Mepolizumab for Severe Eosinophilic Asthma (DREAM): A Multicentre, Double-Blind, Placebo-Controlled Trial
TL;DR: To elucidate the efficacy, safety, and patient characteristics of responsiveness to mepolizumab (a humanized monoclonal antibody against interleukin 5), a large number of patients with severe, eosinophilic asthma were enrolled in 81 multinational centers.
Abstract: ID Pavord, S Korn, P Howarth. Lancet. 2012;380(9842):651–659
To elucidate the efficacy, safety, and patient characteristics of responsiveness to mepolizumab (a humanized monoclonal antibody against interleukin 5). Previous small, proof-of-concept studies in subjects with severe, eosinophilic asthma revealed that mepolizumab decreased exacerbation rates.
From 81 multinational centers, 621 pa-tients were enrolled. Major inclusion criteria included: age 12 to 74 years, asthma diagnosis with objective measures, ≥2 asthma exacerbations requiring oral corticosteroids in the last year, refractory asthma as defined by the American …
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National Institutes of Health1, University of Pittsburgh2, McMaster University3, University of Washington4, University of Cape Town5, Wake Forest University6, University of Leicester7, Karolinska Institutet8, University of Southampton9, Boston Children's Hospital10, John Hunter Hospital11, McGill University12, University of Wisconsin-Madison13, University of Virginia14
TL;DR: Recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults and coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy are provided.
Abstract: Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults. A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations. When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming “uncontrolled” or that remains “uncontrolled” despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided. Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.
2,795 citations
Cites background from "Mepolizumab for Severe Eosinophilic..."
...Eosinophilic inflammation, for instance, is likely to have a Th2 immune component, a reflection of adaptive immunity, as evidenced by four separate studies demonstrating efficacy of a monoclonal antibody to IL-5 in eosinophilic severe asthma in adults [13, 67-69]....
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...A larger study with mepolizumab showed efficacy in adults and adolescents solely in terms of a reduction in exacerbation rate, without improvement in FEV1 and quality of life [67]....
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...Adverse profile side-effects Pavord et al, 2012 [67] Severe, with 2 or > exacerbations in past year/621 R,db,pc,p Mepolizumab (75, 250 or 750 mg infusions at 4 weeks), anti-IL-5, 52w Rate of exacerbations All doses reduced exacerbations by 39 to 52%....
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TL;DR: Mepolizumab administered either intravenously or subcutaneously significantly reduced asthma exacerbations and was associated with improvements in markers of asthma control and the safety profile of mepolIZumab was similar to that of placebo.
Abstract: 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 randomized, 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 Questionnaire (SGRQ) and the 5-item Asthma Control Questionnaire (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 clinically 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 clinically 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 ClinicalTrials.gov number, NCT01691521.).
1,680 citations
TL;DR: In patients with persistent, moderate-to-severe asthma and elevated eosinophil levels who used inhaled glucocorticoids and LABAs, dupilumab therapy, as compared with placebo, was associated with fewer asthma exacerbations when LABs and inhaled GLPAs were withdrawn, with improved lung function and reduced levels of Th2-associated inflammatory markers.
Abstract: Background Moderate-to-severe asthma remains poorly treated. We evaluated the efficacy and safety of dupilumab (SAR231893/REGN668), a fully human monoclonal antibody to the alpha subunit of the interleukin-4 receptor, in patients with persistent, moderate-to-severe asthma and elevated eosinophil levels. Methods We enrolled patients with persistent, moderate-to-severe asthma and a blood eosinophil count of at least 300 cells per microliter or a sputum eosinophil level of at least 3% who used medium-dose to high-dose inhaled glucocorticoids plus long-acting beta-agonists (LABAs). We administered dupilumab (300 mg) or placebo subcutaneously once weekly. Patients were instructed to discontinue LABAs at week 4 and to taper and discontinue inhaled glucocorticoids during weeks 6 through 9. Patients received the study drug for 12 weeks or until a protocol-defined asthma exacerbation occurred. The primary end point was the occurrence of an asthma exacerbation; secondary end points included a range of measures of a...
1,102 citations
Cites background from "Mepolizumab for Severe Eosinophilic..."
...Upper respiratory tract infection 9 (17) 7 (13)...
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University of Oxford1, Wellington Management Company2, University of Barcelona3, University of Melbourne4, University of Amsterdam5, Erasmus University Rotterdam6, Ghent University Hospital7, National Institutes of Health8, Imperial College London9, Université de Montréal10, University of California, San Francisco11, Boston Children's Hospital12, University of Newcastle13, John Hunter Hospital14, Queen's University Belfast15, University of Western Australia16, Université Paris-Saclay17, French Institute of Health and Medical Research18, University of New South Wales19, University of Arizona20, Ludwig Maximilian University of Munich21, University of Pittsburgh22, University of Cape Town23
TL;DR: The only way to make progress in the future is to be much more clear about the meaning of the labels used for asthma and to acknowledge the assumptions associated with them, which are believed to be the most important causes of the stagnation in key clinical outcomes observed in the past 10 years.
