Safety and efficacy of itepekimab in patients with moderate-to-severe COPD: a genetic association study and randomised, double-blind, phase 2a trial.

Genetic data implicate IL-33 in asthma susceptibility. Itepekimab, a monoclonal antibody targeting IL-33, demonstrated clinical activity in asthma, with potential in chronic obstructive pulmonary disease (COPD). In this study we first aimed to test the hypothesis that genetic variants in the IL-33 pathway were also associated with COPD. On the basis of the strong association of IL-33 pathway genes with pulmonary diseases like asthma and COPD, we conducted this phase 2a trial to assess the safety and efficacy of itepekimab in patients with moderate-to-severe COPD on a stable regimen of triple-inhaled or double-inhaled background maintenance therapy. In this two-part study, genetic analyses of loss-of-function and gain-of-function variants in the IL-33 pathway, previously associated with asthma risk, were initially characterised for COPD. We then did a double-blind, phase 2a trial comparing itepekimab with placebo in patients with moderate-to-severe COPD despite standard therapy, at 83 study sites in ten countries. Patients aged 40-75 years who were current or former smokers, had been diagnosed with COPD for at least 1 year, and were on a stable regimen of triple-inhaled or double-inhaled background maintenance therapy, were randomly assigned (1:1) to receive itepekimab 300 mg or placebo, administered as two subcutaneous injections every 2 weeks for 24-52 weeks. The primary endpoint of the phase 2a trial was annualised rate of moderate-to-severe acute exacerbations of COPD during the treatment period. The key secondary outcome was change in prebronchodilator FEV1 from baseline to weeks 16-24. Prespecified subgroup analyses were done for each of the endpoints, including by smoking status. Efficacy and safety analyses were done in all participants who received at least one dose of assigned treatment (modified intention-to-treat population). This trial is registered at ClinicalTrials.gov (NCT03546907). Genetic analyses demonstrated association of loss of function in IL33 with reduced COPD risk, and gain of function in IL33 and IL1RL1 variants with increased risk. Subsequent to this, in the phase 2 trial, 343 patients were randomly assigned to placebo (n=171) or itepekimab (n=172) from July 16, 2018, to Feb 19, 2020. Annualised rates of acute exacerbations of COPD were 1·61 (95% CI 1·32-1·97) in the placebo group and 1·30 (1·05-1·61) in the itepekimab group (relative risk [RR] 0·81 [95% CI 0·61-1·07], p=0·13), and least squares mean prebronchodilator FEV1 change from baseline to weeks 16-24 was 0·0 L (SD 0·02) and 0·06 L (0·02; difference 0·06 L [95% CI 0·01-0·10], p=0·024). When analysis was restricted to former smokers, treatment with itepekimab was associated with nominally significant reductions in acute exacerbations of COPD (RR 0·58 [95% CI 0·39-0·85], p=0·0061) and FEV1 improvement (least squares mean difference 0·09 L [0·02-0·15], p=0·0076) compared with placebo. Current smokers treated with itepekimab showed no treatment benefit versus placebo for exacerbations (RR 1·09 [0·74-1·61], p=0·65) or FEV1 (least squares mean difference 0·02 [-0·05 to 0·09], p=0·54). Treatment-emergent adverse events (TEAEs) occurred in 135 (78%) patients in the itepekimab group and 136 (80%) in the placebo group. The most common TEAEs were nasopharyngitis (28 [16%] in the itepekimab group vs 29 [17%] in the placebo group), bronchitis (18 [10%] vs 14 [8%]), headache (14 [8%] vs 23 [13%]), and upper respiratory tract infection (13 [8%] vs 15 [9%]). The primary endpoint in the overall population was not met, subgroup analysis showed that itepekimab reduced exacerbation rate and improved lung function in former smokers with COPD. Two phase 3 clinical studies are ongoing to confirm the efficacy and safety profile of itepekimab in former smokers with COPD. Sanofi and Regeneron Pharmaceuticals.

