Mepolizumab improves clinical outcomes in patients with severe asthma and comorbid conditions.

BACKGROUND: Comorbidities can complicate the management of severe asthma; therefore, the presence of comorbid conditions or traits often need to be considered when considering treatment options for patients with severe asthma. The aim of this analysis is to investigate the efficacy of mepolizumab in patients with severe eosinophilic asthma and comorbidities. METHODS: This was a post hoc analysis (GSK ID:209140) of data from the Phase IIb/III studies DREAM, MENSA, SIRIUS, and MUSCA. Patients aged ≥ 12 years with severe eosinophilic asthma were randomized to: mepolizumab 750, 250, or 75 mg intravenously or placebo (DREAM); mepolizumab 75 mg intravenously or 100 mg subcutaneously or placebo (MENSA); or mepolizumab 100 mg subcutaneously or placebo (SIRIUS and MUSCA) every 4 weeks for 24 weeks in SIRIUS and MUSCA, 32 weeks in MENSA or 52 weeks in DREAM. In this analysis the primary endpoint was the annual rate of clinically significant exacerbations; secondary endpoints were Asthma Control Questionnaire-5 score, St George's Respiratory Questionnaire total score, and pre-bronchodilator forced expiratory volume in 1 s at study end. Subgroups were based on comorbidities at baseline. RESULTS: Overall, 1878 patients received placebo (n = 689) or mepolizumab (n = 1189). Across all comorbidity subgroups mepolizumab reduced the rate of clinically significant exacerbations by 44-68% versus placebo, improved Asthma Control Questionnaire-5 score by 0.27-0.59 points, and improved St George's Respiratory Questionnaire total score by 5.0-11.6 points. Pre-bronchodilator forced expiratory volume in 1 s was improved by 27.1-286.9 mL in all but one comorbidity subgroup, the diabetes mellitus subgroup. CONCLUSIONS: Mepolizumab reduces exacerbations, and improves asthma control, health-related quality of life, and lung function in patients with severe eosinophilic asthma despite comorbid conditions, including upper respiratory conditions, psychopathologies, cardiovascular conditions, gastroesophageal reflux disease, diabetes mellitus, and obesity. TRIAL REGISTRATION: https://clinicaltrials.gov/ DREAM, MEA112997/NCT01000506; MENSA, MEA115588/NCT01691521; SIRIUS, MEA115575/NCT01842607; MUSCA, 200862/NCT02281318.

Improving the Affordability of Prescription Medications for People with Chronic Respiratory Disease. An Official American Thoracic Society Policy Statement.

BACKGROUND: Mounting evidence indicates that out-of-pocket costs for prescription medications, particularly among low- and middle-income patients with chronic diseases, are imposing financial burden, reducing medication adherence, and worsening health outcomes. This problem is exacerbated by a paucity of generic alternatives for prevalent lung diseases, such as asthma and chronic obstructive pulmonary disease, as well as high-cost medicines for rare diseases, such as cystic fibrosis. Affordability and access challenges are especially salient in the United States, as citizens of many other countries pay lower prices for and have greater access to prescription medications. METHODS: The American Thoracic Society convened a multidisciplinary committee comprising experts in health policy pharmacoeconomics, behavioral sciences, and clinical care, along with individuals providing industry and patient perspectives. The report and its recommendation were iteratively developed over a year of in-person, telephonic, and electronic deliberation. RESULTS: The committee unanimously recommended the establishment of a publicly funded, politically independent, impartial entity to systematically draft evidence-based pharmaceutical policy recommendations. The goal of this entity would be to generate evidence and action steps to ensure people have equitable and affordable access to prescription medications, to maximize the value of public and private pharmaceutical expenditures on health, to support novel drug development within a market-based economy, and to preserve clinician and patient choice regarding personalized treatment. An immediate priority is to examine the evidence and make recommendations regarding the need to have essential medicines with established clinical benefit from each drug class in all Tier 1 formularies and propose recommendations to reduce barriers to timely generic drug availability. CONCLUSIONS: By making explicit, evidence-based recommendations, the entity can support the establishment of coherent national policies that expand access to affordable medications, improve the health of patients with chronic disease, and optimize the use of public and private resources.

