Mepolizumab improvements in health-related quality of life and disease symptoms in a patient population with very severe chronic rhinosinusitis with nasal polyps: psychometric and efficacy analyses from the SYNAPSE study.

BACKGROUND: Although the psychometric properties of patient-reported outcome measures (e.g. the 22-item Sino-nasal Outcomes Test [SNOT-22]) in chronic rhinosinusitis with nasal polyps (CRSwNP) have been defined, these definitions have not been extensively studied in patients with very severe CRSwNP, as defined by recurrent disease despite ≥ 1 previous surgery and a current need for further surgery. Therefore, the psychometric properties of the symptoms visual analogue scales (VAS) were evaluated, and meaningful within-patient change thresholds were calculated for VAS and SNOT-22. METHODS: SYNAPSE (NCT03085797), a randomized, double-blind, placebo-controlled, 52-week trial, assessed the efficacy and safety of 4-weekly mepolizumab 100 mg subcutaneously added to standard of care in very severe CRSwNP. Enrolled patients (n = 407) completed symptom VAS (six items) daily and SNOT-22 every 4 weeks from baseline until Week 52. Blinded psychometric assessment of individual and composite VAS was performed post hoc, including anchor-based thresholds for meaningful within-patient changes for VAS and SNOT-22, supported by cumulative distribution function and probability density function plots. The effect of mepolizumab versus placebo for 52 weeks on VAS and SNOT-22 scores was then determined using these thresholds using unblinded data. RESULTS: Internal consistency was acceptable for VAS and SNOT-22 scores (Cronbach's α-coefficients ≥ 0.70). Test-retest reliability was demonstrated for all symptom VAS (Intra-Class Correlation coefficients > 0.75). Construct validity was acceptable between individual and composite VAS and SNOT-22 total score (r = 0.461-0.598) and between individual symptom VAS and corresponding SNOT-22 items (r = 0.560-0.780), based upon pre-specified ranges. Known-groups validity assessment demonstrated generally acceptable validity based on factors associated with respiratory health, with all VAS responsive to change. Mepolizumab treatment was associated with significantly increased odds of meeting or exceeding meaningful within-patient change thresholds, derived for this very severe cohort using six anchor groups for individual VAS (odds ratio [OR] 2.19-2.68) at Weeks 49-52, and SNOT-22 (OR 1.61-2.96) throughout the study. CONCLUSIONS: Symptoms VAS and SNOT-22 had acceptable psychometric properties for use in very severe CRSwNP. Mepolizumab provided meaningful within-patient improvements in symptom severity and health-related quality of life versus placebo, indicating mepolizumab provides substantial clinical benefits in very severe CRSwNP.

Patients with chronic rhinosinusitis (CRS) often have blocked or runny noses, and loss of sense of smell. They can also have sac-like growths in their nose called nasal polyps, which often require surgical removement. The symptoms of CRS with nasal polyps can affect quality of life. In a clinical study named SYNAPSE, a new treatment option called mepolizumab reduced the size and severity of nasal polyps in patients suffering from very severe CRS with nasal polyps, compared with placebo. Mepolizumab also reduced the need for nasal polyp surgery. The SYNAPSE study also measured if 1 year of mepolizumab treatment improved patients' symptoms and quality of life. This was evaluated by asking patients to complete two separate tasks. These tasks were rating symptoms on a visual analogue scale (VAS) and completing a quality of life questionnaire called SNOT-22. The objective of this analysis was to see if these questionnaires accurately assessed a patient's quality of life. The analysis also assessed how many patients had major improvements in their symptoms with mepolizumab. Overall, data from 407 patients in the SYNAPSE study was analyzed. Results showed that both the VAS and SNOT-22 questionnaires accurately captured CRS symptoms and quality of life. In addition, patients treated with mepolizumab for 1 year had improvements in quality of life compared with placebo. In conclusion, these findings suggest that the VAS and SNOT-22 questionnaires are appropriate evaluation tools for patients with very severe CRS with nasal polyps. The findings also show that mepolizumab treatment is beneficial for these patients.

Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): In-depth sinus surgery analysis.

BACKGROUND: Patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) often require repeat sinus surgery. Mepolizumab reduced the need for sinus surgery in the SYNAPSE trial; this analysis sought to provide a more in-depth assessment of surgery endpoints in SYNAPSE. METHODS: SYNAPSE was a double-blind Phase III trial (NCT03085797) in adults with recurrent, refractory, severe, CRSwNP eligible for repeat sinus surgery despite standard of care treatments and previous surgery. Patients were randomized (1:1) to mepolizumab 100 mg subcutaneously or placebo, plus standard of care, every 4 weeks for 52 weeks. Time to first inclusion on a waiting list for sinus surgery and time to first actual sinus surgery (both up to week 52) were assessed; the latter endpoint was also analyzed post hoc according to time since last sinus surgery before study screening and baseline blood eosinophil count. RESULTS: Among 407 patients (mepolizumab: 206; placebo: 201), mepolizumab versus placebo reduced the risk of being included on a waiting list for sinus surgery (week 52 Kaplan-Meier probability estimate [95% confidence interval]: 13.9% [9.8%, 19.5%] vs. 28.5% [22.7%, 35.4%]). Mepolizumab versus placebo reduced the risk of sinus surgery irrespective of time (<3 vs ≥3 years) since patients' last sinus surgery prior to study screening (hazard ratios [95% confidence intervals] 0.28 [0.09, 0.84] and 0.50 [0.26, 0.98], respectively) and baseline blood eosinophil count. CONCLUSIONS: Mepolizumab reduced the risk of further sinus surgery in patients with recurrent, refractory, severe CRSwNP, irrespective of the patient baseline characteristics assessed.

Mepolizumab for chronic rhinosinusitis with nasal polyps: Treatment efficacy by comorbidity and blood eosinophil count.

BACKGROUND: In the phase III SYNAPSE study, mepolizumab reduced nasal polyp (NP) size and nasal obstruction in chronic rhinosinusitis with NP. OBJECTIVE: We sought to assess the efficacy of mepolizumab in patients from SYNAPSE grouped by comorbid asthma, aspirin-exacerbated respiratory disease (AERD), and baseline blood eosinophil count (BEC). METHODS: SYNAPSE, a randomized, double-blind, 52-week study (NCT03085797), included patients with severe bilateral chronic rhinosinusitis with NP eligible for surgery despite intranasal corticosteroid treatment. Patients received 4-weekly subcutaneous mepolizumab 100 mg or placebo plus standard of care for 52 weeks. Coprimary end points were change in total endoscopic NP score (week 52) and nasal obstruction visual analog scale score (weeks 49-52). Subgroup analyses by comorbid asthma and AERD status, and post hoc by BEC, were exploratory. RESULTS: Analyses included 407 patients (289 with asthma; 108 with AERD; 371 and 278 with BEC counts ≥150 or ≥300 cells/µL, respectively). The proportion of patients with greater than or equal to 1-point improvement from baseline in NP score was higher with mepolizumab versus placebo across comorbid diseases (asthma: 52.9% vs 29.5%; AERD: 51.1% vs 20.6%) and baseline BEC subgroups (<150 cells/µL: 55.0% vs 31.3%; ≥150 cells/µL: 49.5% vs 28.1%; <300 cells/µL: 50.7% vs 29.0%; ≥300 cells/µL: 50.4% vs 28.1%). A similar trend was observed in patients without comorbid asthma or AERD. More patients had more than 3-point improvement in nasal obstruction VAS score with mepolizumab versus placebo across comorbid subgroups. CONCLUSIONS: Mepolizumab reduced polyp size and nasal obstruction in chronic rhinosinusitis with NP regardless of the presence of comorbid asthma or AERD.

