebo . CONCLUSIONS In this trial , patients who received dupilumab  had significantly lower rates of severe asthma exacerbation than those who received placebo , as well as better lung function and asthma control . Greater benefits were seen in patients with higher baseline levels of eosinophils . Hypereosinophilia was observed in some patients . ( Funded by Sanofi and Regeneron Pharmaceuticals ; LIBERTY ASTHMA QUEST Clinical Trials.gov number , NCT02414854 .
Since novel treatments to target eosinophilic inflammation in Type 2 asthma are emerging , we aim ed to evaluate and meta-analyze the efficacy of monoclonal antibodies to reduce exacerbation rate .