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Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine implicated in the initiation and persistence of inflammatory pathways in asthma. Released in response to a range of epithelial insults (eg, allergens, viruses, bacteria, pollutants, and smoke), TSLP initiates multiple downstream innate and adaptive immune responses involved in asthma inflammation. Inhibition of TSLP is postulated to represent a novel approach to treating the diverse phenotypes and endotypes of asthma. Tezepelumab, the TSLP inhibitor farthest along in clinical development, is a human monoclonal antibody (IgG2λ) that binds specifically to TSLP, preventing interactions with its heterodimeric receptor. Results of recently published phase 2 and 3 studies, reviewed in this article, provide evidence of the safety and efficacy of tezepelumab that builds on initial findings. Tezepelumab is safe, well tolerated, and provides clinically meaningful improvements in asthma control, including reduced incidence of exacerbations and hospitalizations in patients with severe asthma. Clinical benefits were associated with reductions in levels of a broad spectrum of cytokines (eg, interleukin [IL]-5, IL-13) and baseline biomarkers (eg, blood eosinophils, immunoglobulin [Ig]E, fractional exhaled nitric oxide [FeNO]) and were observed across a range of severe asthma phenotypes (ie, eosinophilic and non-eosinophilic). These data strengthen the notion that anti-TSLP elicits broad inhibitory effects on pathways that are key to asthma inflammation rather than on narrower inhibition of individual downstream factors. This review presents the rationale for targeting TSLP to treat asthma, as well as the clinical effects of TSLP blockade on asthma outcomes, biomarkers of disease activity, airway inflammation, lung physiology, and patient symptoms.

To assess patient- and physician-reported reasons for discontinuing biologic therapy among patients with severe asthma from a real-world US cohort.This retrospective analysis surveyed US physicians and their patients with severe asthma who were receiving/had previously received biologic therapy between August and December 2019. Physicians managing ≥3 patients with asthma per month completed surveys on disease management, demographics, exacerbation history, and biologic adherence for eligible patients. Patients could voluntarily complete a questionnaire, providing perceptions of their disease and treatment.117 physicians completed case reports for 285 patients; 85 patients had discontinued biologic therapy. Physicians (in/i = 85) and patients (in/i = 64) reported patient request (28.2% and 46.9%), shortness of breath (45.9% and 23.4%), other chronic respiratory symptoms (29.4% and 10.9%), cost/reimbursement (17.7%/9.4% and 20.3%/7.8%), and exacerbations (25.9% and 10.9%) among the main reasons for biologic discontinuation. Patients who continued biologic therapy were older (mean age 47.6 years) than those who discontinued (43.8 years), and were more likely to have ≥2 exacerbations in the previous year (52.5% vs 35.3%), allergic rhinitis (70.0% vs 62.4%), or chronic rhinosinusitis (30.0% vs 12.9%). Side effects were cited as reasons by only 15.3% and 7.8% of physicians and patients, respectively.The most common reasons given for discontinuation of biologic therapy were lack of symptom control, exacerbations, cost, and patient request. These data highlight the complexity of care for this patient group and the need for ongoing, regular assessment of common challenges to biologic continuation and reasons for discontinuation, including both clinical and non-clinical factors.

Background Mepolizumab is a humanized anti–interleukin-5 monoclonal antibody approved for the treatment of patients with severe eosinophilic asthma (SEA). There is limited evidence that patients treated with mepolizumab can reduce inhaled corticosteroid (ICS) use. Objective To investigate changes in ICS use and clinical outcomes in patients with SEA who initiated mepolizumab treatment. Methods This retrospective cohort study (GSK ID: 212695/HO-20-19951) used administrative claims data from the IBM Watson Health MarketScan Database (identification period: November 2015–March 2018). Eligible patients had SEA and were receiving high-dose ICS and mepolizumab. ICS, oral corticosteroid (OCS), short acting β2-agonist (SABA) use, and exacerbation frequency were analyzed quarterly during the 12-month follow-up period following mepolizumab initiation. Results In total, 351 patients were included. The proportion of patients using highdose ICS decreased in quarters 1–4 following mepolizumab initiation (79.8%, 74.6%, 68.9%, 65.5%, respectively); 49.0% of patients reduced or discontinued ICS for ≥1 quarter. Comparing patients who discontinued ICS versus those who remained on high-dose ICS, a lower proportion had chronic OCS use (3.4–9.2% vs 13.9–16.8%) and OCS burst use (15.4–20.8% vs 19.7–26.1%) in quarters 1–4; similarly in quarters 3 and 4, a lower proportion of patients had exacerbations (16.9% and 20.3% vs 27.2% and 27.7%) and SABA claims (35.4% and 39.2% vs 43.3% and 49.0%, respectively). Conclusion: In patients with SEA on high-dose ICS, a reduction in both ICS and OCS use was observed after initiating mepolizumab. These findings have important implications for clinical outcomes and follow-up care in this patient population.

