This study will evaluate two dose regimens of mepolizumab \[75mg intravenous (i.v.) or 100mg subcutaneous (SC) every 4 weeks\] compared with placebo over a 32 week treatment period in subjects with severe refractory asthma with elevated blood eosinophils. Efficacy will be measured by a reduction in the frequency of asthma exacerbations. Additional efficacy assessments will include measurements of lung function, symptom scores, and quality of life. Safety will be assessed by clinical laboratory samples, ECGs, immunogenicity and adverse events.
This study is intended to replicate the Phase IIb/III study MEA112997. Subjects in MEA115588, who meet all eligibility criteria at screening visit, will enter the run-in period. Those subjects that are not able/eligible to be randomised at the end of the 6 week run-in period will be deemed run-in failures. Subjects will remain on their current maintenance therapy throughout the run-in, double-blind treatment administration and follow-up periods. Subjects who meet the randomisation eligibility criteria will be randomised in a 1:1:1 ratio to receive one of the following treatments every 4 weeks for a total of 8 doses: Mepolizumab 75 miligram (mg) i.v. and placebo SC, or Mepolizumab 100 mg SC and placebo i.v. or Placebo i.v. and placebo SC.
Subjects that receive all 8 doses of double-blind treatment, and meet the eligibility criteria for the Open-Label Extension (OLE) Study, will be offered the opportunity to participate in the OLE trial.
<b>BACKGROUND: </b>Some patients with severe asthma have frequent exacerbations associated with persistent eosinophilic inflammation despite continuous treatment with high-dose inhaled glucocorticoids with or without oral glucocorticoids.<b>METHODS: </b>In this randomized, double-blind, double-dummy study, we assigned 576 patients with recurrent asthma exacerbations and evidence of eosinophilic inflammation despite high doses of inhaled glucocorticoids to one of three study groups. Patients were assigned to receive mepolizumab, a humanized monoclonal antibody against interleukin-5, which was administered as either a 75-mg intravenous dose or a 100-mg subcutaneous dose, or placebo every 4 weeks for 32 weeks. The primary outcome was the rate of exacerbations. Other outcomes included the forced expiratory volume in 1 second (FEV1) and scores on the St. George's Respiratory Questionnaire (SGRQ) and the 5-item Asthma Control Questionnaire (ACQ-5). Safety was also assessed.<b>RESULTS: </b>The rate of exacerbations was reduced by 47% (95% confidence interval [CI], 29 to 61) among patients receiving intravenous mepolizumab and by 53% (95% CI, 37 to 65) among those receiving subcutaneous mepolizumab, as compared with those receiving placebo (P<0.001 for both comparisons). Exacerbations necessitating an emergency department visit or hospitalization were reduced by 32% in the group receiving intravenous mepolizumab and by 61% in the group receiving subcutaneous mepolizumab. At week 32, the mean increase from baseline in FEV1 was 100 ml greater in patients receiving intravenous mepolizumab than in those receiving placebo (P=0.02) and 98 ml greater in patients receiving subcutaneous mepolizumab than in those receiving placebo (P=0.03). The improvement from baseline in the SGRQ score was 6.4 points and 7.0 points greater in the intravenous and subcutaneous mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 4 points), and the improvement in the ACQ-5 score was 0.42 points and 0.44 points greater in the two mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 0.5 points) (P<0.001 for all comparisons). The safety profile of mepolizumab was similar to that of placebo.<b>CONCLUSIONS: </b>Mepolizumab administered either intravenously or subcutaneously significantly reduced asthma exacerbations and was associated with improvements in markers of asthma control. (Funded by GlaxoSmithKline; MENSA ClinicalTrials.gov number, NCT01691521.).
BACKGROUND: We performed post hoc analyses to evaluate the effect of humanized monoclonal antibody mepolizumab in patients with severe eosinophilic asthma previously treated with omalizumab.