Association of depressive symptoms with health status and markers of uncontrolled severe asthma.

Background: There are limited data that describe the association between markers of asthma control and depressive symptoms in severe asthma. Objective: To evaluate the association between depressive symptoms and markers of asthma control in patients with uncontrolled severe eosinophilic asthma. Methods: Baseline data from the MENSA and SIRIUS studies (N = 681) of mepolizumab intervention in severe eosinophilic asthma was used. We analyzed the relationships between depressive symptom severity by using the Beck Depression Inventory (BDI-II) and quality of life by using the St. George's Respiratory Questionnaire (SGRQ), asthma control questionnaire-5 (ACQ-5), polypharmacy, and sleep symptoms. Results: When compared with patients with less severe depressive symptoms, patients with more severe depressive symptoms were predominantly female (81% versus 54%), had a higher mean body mass index (30.56 versus 27.67 kg/m²), were more likely to have a blood eosinophil count of ≥300 cells/uL within the previous 12 months (81% versus 68%), and to have experienced a near-fatal asthma event (16% versus 7%). The mean SGRQ score was higher in the severe BDI-II category compared with the minimal depressive symptoms category, which indicated a worse quality of life (71.6 versus 41.4, p < 0.001). Eighty-nine percent of the patients in the severe BDI-II category had poorly controlled asthma (ACQ-5 score ≥ 1.5) compared with 63% in the minimal category (p < 0.001). Conclusion: Increased severity of depressive symptoms was associated with worse respiratory-related quality of life and asthma control in the patients with severe eosinophilic asthma. These findings highlight the need for a multidimensional approach for the management of uncontrolled asthma, including timely identification of depressive symptoms. Additional research is needed to further explore the interactions between the two common conditions.Clinical trials NCT01691521 and NCT01619508, www.clinicaltrials.gov.

Acute and chronic systemic corticosteroid-related complications in patients with severe asthma.

BACKGROUND: Many patients with severe asthma require maintenance treatment with systemic corticosteroids (SCSs) to control daily symptoms and prevent serious acute exacerbations, but chronic SCS use is associated with complications. OBJECTIVE: We sought to evaluate the risk of SCS-related complications by SCS exposure and quantify the associated health care costs and resource use in patients with severe asthma. METHODS: We performed a longitudinal, open-cohort, observational study using health insurance claims data (1997-2013: Medicaid) from Florida, Iowa, Kansas, Missouri, Mississippi, and New Jersey. Eligible patients were 12 years old or older with 2 or more asthma diagnoses and had more than 6 months of continuous SCS use. An open-cohort approach was used to classify patients' follow-up into low, medium, and high SCS exposure (≤ 6, >6-12, and >12 mg/d, respectively). Multivariate generalized estimating equation models were used to estimate the adjusted risk of SCS-related complications for patients with medium and high exposure compared with patients with low exposure and quantify the resulting health care resource use and costs. RESULTS: The study included 3628 patients (mean age, 57.6 years; 68% female). Patients with medium and high SCS exposure had significantly higher risks of SCS-related complications, including infections and cardiovascular, metabolic, psychiatric, ocular, gastrointestinal, and bone-related complications (odds ratio, 1.23-2.12 by complication; P < .05 for all but one) versus those with low (reference group) SCS exposure. Medium and high SCS exposure were also associated with significantly more emergency department visits (incidence rate ratios, 1.31 [P = .0004] and 1.78 [P < .0001]) and inpatient visits (incidence rate ratios, 1.25 [P < .0001] and 1.59 [P < .0001]) versus low SCS exposure. CONCLUSIONS: A significant dose-response relationship was demonstrated between chronic SCS use and risk of SCS-related complications in patients with severe asthma. Effective SCS-sparing strategies might reduce the burden associated with SCS-related complications in patients with severe asthma.

Outcomes following mepolizumab treatment discontinuation: real-world experience from an open-label trial.