BACKGROUND Patients with severe asthma frequently have associated comorbidities, which can compound existing symptoms, complicating asthma management. OBJECTIVE To describe the real-world effectiveness of mepolizumab in patients with severe asthma stratified by common overlapping comorbidities. METHODS This was a retrospective analysis of patients with asthma from the MarketScan Commercial and Medicare Supplemental Database initiating mepolizumab treatment (index date). Eligible patients had more than or equal to 1 claim (excluding claims for diagnostic tests) with a diagnosis code for more than or equal to 1 of 7 comorbidities (atopic disease, nasal polyps, chronic sinusitis, obesity, respiratory infections, chronic obstructive pulmonary disease, and depression/anxiety) during the 12-month preindex baseline period; these were used to stratify patients into 7 nonmutually exclusive subgroups. Outcomes included asthma exacerbations and exacerbation-related health care resource utilization during the 12-month baseline and follow-up periods. Each patient acted as their own control. RESULTS Of the 639 patients included, the most common comorbidities were atopic diseases (73.2%), respiratory infections (55.6%), and chronic sinusitis (45.1%). Across all 7 comorbidity subgroups, there were significant (P < .05) reductions of 38% to 55% and 57% to 83% in exacerbations and exacerbations requiring hospitalization, respectively, during the follow-up vs baseline period, except for exacerbations requiring hospitalization in the nasal polyp subgroup, owing to the small subgroup sample size. During the follow-up vs baseline periods, mean number of oral corticosteroids claims was significantly (P < .001) reduced by 29% to 38%; 39% to 47% of patients achieved greater than or equal to 50% oral corticosteroids dose reduction. Significant reductions in exacerbation-related health care resource utilization were also observed. CONCLUSION Mepolizumab treatment provided real-world clinical benefits in patients.

Approximately 30% to 50% of patients with moderate/severe asthma have inadequately controlled disease despite adherence to inhaled corticosteroid (ICS)/long-acting βTo evaluate the prevalence and burden of uncontrolled asthma in respiratory specialist clinics in the United States.Adults with physician-diagnosed asthma attending pulmonary and allergy clinics with self-reported ICS use in the previous 4 weeks completed an electronic questionnaire including the Asthma Control Test and St George's Respiratory Questionnaire. Additional information was collected using an electronic case report form.Of 774 patients attending 12 pulmonary and 12 allergy clinics, 53% were not well controlled (mean [SD] Asthma Control Test, 14.3 [3.6] vs 22.4 [1.6] in well-controlled patients). Among ICS/LABA users, 56% were not well controlled, which increased with increasing ICS dose (low-dose 45.7%; high-dose 59.7%). The not well-controlled group reported more respiratory illnesses, more comorbidities, and poorer health-related quality of life (mean [SD] St George's Respiratory Questionnaire, 46.1 [18.9] vs 19.8 [12.9] in the well-controlled group). These patients also had more asthma exacerbations (≥1 exacerbation, 68.9% vs 43.1%) and increased health care resource utilization (≥1 asthma-related hospitalization, 10.7% vs 2.7%); 27.3% were also receiving systemic corticosteroids. Approximately 40% of the population were eligible for step-up to ICS/LABA/long-acting muscarinic antagonist triple therapy, and 20% were eligible for biologic therapy.Substantial unmet needs exist among patients with inadequately controlled asthma managed in United States specialist settings, which may be addressed by improved patient and physician education, better guideline implementation, and improved adherence.