METHODS: Data were collected from two randomized double-blind, placebo-controlled studies: MENSA (NCT01691521: 32-week treatment phase) and SIRIUS (NCT01691508: 24-week treatment phase). Active treatment was 75 mg intravenous mepolizumab (MENSA) or 100 mg subcutaneous mepolizumab (MENSA, SIRIUS). Patients had evidence of eosinophilic inflammation ≥150 cells/μl (at screening) or ≥300 cells/μl (during the previous year). Primary outcomes were the rate of exacerbations (MENSA) and the percentage reduction in oral corticosteroid (OCS) dose (SIRIUS). Other outcomes included lung function (forced expiratory volume in 1 s and morning peak expiratory flow), Asthma Control Questionnaire (ACQ-5), St George's Respiratory Questionnaire (SGRQ) scores, and safety.
RESULTS: Overall, 576 patients were included from MENSA and 135 from SIRIUS, with 13% and 33% previously receiving omalizumab, respectively. In MENSA, mepolizumab reduced the rate of exacerbations by 57% (prior omalizumab) and 47% (no prior omalizumab) vs placebo. In SIRIUS, reductions in OCS use were comparable regardless of prior omalizumab use. Despite reducing chronic OCS use, mepolizumab also resulted in similar reductions in exacerbation rate relative to placebo in both subgroups. Asthma control and quality of life improved with mepolizumab vs placebo in both studies independent of prior omalizumab use, as shown by ACQ-5 and SGRQ scores. Adverse events were also comparable irrespective of prior omalizumab use.
CONCLUSIONS: These post hoc analyses indicate that patients with severe eosinophilic asthma respond positively to mepolizumab regardless of prior use of omalizumab.
BACKGROUND: Findings from previous studies showed that mepolizumab significantly reduces the rate of exacerbations in patients with severe eosinophilic asthma. To assess the relationship between baseline blood eosinophil counts and efficacy of mepolizumab we did a secondary analysis of data from two studies, stratifying patients by different baseline blood eosinophil thresholds.
METHODS: We did a post-hoc analysis of data, which was completed on Sept 25, 2015, from two randomised, double-blind, placebo-controlled studies of at least 32 weeks duration (NCT01000506 [DREAM] and NCT01691521 [MENSA]) done between 2009 and 2014. In these studies, mepolizumab (
DREAM: 75 mg, 250 mg, or 750 mg intravenously; MENSA: 75 mg intravenously or 100 mg subcutaneously) versus placebo was given at 4-week intervals in addition to standard care (high-dose inhaled corticosteroids plus ≥1 additional controller with or without daily oral corticosteroids) to patients aged 12 years or older with a clinical diagnosis of asthma, a history of at least two exacerbations in the previous year that required systemic corticosteroid treatment, and evidence of eosinophilic airway inflammation. The primary endpoint in both studies was the annual rate of clinically significant exacerbations (defined as worsening of asthma that required the use of systemic corticosteroids, or admission to hospital, or an emergency-room visit, or a combination of these occurrences). In our analysis, the primary outcome was the annualised rate of exacerbations in patients stratified by baseline eosinophil counts (≥150 cells per μL, ≥300 cells per μL, ≥400 cells per μL, and ≥500 cells per μL) and baseline blood eosinophil ranges (<150 cells per μL, ≥150 cells per μL to <300 cells per μL, ≥300 cells per μL to <500 cells per μL, and ≥500 cells per μL). We based our analysis on the intention-to-treat populations of the two original studies, and all mepolizumab doses were combined for analysis.
FINDINGS: Of 1192 patients, 846 received mepolizumab and 346 received placebo. The overall rate of mean exacerbations per person per year was reduced from 1·91 with placebo to 1·01 with mepolizumab (47% reduction; rate ratio [RR] 0·53, 95% CI 0·44-0·62; p<0·0001). The exacerbation rate reduction with mepolizumab versus placebo increased progressively from 52%; 0·48, 0·39-0·58) in patients with a baseline blood eosinophil count of at least 150 cells per μL to 70%; 0·30, 0·23-0·40]) in patients with a baseline count of at least 500 cells per μL. At a baseline count less than 150 cells per μL, predicted efficacy of mepolizumab was reduced.
