Eric S. Bradford

Mepolizumab for Eosinophilic Chronic Obstructive Pulmonary Disease

BACKGROUND Patients with chronic obstructive pulmonary disease (COPD) with an eosinophilic phenotype may benefit from treatment with mepolizumab, a monoclonal antibody directed against interleukin‐5. METHODS We performed two phase 3, randomized, placebo‐controlled, double‐blind, parallel‐group trials comparing mepolizumab (100 mg in METREX, 100 or 300 mg in METREO) with placebo, given as a subcutaneous injection every 4 weeks for 52 weeks in patients with COPD who had a history of moderate or severe exacerbations while taking inhaled glucocorticoid‐based triple maintenance therapy. In METREX, unselected patients in the modified intention‐to‐treat population with an eosinophilic phenotype were stratified according to blood eosinophil count (≥150 per cubic millimeter at screening or ≥300 per cubic millimeter during the previous year). In METREO, all patients had a blood eosinophil count of at least 150 per cubic millimeter at screening or at least 300 per cubic millimeter during the previous year. The primary end point was the annual rate of moderate or severe exacerbations. Safety was also assessed. RESULTS In METREX, the mean annual rate of moderate or severe exacerbations in the modified intention‐to‐treat population with an eosinophilic phenotype (462 patients) was 1.40 per year in the mepolizumab group versus 1.71 per year in the placebo group (rate ratio, 0.82; 95% confidence interval [CI], 0.68 to 0.98; adjusted P=0.04); no significant between‐group differences were found in the overall modified intention‐to‐treat population (836 patients) (rate ratio, 0.98; 95% CI, 0.85 to 1.12; adjusted P>0.99). In METREO, the mean annual rate of moderate or severe exacerbations was 1.19 per year in the 100‐mg mepolizumab group, 1.27 per year in the 300‐mg mepolizumab group, and 1.49 per year in the placebo group. The rate ratios for exacerbations in the 100‐mg and 300‐mg mepolizumab groups versus the placebo group were 0.80 (95% CI, 0.65 to 0.98; adjusted P=0.07) and 0.86 (95% CI, 0.70 to 1.05; adjusted P=0.14), respectively. A greater effect of mepolizumab, as compared with placebo, on the annual rate of moderate or severe exacerbations was found among patients with higher blood eosinophil counts at screening. The safety profile of mepolizumab was similar to that of placebo. CONCLUSIONS Mepolizumab at a dose of 100 mg was associated with a lower annual rate of moderate or severe exacerbations than placebo among patients with COPD and an eosinophilic phenotype. This finding suggests that eosinophilic airway inflammation contributes to COPD exacerbations. (Funded by GlaxoSmithKline; METREX and METREO ClinicalTrials.gov numbers, NCT02105948 and NCT02105961.)

Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial

BACKGROUND Mepolizumab, an anti-interleukin-5 monoclonal antibody approved as add-on therapy to standard of care for patients with severe eosinophilic asthma, has been shown in previous studies to reduce exacerbations and dependency on oral corticosteroids compared with placebo. We aimed to further assess mepolizumab in patients with severe eosinophilic asthma by examining its effect on health-related quality of life (HRQOL). METHODS We did a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial (MUSCA) in 146 hospitals or research centres in 19 countries worldwide. Eligible participants were patients aged 12 years or older with severe eosinophilic asthma and a history of at least two exacerbations requiring treatment in the previous 12 months before screening despite regular use of high-dose inhaled corticosteroids plus other controller medicines. Exclusion criteria included current smokers or former smokers with a history of at least ten pack-years. We randomly assigned participants (1:1) by country to receive a subcutaneous injection of either mepolizumab 100 mg or placebo, plus standard of care, every 4 weeks for 24 weeks (the final dose was given at week 20). We did the randomisation using an interactive voice response system and a centralised, computer-generated, permuted-block design of block size six. The two treatments were identical in appearance and administered in a masked manner; patients, investigators, other site staff and the entire study team including those assessing outcomes data were also masked to group assignment. The primary endpoint was the mean change from baseline in the St Georges Respiratory Questionnaire (SGRQ) total score at week 24 in the modified intention-to-treat (modified ITT) population (analysed according to their randomly assigned treatment). Safety was assessed in all patients who received at least one dose of trial medication (analysed according to the actual treatment received). This trial is registered with ClinicalTrials.gov, number NCT02281318. FINDINGS We recruited patients between Dec 11, 2014, and Nov 20, 2015, and the study was undertaken between Dec 11, 2014, and June 10, 2016. The modified ITT population comprised 274 patients assigned to mepolizumab 100 mg and 277 assigned to placebo. Mepolizumab versus placebo showed significant improvements at week 24 from baseline in SGRQ total score (least squares mean [SE] change from baseline -15·6 (1·0) vs -7·9 (1·0), a treatment difference of -7·7 (95% CI -10·5 to -4·9; p<0·0001). No deaths occurred during the study. 192 (70%) of 273 patients who received mepolizumab and 207 (74%) of 278 who received placebo reported at least one on-treatment adverse event, the most common of which were headache (in 45 [16%] given mepolizumab vs 59 [21%] given placebo) and nasopharyngitis (in 31 [11%] given mepolizumab vs 46 [17%] given placebo). 15 (5%) and 22 (8%) patients had an on-treatment serious adverse event in the mepolizumab and placebo groups, respectively; the most common was asthma in both groups (in three [1%] given mepolizumab vs nine [3%] given placebo). INTERPRETATION Mepolizumab was associated with significant improvements in HRQOL in patients with severe eosinophilic asthma, and had a safety profile similar to that of placebo. These results add to and support the use of mepolizumab as a favourable add-on treatment option to standard of care in patients with severe eosinophilic asthma. FUNDING GlaxoSmithKline.