Limited information is available on the clinical course of patients with severe asthma following discontinuation of biologic treatment. Therefore, a post hoc analysis was conducted in patients with severe eosinophilic asthma who participated in the COSMOS trial, where patients received mepolizumab for more than 1 year of continuous therapy. The objective of this post hoc analysis was to evaluate changes in the Asthma Control Questionnaire (ACQ-5) and blood eosinophil counts 12 weeks after the last administration of mepolizumab. Cessation of mepolizumab was associated with a rise in the blood eosinophil count and loss of asthma control after stopping therapy. These data suggest that patients with severe disease require extended and continuous treatment. Further studies evaluating longer duration of continuous treatment with mepolizumab could help understanding of whether changes in the presentation of the disease (disease modification) are possible with the use of biologics, such as mepolizumab.

Rapid and Consistent Improvements in Morning PEF in Patients with Severe Eosinophilic Asthma Treated with Mepolizumab.

INTRODUCTION: Previous studies showed that mepolizumab significantly reduces exacerbations and oral corticosteroid use in patients with severe eosinophilic asthma. However, early studies reported inconsistent effects on lung function. This study specifically assessed the onset of clinical effect and the relationship of baseline blood eosinophil count of mepolizumab 100 mg subcutaneous (SC) administration on morning peak expiratory flow (AM PEF). METHODS: Post hoc analysis of data from two randomized, double-blind, placebo-controlled studies (MENSA, NCT01691521; MUSCA, NCT02281318) of 4-weekly mepolizumab 100 mg versus placebo in patients with severe eosinophilic asthma. Individual study results were generated using a mixed model repeated measures model controlling for multiple covariates and were combined using a fixed effects meta-analysis via inverse-variance weighting. RESULTS: Significant improvements in AM PEF after the first dose of mepolizumab 100 mg SC vs. placebo were seen as early as week 1 and continued to improve further with subsequent doses. The mean change in AM PEF was 26 L/min in the mepolizumab group compared to 4 L/min in the placebo group, p < 0.001. When the population was stratified by blood eosinophil thresholds the mean difference from placebo was 24 L/min (≥ 150 cells/µL), 27 L/min (≥ 300 cells/µL), and 34 L/min (≥ 500 cells/µL), p < 0.001 for all subgroups. The < 150 cells/µL (≥ 300 cells/µL in the previous year) group increased 13 L/min, while both 150 to < 300 cells/µL and 300 to < 500 cells/µL ranges demonstrated comparable changes (19 L/min and 17 L/min), respectively. CONCLUSION: Our analysis has shown early and consistent improvements in lung function measured by AM PEF using the study enrollment criterion of ≥ 150 eosinophils/µL. We also identified a relationship between baseline blood eosinophils and improvements in AM PEF with mepolizumab in patients with severe eosinophilic asthma. FUNDING: GlaxoSmithKline (study ID 208091).

Economic analysis of the phase III MENSA study evaluating mepolizumab for severe asthma with eosinophilic phenotype.

BACKGROUND: Severe eosinophilic asthma patients are at risk of exacerbations, which are associated with substantial costs. Mepolizumab lowers eosinophil levels and reduces exacerbation risk in severe eosinophilic asthma. We evaluated asthma-related exacerbation costs in mepolizumab-treated patients (versus placebo). METHODS: A within-trial economic analysis of the Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma (MENSA) trial. Objectives were to quantify the incremental: (1) medical costs of asthma-related exacerbation; (2) asthma-related exacerbation emergency department visit/hospitalization costs; and (3) asthma-related total healthcare resource utilization. RESULTS: Mean medical costs of asthma-related exacerbations at 8 months were $969, $852, and $1692 in the mepolizumab 75 mg intravenous (IV), mepolizumab 100 mg subcutaneous (SC), and placebo groups, respectively (p = 0.16). Mean medical costs from emergency department visits or hospitalizations due to asthma-related exacerbations were $901, $795, and $1557 in the mepolizumab 75 mg IV, mepolizumab 100 mg SC, and placebo groups (p = 0.020). Asthma-related healthcare resource utilization (all services) was lower for the mepolizumab groups versus placebo. CONCLUSIONS: Adding mepolizumab to standard-of-care treatment for severe eosinophilic asthma lowered asthma exacerbation-related medical costs/healthcare resource utilization; although the cost savings ranged from $723-$840 per patient, differences were not statistically significant.

