Mepolizumab for Treating Severe Eosinophilic Asthma: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the company (GlaxoSmithKline) that manufactures mepolizumab (Nucala(®)) to submit evidence on the clinical and cost effectiveness of mepolizumab for the treatment of severe eosinophilic asthma. The School of Health and Related Research Technology Appraisal Group (ScHARR-TAG) at the University of Sheffield was commissioned to act as the independent evidence review group (ERG). The ERG produced a review of the evidence for the clinical and cost effectiveness of mepolizumab as add-on to standard of care (SoC) compared with SoC and omalizumab, based upon the company's submission to NICE. The clinical-effectiveness evidence in the company's submission was based predominantly on three randomised controlled trials (DREAM, MENSA and SIRIUS) comparing add-on mepolizumab with placebo plus SoC. The relevant population was defined in terms of degree of asthma severity (four or more exacerbations in the previous year and/or dependency on maintenance oral corticosteroids [mOCS]) and degree of eosinophilia (a blood eosinophil count of ≥ 300 cells/µl in the previous year) based on post hoc subgroup analyses of the pivotal trials. Other subpopulations were considered throughout the appraisal, defined by different eosinophil measurements, number of exacerbations and dependency (or lack thereof) on mOCS. Statistically significant reductions in clinically significant exacerbations were observed in patients receiving mepolizumab compared with SoC meta-analysed across MENSA and DREAM in the modified intention-to-treat (ITT) population (rate ratio [RR] 0.51; 95% confidence interval [CI] 0.42-0.62) as well as in the relevant population (RR 0.47; 95% CI 0.36-0.62). In terms of quality of life, differences on the St. George's Respiratory Questionnaire in MENSA for add-on subcutaneous mepolizumab 100 mg vs. placebo were 7 and 7.5 units in the modified ITT and relevant populations, respectively. A number of issues in the clinical evidence base warrant caution in its interpretation. The ERG noted that the definition of SoC used in the trials differed from that in clinical practice, where patients with severe uncontrolled asthma start treatment with a mOCS. The company's economic post-consultation analysis incorporating a confidential patient access scheme (PAS) estimated that the incremental cost-effectiveness ratio (ICER) for add-on mepolizumab compared with SoC was £27,418 per quality-adjusted life-year (QALY) gained in the relevant population if patients stopped mepolizumab after 1 year unless (1) the number of exacerbations decreased at least 50% or (2) a reduction in corticosteroids dose was achieved whilst maintaining asthma control. The ERG applied an age adjustment to all utilities and corrected the post-continuation assessment utilities, which resulted in an ICER for add-on mepolizumab compared with SoC of £29,163 per QALY gained. The ERG noted that this ICER was not robust for patients who continued treatment due to a corticosteroid dose reduction where exacerbations had decreased by less than 50%, because corticosteroid dose reduction was not allowed in the main trial in which the evidence was gathered (MENSA). The NICE appraisal committee (AC) concluded that add-on mepolizumab could be recommended as an option for treating severe refractory eosinophilic asthma in adults for the relevant population when the stopping rule suggested by the company was applied. The AC also concluded that the comparison between mepolizumab and omalizumab was not clinically relevant or methodologically robust

Inflammatory Profiles in Chronic Obstructive Pulmonary Disease and Asthma

Historically, asthma and chronic obstructive pulmonary disease (COPD) represent polar ends of the spectrum of airways disease defined in part by distinctive profiles of airway inflammation; in practice, overlap can exist between asthma and COPD. This thesis examined the pattern of inflammatory cell infiltration and cytokine expression within the bronchus in COPD and asthma with further study of moderate-severe asthma. In addition using sputum, cytokine expression was further assessed in COPD and asthma and its relation to severity. Based on previous studies, this thesis examined the expression of specifically Interleukin (IL)-13 and Granulocyte Macrophage Colony Stimulating Factor (GMCSF). We demonstrated mast cell myositis in moderate and severe asthma which reflected increased disease symptoms. Preferential localization of inflammatory cells to airway smooth muscle (ASM) was absent in COPD. CD3+ T-cells infiltration of large airway glands was increased in COPD which may influence mucus hyper-secretion. We demonstrated IL-13 overexpression within the submucosa in moderate-severe asthma with specific increase in the ASM in severe disease. IL-13 expression was related to eosinophilic inflammation. In sputum, IL-13 protein was increased in mild and severe asthma reflecting IL-13 expression in ASM. There was a general absence of bronchus and sputum IL-13 in COPD. Sputum GMCSF was increased in moderate-severe asthma and mild-severe COPD. Parallel upregulation of GMCSF and associated receptor (GMCSFr) expression in the submucosa and ASM was present in severe asthma. GMCSF/GMCSFr expression did not exhibit preferential expression in the large airway of COPD. Our findings suggest inflammatory cell infiltration of the airway structures is present in asthma and COPD which may influence the phenotype. In addition IL-13 is important in severe asthma whilst GMCSF is expressed in asthma and COPD across a range of severity, but to a greater degree in severe asthma