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.

Clinical Development of Mepolizumab for the Treatment of Severe Eosinophilic Asthma: On the Path to Personalized Medicine.

The development of mepolizumab, an anti-IL-5 monoclonal antibody for the treatment of severe eosinophilic asthma, is an example of a clinical development program that evolved over time based on sound, basic scientific principles. Initial clinical data on the effects of mepolizumab on lung function in a general asthmatic population were disappointing. However, it became clear that mepolizumab may be more effective against other clinical endpoints, particularly asthma exacerbations, in patients with more severe disease. Furthermore, a developing understanding of asthma disease pathobiology led to the identification of an appropriate target population and predictive biomarker for mepolizumab treatment: patients with severe eosinophilic asthma and blood eosinophil count. Mepolizumab use provides clinically meaningful benefits in this target population, fulfilling an unmet need. This Clinical Commentary Review describes the clinical development of mepolizumab and details of how this program informed the development of other biologic therapies in patients with severe asthma. This account highlights how a personalized approach toward treatment of patients with severe eosinophilic asthma, supported by a large body of scientific evidence, ultimately led to new and effective treatments and improved patient outcomes.

Mepolizumab or Placebo for Eosinophilic Granulomatosis with Polyangiitis.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis is an eosinophilic vasculitis. Mepolizumab, an anti-interleukin-5 monoclonal antibody, reduces blood eosinophil counts and may have value in the treatment of eosinophilic granulomatosis with polyangiitis. METHODS: In this multicenter, double-blind, parallel-group, phase 3 trial, we randomly assigned participants with relapsing or refractory eosinophilic granulomatosis with polyangiitis who had received treatment for at least 4 weeks and were taking a stable prednisolone or prednisone dose to receive 300 mg of mepolizumab or placebo, administered subcutaneously every 4 weeks, plus standard care, for 52 weeks. The two primary end points were the accrued weeks of remission over a 52-week period, according to categorical quantification, and the proportion of participants in remission at both week 36 and week 48. Secondary end points included the time to first relapse and the average daily glucocorticoid dose (during weeks 48 through 52). The annualized relapse rate and safety were assessed. RESULTS: A total of 136 participants underwent randomization, with 68 participants assigned to receive mepolizumab and 68 to receive placebo. Mepolizumab treatment led to significantly more accrued weeks of remission than placebo (28% vs. 3% of the participants had ≥24 weeks of accrued remission; odds ratio, 5.91; 95% confidence interval [CI], 2.68 to 13.03; P<0.001) and a higher percentage of participants in remission at both week 36 and week 48 (32% vs. 3%; odds ratio, 16.74; 95% CI, 3.61 to 77.56; P<0.001). Remission did not occur in 47% of the participants in the mepolizumab group versus 81% of those in the placebo group. The annualized relapse rate was 1.14 in the mepolizumab group, as compared with 2.27 in the placebo group (rate ratio, 0.50; 95% CI, 0.36 to 0.70; P<0.001). A total of 44% of the participants in the mepolizumab group, as compared with 7% of those in the placebo group, had an average daily dose of prednisolone or prednisone of 4.0 mg or less per day during weeks 48 through 52 (odds ratio, 0.20; 95% CI, 0.09 to 0.41; P<0.001). The safety profile of mepolizumab was similar to that observed in previous studies. CONCLUSIONS: In participants with eosinophilic granulomatosis with polyangiitis, mepolizumab resulted in significantly more weeks in remission and a higher proportion of participants in remission than did placebo, thus allowing for reduced glucocorticoid use. Even so, only approximately half the participants treated with mepolizumab had protocol-defined remission. (Funded by GlaxoSmithKline and the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT02020889 .).

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.

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.

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.

Pharmacokinetics and absolute bioavailability of mepolizumab following administration at subcutaneous and intramuscular sites.