Background Approximately 30% to 50% of patients with moderate/severe asthma have inadequately controlled disease despite adherence to inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) therapy. Data on prevalence and burden of uncontrolled asthma in specialty settings are lacking. Objective To evaluate the prevalence and burden of uncontrolled asthma in respiratory specialist clinics in the United States. Methods Adults with physician-diagnosed asthma attending pulmonary and allergy clinics with self-reported ICS use in the previous 4 weeks completed an electronic questionnaire including the Asthma Control Test and St George’s Respiratory Questionnaire. Additional information was collected using an electronic case report form. Results Of 774 patients attending 12 pulmonary and 12 allergy clinics, 53% were not well controlled (mean [SD] Asthma Control Test, 14.3 [3.6] vs 22.4 [1.6] in well-controlled patients). Among ICS/LABA users, 56% were not well controlled, which increased with increasing ICS dose (low-dose 45.7%; high-dose 59.7%). The not well-controlled group reported more respiratory illnesses, more comorbidities, and poorer health-related quality of life (mean [SD] St George’s Respiratory Questionnaire, 46.1 [18.9] vs 19.8 [12.9] in the well-controlled group). These patients also had more asthma exacerbations (≥1 exacerbation, 68.9% vs 43.1%) and increased health care resource utilization (≥1 asthma-related hospitalization, 10.7% vs 2.7%); 27.3% were also receiving systemic corticosteroids. Approximately 40% of the population were eligible for step-up to ICS/LABA/long-acting muscarinic antagonist triple therapy, and 20% were eligible for biologic therapy. Conclusion Substantial unmet needs exist among patients with inadequately controlled asthma managed in United States specialist settings, which may be addressed by improved patient and physician education, better guideline implementation, and improved adherence.

Summary Background Persistent eosinophilic airway inflammation in asthma increases the risk of exacerbations. In a phase 2b dose-ranging study, we aimed 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 randomised, 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 randomly 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 designed 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 ClinicalTrials.gov, number NCT01238861. Findings Between Jan 3, 2011, and March 6, 2012, we randomly 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 ligand. Further investigation of benralizumab treatment in phase 3 studies is warranted. Funding MedImmune.

Health resource utilization (HRU) and outcomes associated with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) are not well described. Therefore, a population-based cohort study was conducted to characterize patients hospitalized with AECOPD with regard to HRU, mortality, recurrence, and predictors of readmission with AECOPD.Using Danish healthcare databases, this study identified COPD patients with at least one AECOPD hospitalization between 2005-2009 in Northern Denmark. Hospitalized AECOPD patients' HRU, in-hospital mortality, 30-day, 60-day, 90-day, and 180-day post-discharge mortality and recurrence risk, and predictors of readmission with AECOPD in the year following study inclusion were characterized.This study observed 6612 AECOPD hospitalizations among 3176 prevalent COPD patients. Among all AECOPD hospitalizations, median length of stay was 6 days (interquartile range [IQR] 3-9 days); 5 days (IQR 3-9) among those without ICU stay and 11 days (IQR 7-20) among the 8.6% admitted to the ICU. Mechanical ventilation was provided to 193 (2.9%) and non-invasive ventilation to 479 (7.2%) admitted patients. In-hospital mortality was 5.6%. Post-discharge mortality was 4.2%, 7.8%, 10.5%, and 17.4% at 30, 60, 90, and 180 days, respectively. Mortality and readmission risk increased with each AECOPD hospitalization experienced in the first year of follow-up. Readmission at least twice in the first year of follow-up was observed among 286 (9.0%) COPD patients and was related to increasing age, male gender, obesity, asthma, osteoporosis, depression, myocardial infarction, diabetes I and II, any malignancy, and hospitalization with AECOPD or COPD in the prior year.The study included only hospitalized AECOPD patients among prevalent COPD patients. Furthermore, information was lacking on clinical variables.These findings indicate that AECOPD hospitalizations are associated with substantial mortality and risk of recurrence.