Burden of systemic glucocorticoid-related complications in severe asthma.

OBJECTIVES: Although systemic glucocorticoids (SGCs) are efficacious, their chronic use is associated with a range of complications. Yet limited data are available about the risks following chronic use in patients with severe asthma, who are at risk of long-term SGC-related complications. This study was carried out to investigate the risks of developing SGC-related complications, and to quantify the associated healthcare resource utilization and costs for patients with severe asthma in the United States. METHODS: This was a longitudinal, open-cohort, observational study. Medicaid claims data (1997-2013) for patients ≥12 years old with ≥2 asthma diagnoses were used. A total of 26,987 SGC non-users were identified for inclusion in the study, alongside 3628 SGC users with ≥6 months' continuous SGC use. RESULTS: Multivariate generalized estimating equation models were used to estimate the adjusted risk of developing SGC-related complications, and to quantify the associated healthcare resource utilization and costs. This analysis compared SGC users with SGC non-users, and found that SGC users had an increased likelihood of developing complications. A significant dose-response relationship was demonstrated between chronic SGC use and risk of developing any complications (odds ratios for low, medium, and high SGC exposure were 2.03 [p = .0511], 2.85 [p < .0001], and 3.64 [p < .0001], respectively, vs. SGC non-users). The increased likelihood of SGC-related complications translated into estimated annual healthcare costs for SGC users of $2712 to $8560 above those of SGC non-users. A key limitation of this study is the disparity in age between the SGC users and the SGC non-users; however, age was included as a confounding factor in the analysis. CONCLUSIONS: These findings confirm the risk associated with chronic use of SGCs, irrespective of dose level, and highlight the need for new SGC-sparing treatment strategies for patients with severe asthma.

Trials and Tribulations: An Industry Perspective on Conducting Registrational Trials in Alpha-1 Antitrypsin Deficiency.

Registrational trials in rare and orphan diseases present complexities related to the identification of subjects, recruitment, logistical hurdles incumbent with far-flung study sites, and end points that are often less well defined than are those used in more common illnesses. Alpha-1 antitrypsin deficiency is an orphan disease of genetic origin that carries the additional challenges of variable penetration and slow disease progression. Registrational trials of augmentation therapy using plasma-derived alpha-1 antitrypsin carry all of the above-noted burdens, as well as competition from commercially available augmentation therapy in many countries.

Dose-Response Relationship Between Long-Term Systemic Corticosteroid Use and Related Complications in Patients with Severe Asthma.

