Mepolizumab improves work productivity, activity limitation, symptoms, and rescue medication use in severe eosinophilic asthma

Abstract Patients with severe eosinophilic asthma experience daily activity limitations and reduced productivity at work. Using anonymized individual patient‐level data from two previously conducted randomized, double‐blind, placebo‐controlled studies (MENSA [GSK ID:115588/NCT01691521]; MUSCA [GSK ID:200862/NCT02281318]), we investigated the effect of mepolizumab on work productivity, activity limitation, symptoms, and rescue medication use. Patient‐reported outcomes including Work Productivity and Activity Impairment–General Health (WPAI‐GH) scores (impairment percentages, 0%–100%), global activity limitation (scale 1–4), and perceived change in activity limitation (Likert scale 1–7) since the start of the study were analyzed. WPAI‐GH scores from MENSA were analyzed post hoc for employed patients using mixed model repeated measures; global activity limitation and perceived change in activity limitation from MUSCA were analyzed by ordinal logistic regression. Mean changes from baseline in daily asthma symptom scores (scale 0–5) and rescue medication use (occasions/day) were also assessed, via a post hoc meta‐analysis of MENSA and MUSCA. At study end, WPAI‐GH scores indicative of overall work impairment, impairment while working, and activity impairment consistently improved with mepolizumab versus placebo. Overall, 76% versus 54% of patients rated their activity as “much better,” “better,” or “slightly better” since the start of the study with mepolizumab versus placebo. Mepolizumab was associated with numerically larger improvements from baseline in asthma symptoms (treatment difference 0.21–0.29 points) and rescue medication use (treatment difference −0.08 to −0.22 occasions/day) versus placebo. Our results indicate that patients with severe eosinophilic asthma may experience improved activity limitation, work productivity, symptoms, and rescue medication use with mepolizumab.

K E Y W O R D S activities of daily living, eosinophilic asthma, patient-reported outcomes, questionnaire, symptom assessment, work productivity

| INTRODUCTION
Patients with asthma can struggle in their daily activities and ability to work as they cope with numerous symptoms, such as chest tightness, shortness of breath, coughing, wheezing, and difficulty sleeping. 1 These symptoms can result in frequent and high-dose rescue medication use, particularly for patients with severe asthma. 1,2 Those with an eosinophilic phenotype (characterized by persistent airway infiltration with inflammatory eosinophils) 1 typically have reduced lung function, experience frequent exacerbations, and have poor asthma control despite using high-dose inhaled corticosteroids plus ≥1 other controller medication (Global Initiative for Asthma Step IV therapy). 2 They can therefore experience activity limitation, defined as a long-term reduction in a person's capacity to perform the usual type or amount of age-appropriate daily activities. 3 Together with improving symptoms and asthma control, improving work productivity, and minimizing activity limitation are important steps towards addressing the daily disease burden for patients. 2 Mepolizumab is a targeted and selective antiinterleukin 5 monoclonal antibody approved as an addon treatment for severe eosinophilic asthma in multiple regions worldwide, and for eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome in the United States. 4,5 Clinical trials in patients with severe eosinophilic asthma have demonstrated that compared with placebo, mepolizumab reduces blood eosinophil counts, exacerbation rates, and the need for oral corticosteroids (OCS), in addition to improving lung function Very limited n/a n/a 23 (8) 20 (7) Missing n/a n/a 3 (1) 1 (<1) Note: All values are mean (SD) unless otherwise stated; n/a values are owing to data not collected in the parent study. Abbreviations: BMI, body mass index; n/a, not available; PEF, peak expiratory flow; SC, subcutaneous; WPAI-GH, Work Productivity and Activity Impairment-General Health.
F I G U R E 1 Treatment difference in WPAI-GH scores (MENSA) and odds ratio for activity limitation ratings (MUSCA) for mepolizumab versus placebo at study end † . Four MUSCA patients with missing Global Rating of Activity Limitation data at baseline were not included in this analysis. The analysis of MENSA WPAI-GH scores was conducted post hoc. † Study end was Week 32 for MENSA and Week 24 for MUSCA; ‡ due to health. CI, confidence interval; WPAI-GH, Work Productivity and Activity Impairment-General Health and health-related quality of life. 6

