Necdet Gunsoy

Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies

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.

Meta-analysis of asthma-related hospitalization in mepolizumab studies of severe eosinophilic asthma.

Background: Studies show that mepolizumab can reduce the frequency of clinically significant exacerbations in patients with severe eosinophilic asthma, compared with placebo. However, important events such as hospitalizations and emergency room visits are rare and difficult to characterize in single studies. Objective: We sought to compare hospitalization or hospitalization and/or emergency room visit rates in patients with severe eosinophilic asthma treated with mepolizumab or placebo in addition to standard of care for at least 24 weeks. Methods: This study was conducted and reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta‐Analyses statement. PubMed and the GSK Clinical Study Register were searched for suitable studies. The primary end points were the rate of exacerbations requiring hospitalization and the rate of exacerbations requiring hospitalization/emergency room visit. The proportion of patients with 1 or more event was also assessed. All mepolizumab doses were combined and individual patient‐level data were analyzed. Results: Four studies (n = 1388) were eligible for inclusion. Mepolizumab significantly reduced the rate of exacerbations requiring hospitalization (relative rate, 0.49; 95% CI, 0.30‐0.80; P = .004) and hospitalization/emergency room visit (relative rate, 0.49; 95% CI, 0.33‐0.73; P < .001) versus placebo. Significant reductions of 45% and 38% were also observed for the proportion of patients experiencing 1 or more hospitalization and hospitalization and/or emergency room visit, respectively. Conclusions: Mepolizumab approximately halved exacerbations requiring hospitalization and/or emergency room visits compared with placebo in patients with severe eosinophilic asthma. This treatment addresses a key outcome in a patient population with a high unmet need (GSK Study 204664).

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.

Anti–IL-5 treatments in patients with severe asthma by blood eosinophil thresholds: Indirect treatment comparison

Background: Three anti–IL‐5 pathway–directed therapies are approved for use in patients with severe eosinophilic asthma (SEA); however, no head‐to‐head comparison data are available. Objective: We sought to compare the efficacy of licensed doses of mepolizumab, benralizumab, and reslizumab in patients with SEA, according to baseline blood eosinophil counts. Methods: This indirect treatment comparison (ITC) used data from a Cochrane review and independent searches. Eligible studies were randomized controlled trials in patients aged 12 years or greater with SEA. End points included annualized rate of clinically significant exacerbations and change from baseline in Asthma Control Questionnaire score and FEV1. An ITC was performed in patients with Asthma Control Questionnaire scores of 1.5 or greater and stratified by baseline blood eosinophil count. Results: Eleven studies were included. All treatments significantly reduced the rate of clinically significant exacerbations and improved asthma control versus placebo in all blood eosinophil count subgroups. Mepolizumab reduced clinically significant exacerbations by 34% to 45% versus benralizumab across subgroups (rate ratio ≥400 cells/&mgr;L: 0.55 [95% CI, 0.35‐0.87]; ≥300 cells/&mgr;L: 0.61 [95% CI, 0.37‐0.99]; and ≥150 cells/&mgr;L: 0.66 [95% CI, 0.49‐0.89]; all P < .05) and by 45% versus reslizumab in the 400 cells/&mgr;L or greater subgroup (rate ratio, 0.55 [95% CI, 0.36‐0.85]; P = .007). Asthma control was significantly improved with mepolizumab versus benralizumab (all subgroups: P < .05) and versus reslizumab in the 400 cells/&mgr;L or greater subgroup (P = .004). Benralizumab significantly improved lung function versus reslizumab in the 400 cells/&mgr;L or greater subgroup (P = .025). Conclusions: This ITC of the licensed doses suggests that mepolizumab was associated with significantly greater improvements in clinically significant exacerbations and asthma control compared with reslizumab or benralizumab in patients with similar blood eosinophil counts.