BACKGROUND: Systemic corticosteroids are a leading cause of drug-related complications, yet little has been done to quantify the dose-response relationship between systemic corticosteroid exposure and complications in patients with severe asthma. OBJECTIVES: To (a) evaluate the risk of developing systemic corticosteroid-related complications by corticosteroid exposure in severe asthma and (b) quantify the associated health care resource utilization and costs. METHODS: This is a retrospective study using administrative claims data from a large commercial database between 2003 and 2014. Multivariate generalized estimating equation models were used to compare corticosteroid-related complications in patients continuously exposed to at least 5 mg of prednisone or equivalent for ≥ 6 months with a 1:1 ratio of propensity score-matched patients with asthma who did not use corticosteroids. RESULTS: A total of 12,697 corticosteroid users and as many matched nonusers were identified. The odds of developing associated complications increased significantly in a dose-dependent manner with systemic corticosteroid exposure: odds ratios were 2.50, 2.95, and 3.32 (P values <0.05) for low (defined as < 5 mg/day), medium (≥ 5-10 mg/day), and high (>10 mg/day) exposure, respectively, relative to no exposure. Health care resource utilization increased significantly with levels of systemic corticosteroid exposure. Hence, incidence rate ratios for inpatient visits with low, medium, and high exposure relative to none were estimated to be 1.86, 2.40, and 3.37, respectively (P < 0.05). CONCLUSIONS: A significant dose-response relationship was found between the long-term use of systemic corticosteroids and the risk of developing systemic corticosteroid-related complications in patients with severe asthma, resulting in increased burden and costs on the health care system that intensified with systemic corticosteroid exposure. DISCLOSURES: Funding for this study was provided by GlaxoSmithKline, Study number H0-15-15930, to Analysis Group for the conduct of this study. Lefebvre, Duh, and Gozalo are employees of Analysis Group, a contract research organization that has received research grants from GlaxoSmithKline. Robitaille was employed by Analysis Group at the time of this study. Yancey, Forshag, Lin, and Albers are employees of GlaxoSmithKline and own company stock. Dalal and Ortega were employed by GlaxoSmithKline at the time of this study. Lefebvre had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Additionally, all listed authors meet the criteria for authorship set forth by the International Committee for Medical Journal Editors. Study concept and design were contributed by Dalal, Duh, Albers, Yancey, Ortega, Forshag, and Lefebvre. Data acquisition was by Dalal, Gozalo, Robitaille, Forshag, and Lefebvre and was analyzed and interpreted by Dalal, Gozalo, Robitaille, Albers, Yancey, Ortega, Forshag, and Lefebvre. The manuscript was drafted and approved by Dalal, Duh, Gozalo, Robitaille, Albers, Yancey, Ortega, Forshag, Lin, and Lefebvre.

Economic Burden of Illness Among Patients with Severe Asthma in a Managed Care Setting.

BACKGROUND: Despite intensive pharmacotherapy, a considerable number of patients with severe asthma have inadequate disease control. Patients with severe asthma who experience exacerbations consume significant health care resources. OBJECTIVE: To assess health care resource utilization and associated costs among patients with persistent severe asthma who experienced exacerbations compared with patients with persistent but nonsevere asthma. METHODS: This retrospective analysis of a national administrative claims database identified patients aged ≥ 12 years who had at least 1 medical claim with an asthma diagnosis in 2012 and had continuous medical and pharmacy coverage under a commercial or Medicare Advantage plan from January 1, 2012, to December 31, 2013. Patients were assigned to 1 of 2 mutually exclusive cohorts-persistent asthma (PA) or severe asthma (SA)-according to an established algorithm based on asthma-related health care resource use and pharmacy claims for controller medication. SA patients were required to meet PA criteria and also have evidence of ≥2 asthma exacerbations in 2012. Asthma-related health care resource utilization and costs were computed from asthma medication use (rescue and controller therapy) and medical claims with an asthma diagnosis in the primary position in 2012 and 2013. Adherence to controller therapy was assessed over 365 days by using the proportion of days covered (PDC), starting with the first claim for controller therapy in 2012. Differences between the PA and SA cohorts were analyzed by t-test for continuous variables and chi-square test for categorical variables. Asthma-related costs in 2013 were also analyzed using a generalized linear model with a gamma distribution and log link, adjusted for patient demographics (age, gender, region, and insurance type) and Quan-Charlson comorbidity score. RESULTS: A total of 65,359 patients were included: 63,597 (97.3%) PA patients and 1,762 SA patients (2.7%). Compared with the PA cohort, the SA cohort was older (mean age = 50.8 years vs. 46.5 years, P < 0.001) and had higher mean comorbidity score (1.47 vs. 1.31, P< 0.001). The mean count of all asthma medications fills was 2.2-fold (2012) and 2.1-fold (2013) higher in the SA cohort, compared with the PA cohort (P< 0.001). Mean PDC for all oral and inhaled controller therapy was also higher in the SA cohort compared with the PA cohort (0.80 vs. 0.65, P< 0.001). SA patients had a significantly greater mean count of asthma-related hospitalizations, emergency room visits, and ambulatory visits in 2012 and 2013 (P< 0.001). Unadjusted mean annual asthma-related costs in the SA versus PA cohorts were $6,496 versus $2,739 (P < 0.001) in 2012 and $5,174 versus $1,775 (P< 0.001) in 2013. Higher asthma-related costs were driven by greater mean annual asthma medication costs in 2012 ($4,545 vs. $1,738, P< 0.001) and 2013 ($4,068 vs. $1,348, P< 0.001). Adjusted mean annual asthma-related costs in 2013 were $3,336 greater (cost ratio=2.878, P< 0.001) in the SA cohort, and adjusted mean annual asthma medication costs were $2,672 higher (cost ratio=2.982, P< 0.001) in the SA cohort. CONCLUSIONS: Patients with SA who experienced 2 or more exacerbations had 2.1-fold greater use of controller medications across both study years and were more adherent to controller therapy than patients with PA. Despite more intensive pharmacotherapy, SA patients incurred 2.9-fold higher adjusted asthma-related costs and 3-fold higher adjusted asthma medication costs than PA patients. Patients with SA consistently demonstrated a higher rate of health care utilization. DISCLOSURES: Funding for this study (HO-14-14443) was provided by GlaxoSmithKline (GSK). All listed authors meet the criteria for authorship set forth by the International Committee for Medical Journal Editors. Albers, Forshag, and Yancey are employees of GSK and hold stock in GSK. Dalal, Nagar, and Ortega were employees of GSK at the time this research was conducted. Chastek and Korrer are employees of Optum, which received consulting fees from GSK for research related to this study. Study concept and design were contributed by Chastek, Nagar, and Dalal. Korrer took the lead in data collection, along with Chastek, and data interpretation was performed by Chastek, Ortega, Forshag, and Dalal. The manuscript was written by Chastek and Dalal and revised by Albers and Yancy, assisted by the other authors.