| REPORT
Work productivity and activity impairment were assessed in MENSA using the Work Productivity and Activity Impairment-General Health (WPAI-GH) questionnaire 9 (recall period 7 days). Activity limitation was assessed in MUSCA using two single-item questionnaires that quantified patients' global rating of activity limitation and global impression of change in activity limitation since the start of the study. In both studies, asthma symptom scores for the previous 24 h and rescue medication (salbutamol/albuterol) use were monitored via daily eDiary tools. Table S1 provides a summary of all outcomes and the methodology used for their analysis. Ethical approval and written informed patient consent were obtained for both parent studies. patients were using salbutamol/albuterol on 1.5-1.9 occasions/day (Table 1). Following 32 weeks of treatment, we observed consistent improvements with mepolizumab versus placebo in overall work impairment, impairment while working, and activity impairment; a smaller improvement in work time missed was observed ( Figure 1A). Patients' perception of their activity limitation also notably improved with mepolizumab versus placebo ( Figure 1B). After 24 weeks, 76% versus 54% of patients rated their activity as "much better," "better," or "slightly better" since the start of the study with mepolizumab versus placebo ( Figure 2). The proportion of patients rating their activity as "not" or "slightly" limited increased an extra 10% from baseline with mepolizumab versus placebo (Figure 2). Across all follow-up intervals, mean changes from baseline in symptom scores were numerically larger with mepolizumab than placebo (treatment difference 0.21 to 0.29 points; Figure 3). Similarly, mean reductions from baseline in daily salbutamol/albuterol use were numerically larger with mepolizumab versus placebo (treatment difference À0.08 to À0.22 occasions/day; Figure 3).

| RESULTS AND DISCUSSIONS
These results demonstrate that compared with placebo, mepolizumab in addition to optimized standard of care improves work productivity and daily activity limitations for patients with severe eosinophilic asthma. Moreover, mepolizumab appears to improve daily asthma symptoms and the need for rescue medications. Complementary to these findings, a previous analysis of data from the MENSA and MUSCA trials showed that mepolizumab also improves morning peak expiratory flow for patients with severe eosinophilic asthma. 10 Overall, 33% (n = 126/385) and 34% (n = 123/364) of the MENSA patients included in this analysis were in full-time employment (≥35 h/week) at baseline and at study end; this is somewhat lower than the 75% of patients with asthma estimated to be in full-time employment by a recent multinational survey 11 and is likely F I G U R E 3 Mean treatment differences in (A) change from baseline in daily asthma symptom scores and (B) daily rescue medication use, by 4-week period † . † Data collected daily using eDiary tool and averaged over 4-week periods. CI, confidence interval reflective of the increased symptom severity associated with severe eosinophilic asthma. Although only a small difference in work time missed was observed from baseline to follow-up, enabling patients to increase their productivity at work may lead to indirect cost benefits for employers and for society. 12 It is worth noting that owing to the post hoc and exploratory nature of these analyses, statistical significance tests were not performed. Moreover, although the WPAI-GH questionnaire is widely used for assessing work productivity and activity impairment across a range of chronic conditions, it has not been validated specifically for use in patients with asthma. Finally, although both trials demonstrated improvements, real-world analyses could identify any longer-term impact of mepolizumab on daily disease burden.

| CONCLUSIONS
Patients with severe eosinophilic asthma may benefit from improved symptoms with mepolizumab, which may in turn lead to improvements in work productivity, activity limitation, and rescue medication use. These data complement the results of the MENSA and MUSCA studies, which showed reductions in exacerbations and hospitalizations with mepolizumab. Moreover, they demonstrate reductions in daily disease burden with optimized standard of care plus mepolizumab and may be an important consideration for healthcare practitioners in their clinical decision making.

ACKNOWLEDGMENTS
Editorial support (in the form of writing assistance, including preparation of the draft manuscript under the direction and guidance of the authors, collating and incorporating authors' comments for each draft, assembling tables and figures, grammatical editing and referencing) was provided by Bianca Paris PhD, at Fishawack Indicia Ltd, part of Fishawack Health, and was funded by GSK.

CONFLICT OF INTEREST
FCA is an employee of Avillion US, Inc., and a former employee of GSK with stock/stock options in GSK. DJB, SMC, and RAC are all employees of GSK and hold stock/ stock options in GSK. NBG is an employee of AbbVie Ltd and a former employee of GSK. GJB has received research grants from GSK, Novartis, Chiesi, and AstraZeneca; personal fees from ALK-Abello, Sanofi, Novartis, Chiesi, and AstraZeneca.
AUTHOR CONTRIBUTIONS FCA, DJB, NBG, SMC, and RAC all contributed to the conception and design of the analysis. GJB was involved in the acquisition of data. All authors were involved in the analysis and interpretation of the data, critically revised the manuscript for intellectual content, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work.

ETHICS STATEMENT
Ethical approval and written informed patient consent were obtained for the parent studies on which this analysis is based.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.