Rabe KF ，Celli BR ，Wechsler ME ，Abdulai RM ，Luo X ，Boomsma MM ，Staudinger H ，Horowitz JE ，Baras A ，Ferreira MA ，Ruddy MK ，Nivens MC ，Amin N ，Weinreich DM ，Yancopoulos GD ，Goulaouic H ... -  《-》

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

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

Brightling CE ，Bleecker ER ，Panettieri RA Jr ，Bafadhel M ，She D ，Ward CK ，Xu X ，Birrell C ，van der Merwe R ... -  《-》

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.

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 aimed 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. We did this randomised, 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 randomly 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 ClinicalTrials.gov, number NCT01854047, and with the EU Clinical Trials Register, EudraCT number 2013-000856-16. 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%). 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 standard therapy alone. Sanofi-Genzyme and Regeneron Pharmaceuticals.

Wenzel S ，Castro M ，Corren J ，Maspero J ，Wang L ，Zhang B ，Pirozzi G ，Sutherland ER ，Evans RR ，Joish VN ，Eckert L ，Graham NM ，Stahl N ，Yancopoulos GD ，Louis-Tisserand M ，Teper A ... -  《-》

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

Interleukin 13 is a central mediator of asthma. Tralokinumab is a human interleukin-13 neutralising monoclonal antibody. We aimed to assess the efficacy and safety of two dosing regimens of tralokinumab in patients with severe uncontrolled asthma. We did a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 2b study at 98 sites in North America, South America, Europe, and Asia. Patients aged 18-75 years with severe asthma and two to six exacerbations in the previous year were randomly assigned (1:1), via an interactive voice-response or web-response system, to one of two dosing regimen groups (every 2 weeks, or every 2 weeks for 12 weeks then every 4 weeks) and further randomised (2:1), via computer-generated permuted-block randomisation (block size of six), to receive tralokinumab 300 mg or placebo for 1 year. All participants received high-dose fluticasone and salmeterol and continued other pre-study controller drugs. Treatment was administered by an unmasked study investigator not involved in the management of patients; all other study site personnel, patients, the study funder, and data analysts were masked to treatment allocation. The primary endpoint was the annual asthma exacerbation rate at week 52 in the intention-to-treat population. Key secondary endpoints included prebronchodilator forced expiratory volume in 1 s (FEV1), Asthma Control Questionnaire-6 (ACQ-6), and Asthma Quality of Life Questionnaire-Standardised Version (AQLQ[S]). This trial is registered with ClinicalTrials.gov, number NCT01402986. Between Oct 4, 2011, and Feb 22, 2014, we randomly assigned 452 patients to receive placebo (n=151) or tralokinumab every 2 weeks (n=150) or every 4 weeks (n=151), of whom 383 (85%) completed the treatment period up to week 52. The annual asthma exacerbation rate at week 52 was similar between patients receiving tralokinumab every 2 weeks (0.91 per patient per year [95% CI 0.76-1.08]) and every 4 weeks (0.97 [0.81-1.14]), and those receiving placebo (0.90 [0.75-1.08]). At week 52, percentage changes in annual asthma exacerbation rate were not significant with tralokinumab every 2 weeks or every 4 weeks versus placebo (6% [95% CI -31 to 33; p=0.709] and -2% [-46 to 29; p=0.904], respectively), with positive changes showing a decrease in exacerbation rate and negative changes showing an increase. Prebronchodilator FEV1 was significantly increased compared with placebo for tralokinumab every 2 weeks (change from baseline 7.3% [95% CI 2.6-12.0]; p=0.003), but not every 4 weeks (1.8% [-2.9 to 6.6]; p=0.448); however, we did not identify significant changes in the other key secondary endpoints. In a post-hoc subgroup analysis of patients not on long-term oral corticosteroids and with baseline FEV1 reversibility of 12% or greater, we noted a non-significant improvement in asthma exacerbation rate (44% [95% CI -22 to 74]; p=0.147) and significant improvements in key secondary endpoints (FEV1 12.2% [1.7-22.7]; p=0.022; ACQ-6 -0.55 [-1.07 to -0.04]; p=0.036; and AQLQ[S] 0.70 [0.12-1.28]; p=0.019) in patients given tralokinumab every 2 weeks (n=33) compared with placebo (n=48). In patients in this subgroup who also had baseline serum dipeptidyl peptidase-4 (DPP-4) higher than the population baseline median, we noted additional improvements in prebronchodilator FEV1, ACQ-6, and AQLQ(S), and, in those with periostin concentrations higher than the median, we noted improvements in asthma exacerbation rate, prebronchodilator FEV1, and ACQ-6. The incidence of treatment-emergent adverse events was similar between the tralokinumab and placebo groups. Treatment-emergent serious adverse events regarded as related to the study drug were pneumonia (one [1%] patient in the placebo group), pneumococcal pneumonia (one [1%] in the tralokinumab every 2 weeks group), angioedema (one [1%] in the placebo group), and worsening asthma (one [1%] in the tralokinumab every 2 weeks group and two [1%] in the tralokinumab every 4 weeks group). 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. MedImmune.