Biologic treatment eligibility for real-world patients with severe asthma: The IDEAL study

ABSTRACT Objectives: Severe asthma comprises several distinct phenotypes. Consequently, patients with severe asthma can be eligible for more than one biologic treatment targeting Th2 inflammation, such as anti-interleukin (IL)-5 and anti-immunoglobulin (Ig) E. The objective of this study was to describe treatment eligibility and overlap in treatment eligibility for mepolizumab (anti-IL-5), omalizumab (anti-IgE) and reslizumab (anti-IL-5) in patients with severe asthma, who were recruited from clinical practice. Methods: This cross-sectional, single-visit, observational study in six countries enrolled patients with severe asthma (defined by American Thoracic Society/European Respiratory Society guidelines). Assessable patients were analysed as a total cohort and a sub-cohort, who were not currently receiving omalizumab. Treatment eligibility was defined according to the local prescribing information or protocol-defined inclusion/exclusion criteria. Patients currently receiving omalizumab were automatically categorised as omalizumab-eligible. Results: The total cohort comprised 670 patients who met the analysis criteria, of whom 20% were eligible for mepolizumab, 31–41% were eligible for omalizumab (depending on eligibility criteria used), and 5% were eligible for reslizumab. In patients not currently receiving omalizumab (n = 502), proportions eligible for each biologic were similar (mepolizumab: 20%, reslizumab 6%) or lower (omalizumab 7–21%) than those for the total cohort. Overlap in treatment eligibility varied; in mepolizumab-eligible patients not currently receiving omalizumab (n = 101), 27–37% were omalizumab-eligible and 18% were reslizumab-eligible. Conclusions: Treatment eligibility for mepolizumab and omalizumab was higher than that for reslizumab. Although there was some overlap in treatment eligibility, the patient groups eligible for treatment with anti-IL-5 or anti-IgE therapies were often distinct, emphasising the different phenotypes and endotypes in severe asthma.

Response to case report: Airway autoimmune responses in severe eosinophilic asthma following low-dose Mepolizumab therapy

© The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. To the Editor,

The impact of long-term systemic glucocorticoid use in severe asthma: A UK retrospective cohort analysis

ABSTRACT Objective: Systemic glucocorticoids (SGCs) are a treatment option for severe asthma but are associated with the development of adverse events (AEs). Evidence on the extent of SGC use and the relationship between SGC dose and AE risk in severe asthma is limited. Methods: Patients with severe asthma (Global Initiative for Asthma step 4/5), with no SGC use during the <6–12 months before severe asthma determination (index date) were identified in the UK-based Clinical Practice Research Datalink database (2004–2012). Patients were assessed for SGC exposure and an incident diagnosis of an SGC-related AE (cataracts, diabetes, myocardial infarction [MI], osteoporosis, peptic ulcer or stroke) during the 8-year observation phase. The dose-related risk of an SGC-related AE was determined using AE-specific Cox proportional hazards models. Results: Overall, 75% of 60,418 patients identified with severe asthma received SGC during the 8-year follow-up, with the majority receiving an average of >0–≤2.5 mg/day. The risk of diabetes (hazard ratio [HR]:1.20 [95% confidence interval (CI): 1.11, 1.30]), MI (HR: 1.25 [95% CI: 1.09, 1.43]) and osteoporosis (HR: 1.64 [95% CI: 1.51, 1.78]) was increased at low SGC doses (0–2.5 mg/day), with further risk increases at doses >2.5 mg/day versus no SGC use. Compared with no SGC use, SGC increased the risk of peptic ulcer in a non-dose-dependent manner, but the risk of stroke was unchanged. Conclusions: Most patients with severe asthma are exposed to SGC, which increases SGC-related AE risk. This suggests that SGC exposure should be minimized as recommended by asthma treatment guidelines.