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.SETTINGS: 47 ambulatory asthma care centres globally.PRIMARY OUTCOME MEASURES: Change in FEV1 at week 24.PARTICIPANTS: 311 were screened, 160 were randomised 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.

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 randomised 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 Questionnaire 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 β2-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. β2-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.

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology with considerable morbidity and mortality. Cigarette smoking is one of the most recognized risk factors for development of IPF. Furthermore, recent work suggests that smoking may have a detrimental effect on survival of patients with IPF. The mechanism by which smoking may contribute to the pathogenesis of IPF is largely unknown. However, accumulating evidence suggests that increased oxidative stress might promote disease progression in IPF patients who are current and former smokers. In this review, potential mechanisms by which cigarette smoking affects IPF, the effects of cigarette smoking on accelerated loss of lung function in patients with IPF, key genetic studies evaluating the potential candidate genes and gene-environment (smoking) interaction, diagnosis, and treatment with emphasis on recently closed and ongoing clinical trials are presented.

Background In individuals with asthma, potential central nervous system changes can occur as a consequence of their asthma or therapy. Clinical trials of anti-asthmatic therapies might benefit from using magnetic resonance imaging (MRI) to assess potential brain abnormalities. Purpose As part of the clinical safety evaluation of a monoclonal antibody directed against interleukin-9 for the treatment of asthma, we assessed whether brain MRI is an appropriate screening tool to evaluate potential neurotoxicity. Methods Brain MRIs were conducted as part of a prespecified safety evaluation in adults aged 19 to 47 years with mild to moderate asthma treated with either the investigational monoclonal antibody or placebo. An independent neuroradiologist performed a blinded review of brain MRI scans obtained at baseline before dosing and day 28 after dosing from two separate clinical studies. Results Fifteen brain MRI abnormalities were noted in 13 of 21 subjects with asthma (62%). Nonspecific deep white matter hyperintensities (24%), perivascular space (24%), and abnormal anatomic findings (14%) were noted either at baseline or follow-up. Only 8 of 21 subjects (38%) with asthma had normal brain MRI results. Conclusions The high rate of incidental brain MRI findings suggests that these abnormalities are relatively common in patients with asthma. Thus, brain MRI may not be an appropriate screening tool to evaluate potential neurotoxicity in subjects during routine clinical studies without a baseline examination. Due to artifacts simulating lesions, an experienced radiologist should interpret all brain MRI results.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The safety profile and effective dose of CAT-354 have been determined with intravenous (i.v.) administration, but no information is available on subcutaneous (s.c.) administration. WHAT THIS STUDY ADDS • This study characterized the pharmacokinetics of CAT-354 following s.c. administration of 150 mg and 300 mg doses, and indicated a bioavailability of approximately 60%. AIM To assess the bioavailability and pharmacokinetics of CAT-354, an anti-IL-13 human monoclonal IgG4 antibody, following subcutaneous (s.c.) and intravenous (i.v.) administration. METHODS This was a single-dose, randomized, open-label, parallel-group bioavailability study. Healthy male subjects aged 20–54 years were randomly assigned to one of three dose groups (n= 10/group) to receive CAT-354: 150 mg i.v.; 150 mg s.c. or 300 mg s.c. (two 150 mg injections). Serum pharmacokinetics, adverse events (AEs), vital signs, electrocardiograms and laboratory parameters were assessed. RESULTS CAT-354 showed bioavailability of 62% and 60% after 150 mg and 300 mg s.c. doses, respectively, and linear pharmacokinetics over the dose range tested. Peak serum concentrations in the s.c. groups occurred after 3–9 (median 5) days, with a mean elimination half-life of 19.2 ± 3.1 days (150 mg) and 19.4 ± 3.59 days (300 mg) after s.c. and 21.4 ± 2.46 days after i.v. administration. Volume of distribution at steady state (Vss) was 4960 ± 1440 ml kg−1 after i.v. (slightly greater than plasma volume). Average apparent clearances (CL/F) were 292 ± 82.3 and 307 ± 109 ml day−1 after 150 and 300 mg s.c., respectively; systemic CL of 188 ± 84.0 ml day−1 after i.v. dosing was consistent with endogenous IgG and reticuloendothelial elimination. No severe or serious AEs occurred. Among 40 reported AEs, 25 were headache, sinus disorders/respiratory symptoms and changes in body temperature perception. CONCLUSIONS CAT-354 exhibited bioavailability of approximately 60% when given s.c. to healthy male subjects.