Inflammatory profiles in chronic obstructive pulmonary disease and asthma

Historically, asthma and chronic obstructive pulmonary disease (COPD) represent polar ends of the spectrum of airways disease defined in part by distinctive profiles of airway inflammation; in practice, overlap can exist between asthma and COPD. This thesis examined the pattern of inflammatory cell infiltration and cytokine expression within the bronchus in COPD and asthma with further study of moderate-severe asthma. In addition using sputum, cytokine expression was further assessed in COPD and asthma and its relation to severity. Based on previous studies, this thesis examined the expression of specifically Interleukin (IL)-13 and Granulocyte Macrophage Colony Stimulating Factor (GMCSF). We demonstrated mast cell myositis in moderate and severe asthma which reflected increased disease symptoms. Preferential localization of inflammatory cells to airway smooth muscle (ASM) was absent in COPD. CD3+ T-cells infiltration of large airway glands was increased in COPD which may influence mucus hyper-secretion. We demonstrated IL-13 overexpression within the submucosa in moderate-severe asthma with specific increase in the ASM in severe disease. IL-13 expression was related to eosinophilic inflammation. In sputum, IL-13 protein was increased in mild and severe asthma reflecting IL-13 expression in ASM. There was a general absence of bronchus and sputum IL-13 in COPD. Sputum GMCSF was increased in moderate-severe asthma and mild-severe COPD. Parallel upregulation of GMCSF and associated receptor (GMCSFr) expression in the submucosa and ASM was present in severe asthma. GMCSF/GMCSFr expression did not exhibit preferential expression in the large airway of COPD. Our findings suggest inflammatory cell infiltration of the airway structures is present in asthma and COPD which may influence the phenotype. In addition IL-13 is important in severe asthma whilst GMCSF is expressed in asthma and COPD across a range of severity, but to a greater degree in severe asthma.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Granulocyte-macrophage colony-stimulating factor expression in induced sputum and bronchial mucosa in asthma and COPD

Background: Granulocyte–macrophage colony-stimulating factor (GM-CSF) has been implicated as an important mediator in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). However, the expression of GM-CSF and its receptor in airway samples in asthma and COPD across disease severity needs to be further defined. Methods: Sputum GM-CSF was measured in 18 control subjects, 45 subjects with asthma and 47 subjects with COPD. Enumeration of GM-CSF+ cells in the bronchial submucosa and airway smooth muscle bundle was performed in 29 control subjects, 36 subjects with asthma and 10 subjects with COPD. Results: The proportion of subjects with measurable GMCSF in the sputum was raised in those with moderate (7/ 14) and severe (11/18) asthma, and in those with COPD GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage II (7/16), III (8/17) and IV (7/14) compared with controls (1/18) and those with mild asthma (0/13); p=0.001. The sputum GM-CSF concentration was correlated with the sputum eosinophilia in subjects with moderate to severe asthma (rs=0.41; p=0.018). The median (interquartile range) GM-CSF+ and GM-CSFR+ cells/mm2 of submucosa was increased in severe asthma (1.4 (3.0) and 2.1 (8.4)) compared with those with mild to moderate asthma (0 (2.5) and 1.1 (5)) and healthy controls (0 (0.5) and 0 (1.6)), (p=0.004 and p=0.02, respectively). Conclusions: The findings support a potential role for GM-CSF in asthma and COPD and suggest that overexpression of GM-CSF in sputum and the bronchial mucosa is a particular feature of severe asthma