Reappraisal of the clinical effect of mepolizumab – Authors' reply

Authors’ reply In reference to the letter by Brian J Lipworth and Sunny Jabbal on our MUSCA publication, 1 we would like to respond to the points presented. They state that the St George’s Respiratory Questionnaire (SGRQ) is not suitable for assessing health-related quality of life (HRQOL) in asthma. However, the SGRQ was actually developed with input from patients with asthma. Additionally, the specific content validity of the SGRQ in severe eosinophilic asthma has been shown. By contrast, studies using the asthma QOL questionnaire have shown poor responsiveness in distinguishing treatment differences with novel therapies. Lipworth and Jabbal also questioned the clinical relevance of the SGRQ results. However, the 7·7 unit change in MUSCA was approximately twice the minimum clinically important difference (MCID), defined as “the smallest difference in score that patients perceive as beneficial”. Additionally, in the MUSCA study the treatment difference between mepolizumab versus placebo was similar for patients with severe eosinophilic asthma with a 4 point or more versus 8 point or more improvement from baseline in SGRQ (table), implying consistent treatment benefit regardless of specific SGRQ thresholds. Furthermore, these results are supported by Jones and colleagues’ publication, which showed that treatment differences are largely independent of the responder threshold. The authors’ also stated that the 120 mL improvement in FEV1 did not exceed the MCID of 230 mL. However, this MCID was determined in patients with mild-to-moderate asthma and might not be suitable for patients with severe eosinophilic asthma. Furthermore, 120 mL was the mepolizumab versus placebo treatment difference and not the within patient change from baseline. Additionally, while current smokers were excluded and there was a high degree of reversibility in patients with severe eosinophilic asthma, these characteristics are generally consistent with previous studies. In summary, there is clear evidence that the SGRQ is an appropriate measure of HRQOL in severe asthma, and that the MUSCA study showed clinically meaningful improvements in HRQOL and improvements in lung function in patients with severe eosinophilic asthma.

Characteristics of adult onset vs. late onset asthma - a multinational database cohort study

Background: Although early onset asthma has been well characterised, data on adult onset asthma are scarce. Aims: To describe characteristics of adult onset asthma using data from 5 European electronic health record (EHR) databases in the study period 2008-2013. Methods: Asthma patients aged ≥18 yrs at diagnosis (COPD excluded) and with ≥1 year of follow-up were identified in EHR databases from the Netherlands (IPCI), Italy (HSD), UK (CPRD), Denmark (AUH) and Spain (SIDIAP). Patients were categorised into early adult onset asthma (>=18-39 yrs) or late onset asthma (>=40 yrs) based on the age at diagnosis. Characteristics were assessed at study start. Differences were tested with Chi-Square and Mann Whitney U test. The analysis was repeated in severe asthma only (use of high dose ICS + controller therapy for ≥120 days). Results: We included 504,745 patients (median age from 44.5-48.0 yrs) with asthma of whom 40,193 (8.0%) had severe asthma. The proportion of late onset asthma was 56.8% (range 56-60.1% across database) which increased to 70.4% (range 66.5-91.6%) in severe asthma. Compared to early adult onset asthma, patients with late onset asthma were less frequently atopic (range 9.2-28.7% across database vs. 21.5-39.5%), suffered more frequently from chronic rhinosinusitis (0.4-11.2% vs. 0.2-8.0%) and/or nasal polyposis (0.6-4.6% vs. 0.3-1.7%), GERD (2.8-14.3% vs. 0.9-7.5%) and obesity (10.5-72.2% vs. 9.3-54.7%) and had lower median IgE levels (63-91 vs. 108-226 IU/L)(all significant). Similar patterns were observed among severe asthma only. Conclusion: Differences in comorbidity in late onset vs. early adult onset asthma may be important for asthma management. GSK funded (PRJ2284)