Brightling CE ，Chanez P ，Leigh R ，O'Byrne PM ，Korn S ，She D ，May RD ，Streicher K ，Ranade K ，Piper E ... -  《-》

Efficacy and safety of once-daily single-inhaler triple therapy (FF/UMEC/VI) versus FF/VI in patients with inadequately controlled asthma (CAPTAIN): a double-blind, randomised, phase 3A trial.

Despite inhaled corticosteroid plus long-acting β2-agonist (ICS/LABA) therapy, 30-50% of patients with moderate or severe asthma remain inadequately controlled. We investigated the safety and efficacy of single-inhaler fluticasone furoate plus umeclidinium plus vilanterol (FF/UMEC/VI) compared with FF/VI. In this double-blind, randomised, parallel-group, phase 3A study (Clinical Study in Asthma Patients Receiving Triple Therapy in a Single Inhaler [CAPTAIN]), participants were recruited from 416 hospitals and primary care centres across 15 countries. Participants were eligible if they were aged 18 years or older, with inadequately controlled asthma (Asthma Control Questionnaire [ACQ]-6 score of ≥1·5) despite ICS/LABA, a documented health-care contact or a documented temporary change in asthma therapy for treatment of acute asthma symptoms in the year before screening, pre-bronchodilator FEV1 between 30% and less than 85% of predicted normal value, and reversibility (defined as an increase in FEV1 of ≥12% and ≥200 mL in the 20-60 min after four inhalations of albuterol or salbutamol) at screening. Participants were randomly assigned (1:1:1:1:1:1), via central based randomisation stratified by pre-study ICS dose at study entry, to once-daily FF/VI (100/25 μg or 200/25 μg) or FF/UMEC/VI (100/31·25/25 μg, 100/62·5/25 μg, 200/31·25/25 μg, or 200/62·5/25 μg) administered via Ellipta dry powder inhaler (Glaxo Operations UK, Hertfordshire, UK). Patients, investigators, and the funder were masked to treatment allocation. Endpoints assessed in the intention-to-treat population were change from baseline in clinic trough FEV1 at week 24 (primary) and annualised moderate and/or severe asthma exacerbation rate (key secondary). Other secondary endpoints were change from baseline in clinic FEV1 at 3 h post-dose, St George's Respiratory Questionnaire (SGRQ) total score, and ACQ-7 total score, all at week 24. Change from baseline in Evaluating Respiratory Symptoms in Asthma total score at weeks 21-24 was also a secondary endpoint but is not reported here. Exploratory analyses of biomarkers of type 2 airway inflammation on treatment response were also done. This study is registered with ClinicalTrials.gov, NCT02924688, and is now complete. Between Dec 16, 2016, and Aug 31, 2018, 5185 patients were screened and 2439 were recruited and randomly assigned to FF/VI (100/25 μg n=407; 200/25 μg n=406) or FF/UMEC/VI (100/31·25/25 μg n=405; 100/62·5/25 μg n=406; 200/31·25/25 μg n=404; 200/62·5/25 μg n=408), with three patients randomly assigned in error and not included in analyses. In the intention-to-treat population, 922 (38%) patients were men, the mean age was 53·2 years (SD 13·1) and body-mass index was 29·4 (6·6). Baseline demographics were generally similar across all treatment