US hospital database analysis of invasive aspergillosis in the chronic obstructive pulmonary disease non-traditional host.

OBJECTIVES: Invasive aspergillosis (IA) is reported increasingly in non-traditional hosts, typically patients with chronic obstructive pulmonary disease (COPD). Objectives were to describe the excess burden of IA in COPD, including mortality, resource utilization, and costs, as well as to examine the impact of initial antifungal selection on clinical and economic outcomes. METHODS: This retrospective cohort study used national data from 2005 to 2008, from the Premier Perspective hospital database. IA was identified using proxy ICD-9 codes based on published algorithms. The COPD + IA patient cohort was analyzed using descriptive statistics. Excess resource utilization was analyzed by matching cases (COPD + IA) and controls (COPD patients without aspergillosis) on demographic and clinical variables. Multivariate analyses were used to assess the impact of initial antifungal drug selection on outcomes in COPD + IA. RESULTS: In total, 475 COPD + IA patients were identified (mean age 69 years, 50% male, 76% Caucasian). COPD + IA cases had significantly higher costs, length of stay, intensive care unit (ICU) stay, and mortality compared to COPD controls (all p < 0.01). On average, antifungal therapy was initiated on hospital day 6, with mean length of therapy 15 days, and one-third of patients were in the ICU when antifungal treatment was initiated. Most commonly used antifungals were voriconazole, fluconazole, and caspofungin. Patients receiving fluconazole as the initial antifungal, an agent inactive against moulds, had almost two times greater mortality (p = 0.016), two additional hospital days (p = 0.002), and 25% greater costs (p = 0.007), compared to patients receiving voriconazole first-line. Findings were consistent in sub-analyses including ICU patients. LIMITATIONS: 'Invasive' form of aspergillosis was identified using proxy ICD-9 codes based on published literature. Additional limitations stem from the study's non-randomized, retrospective design that is typical with any database analyses. CONCLUSIONS: COPD + IA patients had significantly higher mortality, resource utilization, and costs versus COPD controls. Treatment with an agent active against Aspergillus was associated with better survival and reduced economic burden, therefore this potential etiology of pneumonia should be considered when contemplating antifungal therapy in COPD patients.