P15 Cost effectiveness of mepolizumab for severe eosinophilic asthma from the uk perspective

Introduction Severe asthma patients have limited therapeutic options. These patients remain at risk of exacerbations, their quality of life is negatively impacted and they place a significant burden on the health service. Mepolizumab is licensed for use in patients with severe eosinophilic asthma. As reimbursement authorities expect evidence of health economic benefits, this study aimed to estimate the cost-utility of mepolizumab as an add-on therapy to standard of care (SOC) versus SOC alone. Methods A de novo Markov cost-utility model was produced which compared the costs and outcomes of mepolizumab vs. SOC over a lifetime horizon. Primary analysis was based on data from the MENSA clinical trial (NCT01691521). Patients entering the model were assigned to mepolizumab or SOC and experienced treatment-specific probabilities of exacerbation events with an associated risk of mortality and disutility. The model included a continuation criteria where patients on mepolizumab who failed to demonstrate an exacerbation reduction were transitioned to the SOC arm. Costs and health outcomes were discounted annually at 3.5%. The model did not account for indirect costs or value in steroid reduction. Results In the basecase analysis (patients with ≥300 eosinophil cells/µL and ≥4 exacerbations in the previous 12 months) the incremental cost-effectiveness ratio (ICER) of add-on mepolizumab compared with SOC was £30,268/QALY gained. Scenario analyses showed that the ICER was sensitive to the starting age of the cohort, the source of utility and asthma-related mortality. Conclusion Mepolizumab represents a clinically efficacious and cost-effective alternative to SOC.

Predictors of respiratory health status in patients with severe asthma

Rationale: Patients with severe asthma experience substantial impact on health related quality of life. Characterization of predictors of worse health status in severe asthma may help identify patients requiring additional interventions. This post-hoc analysis of the IDEAL study (201722; NCT02293265) evaluated predictors of respiratory health status, measured by the St George9s Respiratory Questionnaire (SGRQ). Methods: The IDEAL study was a cross-sectional, non-interventional study in 6 countries, and included subjects ≥12 years with severe asthma (ATS/ERS guidelines) treated with high-dose ICS plus additional controller(s) for ≥12 months. Assessments included a blood sample, spirometry, and PRO, including the SGRQ. Clinical and demographic characteristics predictive of SGRQ score in the total cohort were evaluated with univariate analysis and multivariate linear regression. Results: In univariate analysis, predictors of SGRQ included gender, pre-bronchodilator FEV 1 %predicted, bronchodilator reversibility, smoking status, use of maintenance oral corticosteroids (OCS), history of clinically significant exacerbations (prior 12 months), and blood eosinophil level. Total IgE and use of omalizumab were not associated with SGRQ. In multivariate regression, predictors of lower health status score included history of clinically significant exacerbations, lower FEV 1 %predicted, OCS use, female gender, and current or a history of smoking. Conclusions: Among patients with severe asthma, there are clinical and demographic characteristics associated with an impact on respiratory health status measured by the SGRQ, that could be addressed by targeted intervention. Funding: GSK (NCT02293265).

Clinical characteristics and burden of illness in a cohort of severe asthma patients

Objectives: Describe demographic and clinical traits among patients with severe asthma (SA) and a subset of patients with inadequately controlled severe eosinophilic asthma (SEA). Methods: IDEAL study (201722; NCT02293265) is a cross-sectional cohort of SA patients (age ≥12 years, high-dose ICS + additional controller/s for ≥12 months) recruited from specialist clinics in 6 countries. Inadequately controlled SEA was defined as (1) blood eosinophil count of ≥300 cells/μL in the past 12 months prior to study visit OR ≥150 cells/μL at study visit AND (2) ≥2 or more severe exacerbations of asthma (requiring systemic corticosteroid and/or emergency room (ER) visit and/or hospitalization) in the past 12 months. Extensive medical history supplemented with existing medical records and a blood sample were collected. Results: The cohort consisted of 670 SA patients, of whom 137 (20%) had SEA. Compared to the total SA cohort, the subset with SEA had equal proportion of females (62%), was slightly younger (mean: 48 vs. 51 yrs) and had more significant smoking history (45% vs. 36%). Mean of severe exacerbations was 3.2 vs. 1.2/patient-year and 23% vs 9% had ≥1 asthma hospitalization, with more frequent regular OCS use (20% vs. 14%). Further, higher levels of IgE (179 vs. 155 KU/L), lower FEV 1 values (64 vs. 68 FEV 1 % pred.) and more frequent comorbidities were observed. Conclusions: The IDEAL study shows a considerable disease burden in a cohort of patients with severe asthma, with impaired lung function and on average more than one exacerbation/yr. The subset with inadequately controlled severe eosinophilic asthma with more than 3 exacerbations/yr seems to drive much of this disease burden. Funded by GSK.