Chronic obstructive pulmonary disease (COPD) encompasses three different phenotypes, chronic severe asthma, chronic bronchitis and emphysema. Although COPD is currently treated with long-acting bronchodilators and inhaled corticosteroids, new therapies are needed that with acceptable safety profile will maintain pulmonary function over time, accompanied by reduced morbidity and mortality and improved quality of life. Several new therapies are presently under development for COPD, and those aiming to modify relatively new targets are discussed in this review.

Background Theophylline is a nonspecific inhibitor of phosphodiesterases that, despite exerting bronchodilator and anti-inflammatory effects, is a third-line therapy rarely used to treat chronic airflow limitation. We wished to evaluate the efficacy of oral theophylline as measured by improvements in trough (pre-dose) or peak (post-dose) FEV1 and FVC in patients with clinically stable COPD. Design Meta-analysis of randomized, placebo-controlled trials reported as of June 2005 in which theophylline was orally administered to stable COPD patients and the functional evaluations included pre- and post-theophylline values for FEV1 and FVC. Results Atotal of 18 trials were included in the meta-analysis. The weighted mean differences (WMD) with 95% confidence intervals (95% CI) for improvement over placebo in trough FEV1 and FVC were 0.108L (0.053-0.163) and 0.186L (0.036-0.336), respectively, while peak FEV1 and FVC improved by 0.096L (0.044-0.147) and 0.242L (0.11-0.374), respectively. Conclusions Treatment with oral theophylline improves both trough and peak FEV1 and FVC in clinically stable COPD patients. These results support previously reported benefits of theophylline in COPD.

Twenty-three myasthenia gravis (MG) subjects, mean (SD) age 41.6 years (14), showing poor disease control or steroid-related side effects, received treatment for 12 months with intravenous cyclophosphamide (CP; n = 12) or placebo (PL; n = 11) in a randomized, double-blind trial. Pulses were given monthly at an initial dose of 500 mg/m(2) of body surface, and titrated according to changes of peripheral muscle strength or side effects. Changes of muscle strength, steroid and pyridostigmine requirements, and development of ventilatory failure or swallowing impairment were evaluated at 0, 3, 6, and 12 months. No differences were observed between groups at baseline. Statistically significant reductions of methylprednisone doses were noted in both groups but were more pronounced in subjects receiving CP than PL at 6 months (P < 0.05) and at 12 months (P < 0.03). At 12 months, five subjects on CP had tapered off their steroids whereas no subject on PL achieved further reductions (P < 0.03). Four CP subjects were not receiving steroids 36 months after completing the study and three other CP subjects had stopped pyridostigmine. CP improved muscle strength at 3 and 6 months, and this reached statistical significance compared to PL at 12 months mainly in the bulbar and masticatory (P < 0.009) and extraocular muscles (P < 0.03). Ventilatory failure was noted in one subject on CP (due to bronchopneumonia) and two on PL (due to muscle weakness). No significant increases of CP-related side effects were observed. Thus, this study suggests that intravenous pulses of CP allow reductions of systemic steroids usage without muscle strength deterioration or CP-related side effects.

Background Patients with frequent asthma exacerbations resulting 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 randomized, 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 resource 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 resulting 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.