INTERPRETATION: Our analysis has shown a close relationship between baseline blood eosinophil count and clinical efficacy of mepolizumab in patients with severe eosinophilic asthma and a history of exacerbations. We noted clinically relevant reductions in exacerbation frequency in patients with a count of 150 cells per μL or more at baseline. The use of this baseline biomarker will help to select patients who are likely to achieve important asthma outcomes with mepolizumab.
FUNDING: GlaxoSmithKline.
BACKGROUND: The MENSA trial assessed the efficacy and safety of mepolizumab in patients with severe eosinophilic asthma. This report describes the efficacy and safety of mepolizumab in Japanese patients from MENSA.
METHODS: A post hoc analysis of the Japanese subgroup from the randomized, double-blind, placebo-controlled, double-dummy, Phase III MENSA trial (NCT01691521). Patients ≥12 years with severe eosinophilic asthma received mepolizumab 75 mg intravenously (IV), 100 mg subcutaneously (SC), or placebo, every 4 weeks for 32 weeks. The primary endpoint was the annualized rate of exacerbations. Secondary and other endpoints included annualized rate of exacerbations requiring emergency department (ED) visit/hospitalization, morning peak expiratory flow (PEF), St George's Respiratory Questionnaire (SGRQ) score and eosinophil counts. Adverse events (AEs) were monitored.
RESULTS: In the Japanese subgroup (N = 50), the rate of clinically significant exacerbations was reduced by 90% (rate ratio [RR]: 0.10; 95% confidence interval [CI]: 0.02-0.57; P = 0.010) with mepolizumab IV and 62% (RR: 0.38; 95% CI: 0.12-1.18; P = 0.094) with mepolizumab SC, versus placebo. No exacerbations requiring ED visit/hospitalization were reported with mepolizumab IV; exacerbations were reduced by 73% (RR: 0.27; 95% CI: 0.06-1.29; P = 0.102) with mepolizumab SC versus placebo. Compared with placebo, mepolizumab IV and SC numerically increased morning PEF from baseline by 40 L/min and 13 L/min, improved quality of life by greater than the minimal clinically important difference (SGRQ: 9.5 [P = 0.083] and 7.9 [P = 0.171] points) and reduced eosinophil counts. AE incidence was similar between treatments. Results were broadly consistent with the overall population.
CONCLUSIONS: Mepolizumab was efficacious and well tolerated in Japanese patients with severe eosinophilic asthma, producing similar responses to the overall MENSA population.
<b>BACKGROUND: </b>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).<b>METHODS: </b>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.<b>RESULTS: </b>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.<b>CONCLUSIONS: </b>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.
This study will evaluate two dose regimens of mepolizumab \[75mg intravenous (i.v.) or 100mg subcutaneous (SC) every 4 weeks\] compared with placebo over a 32 week treatment period in subjects with severe refractory asthma with elevated blood eosinophils. Efficacy will be measured by a reduction in the frequency of asthma exacerbations. Additional efficacy assessments will include measurements of lung function, symptom scores, and quality of life. Safety will be assessed by clinical laboratory samples, ECGs, immunogenicity and adverse events.
This study is intended to replicate the Phase IIb/III study MEA112997. Subjects in MEA115588, who meet all eligibility criteria at screening visit, will enter the run-in period. Those subjects that are not able/eligible to be randomised at the end of the 6 week run-in period will be deemed run-in failures. Subjects will remain on their current maintenance therapy throughout the run-in, double-blind treatment administration and follow-up periods. Subjects who meet the randomisation eligibility criteria will be randomised in a 1:1:1 ratio to receive one of the following treatments every 4 weeks for a total of 8 doses: Mepolizumab 75 miligram (mg) i.v. and placebo SC, or Mepolizumab 100 mg SC and placebo i.v. or Placebo i.v. and placebo SC.
Subjects that receive all 8 doses of double-blind treatment, and meet the eligibility criteria for the Open-Label Extension (OLE) Study, will be offered the opportunity to participate in the OLE trial.