This study characterized the pharmacokinetics (PK) of mepolizumab, after a single intravenous (IV), subcutaneous (SC), or intramuscular (IM) dose in healthy adults and determined the absolute bioavailability of SC and IM mepolizumab delivered at different anatomical regions. Sixty healthy subjects were randomly assigned to receive a single dose of either mepolizumab 250 mg by IV, SC injection (upper arm, abdomen, or thigh); or IM injection (thigh). Following IV administration, the mean maximum observed plasma mepolizumab concentration (Cmax ) and the mean area under the concentration versus time curves from time zero to infinity (AUC(0-∞) ) were 109 ± 17 µg/mL and 1,557 ± 250 µg d/mL, respectively. After SC administration, the mean (±SD) values of Cmax and AUC(0-∞) were 34.1-38.2 ± 7.3-12.1 µg/mL and 1,110-1,238 ± 228-372 µg d/mL, respectively. Following IM administration, the mean values of Cmax and AUC(0-∞) were 46.9 ± 10.6 µg/mL and 1,395 ± 348 µg d/mL. The median terminal half-life was similar for SC, IM and IV administration (17.9-20.4, 19.2, and 18.5 days, respectively). The overall mean bioavailability of SC mepolizumab was 64-75%, and absorption was relatively similar for the three SC injection sites. Mepolizumab 250 mg was generally well tolerated in this study. These results support flexibility in the SC injection site for mepolizumab.

Controller medications and their effects on asthma exacerbations temporally associated with upper respiratory infections.

BACKGROUND: Exacerbations are a major risk and a cause of asthma morbidity and healthcare utilization. Viral-induced upper respiratory tract infections are the most frequent trigger of asthma-related exacerbations. Studies have traditionally assessed exacerbations without documentation regarding exacerbation etiology. Therefore, it remains unknown whether asthma medications can alter exacerbation susceptibility based on a specific etiology. OBJECTIVE: To examine whether treatment with inhaled corticosteroids plus long-acting beta(2)-agonists reduced the number of exacerbations associated with upper respiratory tract infections versus inhaled corticosteroids alone. METHODS: Two large datasets comparing treatment with fluticasone propionate and fluticasone propionate plus salmeterol were analyzed, including the number of clinically reported upper respiratory tract infections, asthma-related exacerbations, and the presence of an exacerbation and concurrent report of an upper respiratory tract infection. RESULTS: Both treatment groups had similar incidences of upper respiratory tract infections. Of those reporting an upper respiratory tract infection, statistically significantly fewer reported an asthma-related exacerbation comparing fluticasone propionate plus salmeterol with fluticasone propionate (p=0.0057). DISCUSSION: This retrospective analysis suggests that therapy with fluticasone propionate plus salmeterol provides protection against asthma exacerbations temporally associated with upper respiratory tract infections. This retrospective analysis supports the hypothesis that specific therapeutic approaches to mitigate virus-associated exacerbations may benefit asthma care. Well-controlled prospective studies are warranted.

Ecologic analysis of asthma-related events and dispensing of inhaled corticosteroid- and salmeterol-containing products.

BACKGROUND: An association between salmeterol use and serious asthma episodes or asthma-related mortality has been noted in 2 clinical trials; however, a causal relationship has not been established. To date, observational studies have not replicated this finding. OBJECTIVE: To examine the relationship between number of prescriptions dispensed of salmeterol-containing products and inhaled corticosteroid (ICS)-containing products and the rates of asthma-related hospitalizations and mortality in the United States. METHODS: In this ecologic study, annual age-adjusted rates of asthma-related hospitalization and asthma-related mortality from US population-based sources were graphed alongside annual number of prescriptions dispensed of salmeterol- and ICS-containing products by year from 1991 to 2004. We computed the Spearman rank correlations between number of prescriptions dispensed and serious events (asthma-related hospitalization rate, number of hospitalizations, asthma-related mortality rate, and number of asthma deaths). RESULTS: During more than 14 years, while number of prescriptions dispensed of salmeterol-containing and ICS-containing products increased, age-adjusted asthma-related mortality rates declined and asthma-related hospitalization rates remained relatively stable. The number of asthma-related deaths has decreased steadily since the mid-1990s. CONCLUSION: This study provides population-level evidence that asthma-related death rates declined and asthma-related hospitalization rates remained relatively constant for more than 14 years during a period of improvements in asthma management per treatment guidelines, including increased use of maintenance medications, such as ICSs and salmeterol.