Slow-onset asthma deaths are characterized by eosinophilic airway infiltrates and thickening of the basal membrane, while rapid-onset asthma deaths are associated with fewer airway inflammatory changes, suggesting that bronchospasm may be responsible for the latter events. Airway tone is primarily controlled by the autonomous nervous system and can be pharmacologically modified. Therapies that stimulate the sympathetic beta(2) adrenoreceptor or inhibit the muscarinic receptor signal transduction induce bronchodilation. Parasympathetic (vagal) airway tone is enhanced in some asthmatics due to a number of stimuli, while in others it is constitutively heightened. Mainstream asthma therapy, however, only consists of corticosteroids and beta(2) agonists, not addressing this aspect. In this publication, I propose that increased vagal airway tone resulting in overwhelming bronchoconstriction and mucus plugging could be responsible for the near-fatal or fatal events observed in a number of asthmatics, in spite of their adequate treatment with standard therapies. On the basis of this hypothesis, I recommend that vagal airway tone be assessed in all patients with asthma, particularly in those with a history of near-fatal events. If the airway tone is increased, individuals should be treated with a triple combination of long-acting beta(2) agonists, inhaled steroids, and inhaled anticholinergics to prevent vagally mediated fatal events.

We assessed the acute bronchodilator effect of nebulized furosemide when added to conventional therapy of acute emergency department (ED) asthma. Using a double-blind design, 42 patients with acute asthma were randomized to receive 2.5 mg nebulized salbutamol and either 40 mg of nebulized furosemide or saline solution. We recorded clinical variables (respiratory rate, heart rate, and pulsus paradoxus) and peak expiratory flow rates (PEFR) before and 15 and 30 min after therapy. We found no significant difference in PEFR between salbutamol/furosemide and salbutamol/saline-treated patients 15 and 30 min following inhalation. Other endpoints were equally unaffected. However, when we examined separately those patients whose exacerbations were of relative short duration (8 hr), PEFR improved significantly more in the furosemide-treated group. At 15 min, PEFR increased by 82 +/- 48% in the furosemide group compared to 35 +/- 40% in the control group (p = 0.03), an effect that was also evident at 30 min when PEFR had increased by 113 +/- 49% in the furosemide group versus 61 +/- 35% in the control group (p = 0.014). Respiratory rate, heart rate, and pulsus paradoxus improved with no differences between the groups. The beneficial effect of furosemide was not evident in patients who reported more prolonged duration (8 hr) of asthmatic symptoms. The response to furosemide appeared to be unrelated to concomitant ED therapy with corticosteroids, to baseline pulmonary function, or to patient demographic variables. We conclude that furosemide may offer additive bronchodilator benefits in acute naturally occurring asthma of relative short duration.

Background Preclinical 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 prospective double-blind, multicenter, parallel-group study, 329 subjects were randomized (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 Questionnaire-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 Questionnaire 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 ClinicalTrials.gov: NCT00968669.

Breakthroughs occur every day in the medical sciences, and yet, breakthroughs that are clinically significant, affordable, replicated and approved by health authorities for use in humans are scarce. Breakthrough therapies consist of the combination of new and promising discoveries that become safe, efficacious and cost-effective medicines. In respiratory medicine, the use of targeted therapies that can achieve greater benefits with potentially less side effects has started a trend of breakthroughs. In this editorial, I review three of such breakthroughs that have come to light relatively recently. Their use will likely increase because they have the potential not only to improve the quality of life and survival in patients with respiratory diseases, such as multidrug-resistant tuberculosis (MDR-TB), cystic fibrosis (CF) and non-small-cell lung cancer (NSCLC), but also to change the standard of care. Of note, the term ‘breakthrough’ in this editorial does not necessarily coincide with the regulatory ‘breakthrough’ designation established by the US FDA as part of the Prescription Drug User Fee Act V; title IX section 902 [1].

Emphysema is included in the syndrome of chronic obstructive pulmonary disease (COPD). Alpha 1-antitrypsin (AAT) deficiency is a proven genetic determinant of COPD. However, only a small percentage of patients with COPD inherit severe AAT deficiency, and additional genetic factors likely influence the development of COPD. Further efforts in linkage analysis, association studies, and animal models may lead to the identification of such factors. Identification of genetic factors influencing the development of COPD and characterization of the interactions between genetic determinants and environmental factors could lead to new therapeutic interventions for COPD.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. Current therapies confer partial benefits either by incompletely improving airflow limitation or by reducing acute exacerbations, hence new therapies are desirable. In the absence of robust early predictors of clinical efficacy, the potential success of novel therapeutic agents in COPD will not entirely be known until the drugs enter relatively large and costly clinical trials. New predictive models in humans, and new study designs are being sought to allow for confirmation of pharmacodynamic and potentially clinically meaningful effects in early development. This review focuses on human challenge models with lipopolysaccharide endotoxin, ozone, and rhinovirus, in the early clinical development phases of novel therapeutic agents for the treatment and reduction of exacerbations in COPD.