712 citations
TL;DR: The power of ILCs may be controlled or unleashed to regulate or enhance immune responses in disease prevention and therapy and in immunopathology, where they play an intriguing role beyond immunity.
Abstract: Innate lymphoid cells (ILCs) are a growing family of immune cells that mirror the phenotypes and functions of T cells. However, in contrast to T cells, ILCs do not express acquired antigen receptors or undergo clonal selection and expansion when stimulated. Instead, ILCs react promptly to signals from infected or injured tissues and produce an array of secreted proteins termed cytokines that direct the developing immune response into one that is adapted to the original insult. The complex cross-talk between microenvironment, ILCs, and adaptive immunity remains to be fully deciphered. Only by understanding these complex regulatory networks can the power of ILCs be controlled or unleashed in order to regulate or enhance immune responses in disease prevention and therapy.
663 citations
References
More filters
National Institutes of Health1, University of Pittsburgh2, McMaster University3, University of Washington4, University of Cape Town5, Wake Forest University6, University of Leicester7, Karolinska Institutet8, University of Southampton9, Boston Children's Hospital10, John Hunter Hospital11, McGill University12, University of Wisconsin-Madison13, University of Virginia14
TL;DR: Recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults and coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy are provided.
Abstract: Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults. A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations. When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming “uncontrolled” or that remains “uncontrolled” despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided. Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.
2,795 citations
TL;DR: Mepolizumab administered either intravenously or subcutaneously significantly reduced asthma exacerbations and was associated with improvements in markers of asthma control and the safety profile of mepolIZumab was similar to that of placebo.
Abstract: 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 randomized, 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 Questionnaire (SGRQ) and the 5-item Asthma Control Questionnaire (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 clinically 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 clinically 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 ClinicalTrials.gov number, NCT01691521.).
1,680 citations
TL;DR: In patients with persistent, moderate-to-severe asthma and elevated eosinophil levels who used inhaled glucocorticoids and LABAs, dupilumab therapy, as compared with placebo, was associated with fewer asthma exacerbations when LABs and inhaled GLPAs were withdrawn, with improved lung function and reduced levels of Th2-associated inflammatory markers.
Abstract: Background Moderate-to-severe asthma remains poorly treated. We evaluated the efficacy and safety of dupilumab (SAR231893/REGN668), a fully human monoclonal antibody to the alpha subunit of the interleukin-4 receptor, in patients with persistent, moderate-to-severe asthma and elevated eosinophil levels. Methods We enrolled patients with persistent, moderate-to-severe asthma and a blood eosinophil count of at least 300 cells per microliter or a sputum eosinophil level of at least 3% who used medium-dose to high-dose inhaled glucocorticoids plus long-acting beta-agonists (LABAs). We administered dupilumab (300 mg) or placebo subcutaneously once weekly. Patients were instructed to discontinue LABAs at week 4 and to taper and discontinue inhaled glucocorticoids during weeks 6 through 9. Patients received the study drug for 12 weeks or until a protocol-defined asthma exacerbation occurred. The primary end point was the occurrence of an asthma exacerbation; secondary end points included a range of measures of a...
1,102 citations
University of Oxford1, Wellington Management Company2, University of Barcelona3, University of Melbourne4, University of Amsterdam5, Erasmus University Rotterdam6, Ghent University Hospital7, National Institutes of Health8, Imperial College London9, Université de Montréal10, University of California, San Francisco11, Boston Children's Hospital12, University of Newcastle13, John Hunter Hospital14, Queen's University Belfast15, University of Western Australia16, Université Paris-Saclay17, French Institute of Health and Medical Research18, University of New South Wales19, University of Arizona20, Ludwig Maximilian University of Munich21, University of Pittsburgh22, University of Cape Town23
TL;DR: The only way to make progress in the future is to be much more clear about the meaning of the labels used for asthma and to acknowledge the assumptions associated with them, which are believed to be the most important causes of the stagnation in key clinical outcomes observed in the past 10 years.
712 citations
TL;DR: The power of ILCs may be controlled or unleashed to regulate or enhance immune responses in disease prevention and therapy and in immunopathology, where they play an intriguing role beyond immunity.
Abstract: Innate lymphoid cells (ILCs) are a growing family of immune cells that mirror the phenotypes and functions of T cells. However, in contrast to T cells, ILCs do not express acquired antigen receptors or undergo clonal selection and expansion when stimulated. Instead, ILCs react promptly to signals from infected or injured tissues and produce an array of secreted proteins termed cytokines that direct the developing immune response into one that is adapted to the original insult. The complex cross-talk between microenvironment, ILCs, and adaptive immunity remains to be fully deciphered. Only by understanding these complex regulatory networks can the power of ILCs be controlled or unleashed in order to regulate or enhance immune responses in disease prevention and therapy.
663 citations