groups. The least squares mean improvement in FEV1 change from baseline for FF/UMEC/VI 100/62·5/25 μg versus FF/VI 100/25 μg was 110 mL (95% CI 66-153; p<0·0001) and for 200/62·5/25 μg versus 200/25 μg was 92 mL (49-135; p<0·0001). Adding UMEC 31·25 μg to FF/VI produced similar improvements (FF/UMEC/VI 100/31·25/25 μg vs FF/VI 100/25 μg: 96 mL [52-139; p<0·0001]; and 200/31·25/25 μg vs 200/25 μg: 82 mL [39-125; p=0·0002]). These results were supported by the analysis of clinic FEV1 at 3 h post-dose. Non-significant reductions in moderate and/or severe exacerbation rates were observed for FF/UMEC 62·5 μg/VI versus FF/VI (pooled analysis), with rates lower in FF 200 μg-containing versus FF 100 μg-containing treatment groups. All pooled treatment groups demonstrated mean improvements (decreases) in SGRQ total score at week 24 compared with baseline in excess of the minimal clinically important difference of 4 points; however, there were no differences between treatment groups. For mean change from baseline to week 24 in asthma control questionnaire-7 score, improvements (decreases) exceeding the minimal clinically important difference of 0·5 points were observed in all pooled treatment groups. Adding UMEC to FF/VI resulted in small, dose-related improvements compared with FF/VI (pooled analysis: FF/UMEC 31·25 μg/VI versus FF/VI, -0·06 (95% CI -0·12 to 0·01; p=0·094) FF/UMEC 62·5 μg/VI versus FF/VI, -0·09 (-0·16 to -0·02, p=0·0084). By contrast with adding UMEC, the effects of higher dose FF on clinic trough FEV1 and annualised moderate and/or severe exacerbation rate were increased in patients with higher baseline blood eosinophil count and exhaled nitric oxide. Occurrence of adverse events was similar across treatment groups (patients with at least one event ranged from 210 [52%] to 258 [63%]), with the most commonly reported adverse events being nasopharyngitis (51 [13%]-63 [15%]), headache (19 [5%]-36 [9%]), and upper respiratory tract infection (13 [3%]-24 [6%]). The incidence of serious adverse events was similar across all groups (range 18 [4%]-25 [6%)). Three deaths occurred, of which one was considered to be related to study drug (pulmonary embolism in a patient in the FF/UMEC/VI 100/31·25/25 μg group). In patients with uncontrolled moderate or severe asthma on ICS/LABA, adding UMEC improved lung function but did not lead to a significant reduction in moderate and/or severe exacerbations. For such patients, single-inhaler FF/UMEC/VI is an effective treatment option with a favourable risk-benefit profile. Higher dose FF primarily reduced the rate of exacerbations, particularly in patients with raised biomarkers of type 2 airway inflammation. Further confirmatory studies into the differentiating effect of type 2 inflammatory biomarkers on treatment outcomes in asthma are required to build on these exploratory findings and further guide clinical practice. GSK.

Lee LA ，Bailes Z ，Barnes N ，Boulet LP ，Edwards D ，Fowler A ，Hanania NA ，Kerstjens HAM ，Kerwin E ，Nathan R ，Oppenheimer J ，Papi A ，Pascoe S ，Brusselle G ，Peachey G ，Sule N ，Tabberer M ，Pavord ID ... -  《-》