Severe asthma continues to be an important source of morbidity despite the availability of bronchodilators and corticosteroids. Although new treatments are needed, better identification of asthma phenotypes may improve treatment effectiveness. One phenotype that has emerged is eosinophilic asthma. Eosinophils in asthma have been studied for many years, and the evidence suggests they play a major role in some forms of asthma. Eosinophilic asthma can be diagnosed using peripheral blood, sputum eosinophil count or exhaled nitric oxide. Depletion of eosinophils can be achieved by corticosteroids, specific anti-interleukin 5 (IL-5) or anti-IL-5-receptor-alpha therapies, or anti-immunoglobulin E approaches. This editorial refers to the approaches that are being taken in eosinophilic asthma with emphasis on the new investigational anti-IL-5-receptor-alpha antibody, benralizumab.

Interleukin-5 is a Th2 homodimeric cytokine involved in the differentiation, maturation, migration, development, survival, trafficking and effector function of blood and local tissue eosinophils, in addition to basophils and mast cells. The IL-5 receptor (IL-5R) consists of an IL-5-specific α subunit that interacts in conformationally dynamic ways with the receptor's βc subunit, an aggregate of domains it shares with binding sites of IL-3 and granulocyte-macrophage colony-stimulating factor. IL-5 and IL-5R drive allergic and inflammatory immune responses characterizing numerous diseases, such as asthma, atopic dermatitis, chronic obstructive pulmonary disease, eosinophilic gastrointestinal diseases, hyper-eosinophilic syndrome, Churg-Strauss syndrome and eosinophilic nasal polyposis. Although corticosteroid therapy is the primary treatment for these diseases, a substantial number of patients exhibit incomplete responses and suffer side-effects. Two monoclonal antibodies have been designed to neutralize IL-5 (mepolizumab and reslizumab). Both antibodies have demonstrated the ability to reduce blood and tissue eosinophil counts. One additional monoclonal antibody, benralizumab (MEDI-563), has been developed to target IL-5R and attenuate eosinophilia through antibody-dependent cellular cytotoxicity. All three monoclonal antibodies are being clinically evaluated. Antisense oligonucleotide technology targeting the common βc IL-5R subunit is also being used therapeutically to inhibit IL-5-mediated effects (TPI ASM8). Small interfering RNA technology has also been used therapeutically to inhibit the expression of IL-5 in animal models. This review summarizes the structural interactions between IL-5 and IL-5R and the functional consequences of such interactions, and describes the pre-clinical and clinical evidence supporting IL-5R as a therapeutic target.

Asthma is a complex disease characterized by variable airflow limitation, hyperresponsiveness, and airways inflammation. Despite valuable therapeutic advances to control asthma symptoms in the last decade, a quantifiable proportion of patients with moderate to severe asthma continue to experience inadequate disease control, highlighting an important unmet need. In animal models of asthma, interleukin (IL)-9 regulates the development of airway inflammation, mucus production, airway hyperresponsiveness, and airway fibrosis largely by increasing mast cell numbers and activity in the airways. Mast cells are involved in the pathogenesis of eosinophilic and noneosinophilic asthma. Thus, targeting the IL-9 pathway may provide a new therapeutic modality for asthma. The purpose of this review is to summarize the IL-9-mast cell axis in the pathogenesis of asthma and discuss clinical studies with a humanized anti-IL-9 monoclonal antibody, MEDI-528, in subjects with asthma.