Asthma exacerbations in African Americans treated for 1 year with combination fluticasone propionate and salmeterol or fluticasone propionate alone.

OBJECTIVE: This long-term prospective study was conducted in African Americans with persistent asthma to examine the safety and effectiveness of the combination of the inhaled corticosteroid, fluticasone propionate (FP), and the long-acting beta-agonist, salmeterol, compared with FP alone. RESEARCH AND DESIGN METHODS: This was a randomized, double-blind, parallel group, multi-center trial in adolescent and adult subjects >/=12 years of age symptomatic on a low dose of an inhaled corticosteroid (ICS). The study consisted of a 2-week screening period on low dose ICS; a 4-week open-label FP 250 mcg twice daily (BID) run-in; a 52-week double-blind period (FP/salmeterol [FSC] 100/50 mcg [n=239] or FP 100 mcg [n=236] BID), and a 4-week FP 250 mcg BID run-out period. Annualized exacerbation rate was the primary outcome for comparing the two treatments. Other measures of asthma control included peak expiratory flow, asthma symptoms, and albuterol use. Safety was assessed through adverse events. RESULTS: Exacerbation rates were not significantly different in those treated with FSC 100/50 mcg (0.449 per year) compared with FP 100 mcg (0.529 per year, p=0.169). When the per-protocol analysis was applied, the rates were 0.465 and 0.769 per year for FSC 100/50 mcg and FP 100 mcg, respectively. Treatment with FSC 100/50 mcg provided statistically greater improvements in lung function measures and nighttime awakenings (p

Does measuring BHR add to guideline derived clinical measures in determining treatment for patients with persistent asthma?

RATIONALE: Little is known about the use of biomarkers in guiding treatment decisions in routine asthma management. The objective of this study was to determine whether adding a LABA to an ICS would control bronchial hyperresponsiveness (BHR) at an overall lower dose of ICS when titration of medication was based upon the assessment of routine clinical measures with or without the measurement of BHR. METHODS: After a 2-week run-in period, subjects (> or = 12 years) were randomized to one of three treatment groups. Two groups followed a BHR treatment strategy (based on clinical parameters [lung function, asthma symptoms, and bronchodilator use] and BHR) and were treated with either fluticasone propionate/salmeterol (FSC(BHR) group) or fluticasone propionate (FP(BHR) group) (n=156 each). The third group followed a clinical treatment algorithm (based on clinical parameters alone) and were treated with fluticasone propionate (FP(REF) group; n=154). All treatments were administered via Diskus. Treatment doses were adjusted as needed every 8 weeks for 40 weeks according to the subject's derived severity class, which was based on clinical measures of asthma control with or without BHR. RESULTS: The mean total daily inhaled corticosteroids (ICS) dose during the double-blind treatment period was lower, although not statistically significant, in the FSC(BHR) group compared with the FP(BHR) group (a difference of -42.9 mcg; p=0.07). Compared with the FP(REF) group, the mean total daily ICS dose was higher in the FSC(BHR) group (a difference of 85.2 mcg) and was significantly higher in the FP(BHR) group (a difference of 131.2 mcg, p=0.037). CONCLUSION: This study demonstrated that for most subjects, control of BHR was maintained when treatment was directed toward control of clinical parameters. In addition, there was a trend towards control of BHR and clinical measures at a lower dose of ICS when used concurrently with salmeterol.