Asthma is a complex, persistent, inflammatory disease characterised by airway hyperresponsiveness in association with airway inflammation. Studies suggest that regular use of high-dose inhaled corticosteroids and long-acting bronchodilators or omalizumab (a humanised monoclonal antibody that binds to immunoglobulin E and is often used as next-step therapy) may not be sufficient to provide asthma control in all patients, highlighting an important unmet need. Interleukin-4, interleukin-13, and the signal transducer and activator of transcription factor-6 are key components in the development of airway inflammation, mucus production, and airway hyperresponsiveness in asthma. Biological compounds targeting these molecules may provide a new therapeutic modality for patients with uncontrolled severe asthma. The purpose of this review is to summarise current studies of compounds targeting the interleukin-4/interleukin-13 pathway and to provide a rationale for the development of such compounds for this use.

To assess the bioavailability and pharmacokinetics of CAT-354, an anti-IL-13 human monoclonal IgG4 antibody, following subcutaneous (s.c.) and intravenous (i.v.) administration.This was a single-dose, randomized, open-label, parallel-group bioavailability study. Healthy male subjects aged 20-54 years were randomly assigned to one of three dose groups (n= 10/group) to receive CAT-354: 150 mg i.v.; 150 mg s.c. or 300 mg s.c. (two 150 mg injections). Serum pharmacokinetics, adverse events (AEs), vital signs, electrocardiograms and laboratory parameters were assessed.CAT-354 showed bioavailability of 62% and 60% after 150 mg and 300 mg s.c. doses, respectively, and linear pharmacokinetics over the dose range tested. Peak serum concentrations in the s.c. groups occurred after 3-9 (median 5) days, with a mean elimination half-life of 19.2 +/- 3.1 days (150 mg) and 19.4 +/- 3.59 days (300 mg) after s.c. and 21.4 +/- 2.46 days after i.v. administration. Volume of distribution at steady state (V(ss)) was 4960 +/- 1440 ml kg(-1) after i.v. (slightly greater than plasma volume). Average apparent clearances (CL/F) were 292 +/- 82.3 and 307 +/- 109 ml day(-1) after 150 and 300 mg s.c., respectively; systemic CL of 188 +/- 84.0 ml day(-1) after i.v. dosing was consistent with endogenous IgG and reticuloendothelial elimination. No severe or serious AEs occurred. Among 40 reported AEs, 25 were headache, sinus disorders/respiratory symptoms and changes in body temperature perception.CAT-354 exhibited bioavailability of approximately 60% when given s.c. to healthy male subjects.

Background IL-13 has been implicated in the development of airway inflammation and hyperresponsiveness. This study investigated the multiple-dose pharmacokinetics and safety profile of human anti-IL-13 antibody (CAT-354) in adults with asthma. Methods This was a multiple-dose, randomised, double-blind, placebo-controlled phase 1 study in asthmatics (forced expiratory volume in 1 second [FEV1] ≥ 80% predicted). Subjects were randomised to receive three intravenous infusions of CAT-354 (1 mg/kg, 5 mg/kg or 10 mg/kg) or placebo at 28-day intervals. Blood samples were taken for pharmacokinetic measurements. Safety was assessed by adverse events, vital signs, ECGs, laboratory and pulmonary function parameters. Results Twenty-three subjects (aged 21-60 years, FEV1 88-95% predicted) received ≥ 1 dose of study medication. The half-life of CAT-354 was 12-17 days and was dose-independent. The maximum serum concentration and area under the curve were dose-dependent. Clearance (2.2-2.6 mL/day/kg) and volume of distribution (44-57 mL/kg) were both low and dose-independent. The observed maximum serum concentration after each dose increased slightly from dose 1 through dose 3 at all dose levels, consistent with an accumulation ratio of 1.4 to 1.7 for area under the curve. Most adverse events were deemed mild to moderate and unrelated to study medication. One SAE was reported and deemed unrelated to study drug. There were no effects of clinical concern for vital signs, ECG, laboratory or pulmonary parameters. Conclusions CAT-354 exhibited linear pharmacokinetics and an acceptable safety profile. These findings suggest that at the doses tested, CAT-354 can be safely administered in multiple doses to patients with asthma. Trial registration NCT00974675.