Eosinophil-derived neurotoxin and clinical outcomes with mepolizumab in severe eosinophilic asthma.
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ABSTRACT:
SUBMITTER: Howarth P
PROVIDER: S-EPMC7592754 | biostudies-literature | 2020 Aug
REPOSITORIES: biostudies-literature
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Eosinophil-derived neurotoxin and clinical outcomes with mepolizumab in severe eosinophilic asthma.
Howarth Peter P Quirce Santiago S Papi Alberto A Israel Elliot E Mallett Stephen S Bates Stewart S Yancey Steve S Albers Frank C FC Kwon Namhee N
Allergy 20200323 8
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Project description:Asthma is a chronic inflammatory disorder of the airways with variable clinical severity from very mild and occasional symptoms to recurrent critical exacerbations, at risk of fatal or near-fatal outcome, in a small percentage of patients. Within the different inflammatory cascades involved in asthma, eosinophils play a central role in the pathogenesis and largely influence disease severity. Interleukin-5 (IL-5) is the main cytokine controlling eosinophil activity and proliferation at the site of inflammation. Mepolizumab was the first biological humanized anti-IL-5 monoclonal antibody tested in randomized clinical trials on eosinophilic asthma and other eosinophilic diseases. On the basis of several positive clinical efficacy data, it has recently been approved by the US Food and Drug Administration for the treatment of severe eosinophilic asthma. Unfortunately, high costs are at present a critical issue. Future studies will probably help in the correct selection of a potential "responder phenotype", allowing the prescription of this promising therapy to appropriate patients and best define cost-effectiveness issues.
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Project description:Asthma worsening and symptom control are clinically important health outcomes in patients with severe eosinophilic asthma. This analysis of COMET evaluated whether stopping versus continuing long-term mepolizumab therapy impacted these outcomes. Patients with severe eosinophilic asthma with ≥3 years continuous mepolizumab treatment (via COLUMBA (NCT01691859) or COSMEX (NCT02135692) open-label studies) were eligible to enter COMET (NCT02555371), a randomised, double-blind, placebo-controlled study. Patients were randomised 1:1 to continue mepolizumab 100 mg subcutaneous every 4 weeks or to stop mepolizumab, plus standard of care asthma treatment. Patients could switch to open-label mepolizumab following an exacerbation. Health outcome endpoints included time to first asthma worsening (composite endpoint: rescue use, symptoms, awakening at night and morning peak expiratory flow (PEF)), patient and clinician assessed global rating of asthma severity and overall perception of response to therapy, and unscheduled healthcare resource utilisation. Patients who stopped mepolizumab showed increased risk of and shorter time to first asthma worsening compared with those who continued mepolizumab (hazard ratio (HR) 1.71; 95% CI 1.17-2.52; p=0.006), including reduced asthma control (increased risk of first worsening in rescue use (HR 1.36; 95% CI 1.00-1.84; p=0.047) and morning PEF (HR 1.77; 95% CI 1.21-2.59; p=0.003). There was a higher probability of any unscheduled healthcare resource use (HR 1.81; 95% CI 1.31-2.49; p<0.001), and patients and clinicians reported greater asthma severity and less favourable perceived response to therapy for patients who stopped versus continued mepolizumab. These data suggest that patients with severe eosinophilic asthma continuing long-term mepolizumab treatment sustain clinically important improvements in health outcomes.
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Project description:Severe asthma is characterized by major impairment of quality of life, poor symptom control and frequent exacerbations. Inflammatory, clinical and causative factors identify different phenotypes and endotypes of asthma. In the last few years, new treatment options have allowed for targeted treatments according to the different phenotypes of the disease. To accurately select a specific treatment for each asthmatic variant, the identification of appropriate biomarkers is required. Eosinophilic asthma is a distinct phenotype characterized by thickening of the basement membrane and corticosteroid responsiveness. This review reports the latest evidence on an anti-IL-5 monoclonal antibody, mepolizumab, a new and promising biological agent recently approved by the FDA specifically for the treatment of severe eosinophilic refractory asthma.
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Project description:BackgroundMepolizumab and omalizumab are treatments for distinct but overlapping severe asthma phenotypes.ObjectiveTo assess if patients eligible for both biologics but not optimally controlled with omalizumab experience improved asthma control when switched directly to mepolizumab.MethodsOSMO was a multicenter, open-label, single-arm, 32-week trial in patients with ≥2 asthma exacerbations in the year prior to enrollment, despite receiving high-dose inhaled corticosteroids and other controller(s), plus omalizumab (≥4 months). At baseline, patients with blood eosinophil counts ≥150 cells/µL (or ≥300 cells/µL in the prior year) and an Asthma Control Questionnaire (ACQ)-5 score ≥1.5 discontinued omalizumab and immediately commenced mepolizumab 100 mg subcutaneously every 4 weeks. Endpoints included change from baseline in ACQ-5 score (primary), St George's Respiratory Questionnaire (SGRQ) score and the proportions of ACQ-5 and SGRQ responders, all at Week 32, and the annualized exacerbation rate over the study period.ResultsAt Week 32 (intent-to-treat population [n = 145]), the least squares (LS) mean changes (standard error [SE]) in ACQ-5 and SGRQ total scores were -1.45 (0.107) and -19.0 (1.64) points; with 77% and 79% of patients achieving the minimum clinically important differences (ACQ-5: ≥0.5 points; SGRQ: ≥4 points), respectively. The annualized rate of clinically significant exacerbations was 1.18 events/year, a 64% reduction from 3.26 events/year during the previous year. Safety and immunogenicity profiles were consistent with previous trials.ConclusionAfter directly switching from omalizumab to mepolizumab, patients with uncontrolled severe eosinophilic asthma experienced clinically significant improvements in asthma control, health status, and exacerbation rate, with no tolerability issues reported.
| S-EPMC6790683 | biostudies-literature
Project description:Asthma is a chronic complex pulmonary disease characterized by airway inflammation, remodeling, and hyperresponsiveness. Vascular endothelial growth factor (VEGF) and eosinophil-derived neurotoxin (EDN) are two significant mediators involved in the pathophysiology of asthma. In asthma, VEGF and EDN levels are elevated and correlate with disease severity and airway hyperresponsiveness. Diversity in VEGF polymorphisms results in the variability of responses to glucocorticosteroids and leukotriene antagonist treatment. Targeting VEGF and eosinophils is a promising therapeutic approach for asthma. We identified lichochalcone A, bevacizumab, azithromycin (AZT), vitamin D, diosmetin, epigallocatechin gallate, IGFBP-3, Neovastat (AE-941), endostatin, PEDF, and melatonin as putative add-on drugs in asthma with anti-VEGF properties. Further studies and clinical trials are needed to evaluate the efficacy of those drugs. AZT reduces the exacerbation rate and may be considered in adults with persistent symptomatic asthma. However, the long-term effects of AZT on community microbial resistance require further investigation. Vitamin D supplementation may enhance corticosteroid responsiveness. Herein, anti-eosinophil drugs are reviewed. Among them are, e.g., anti-IL-5 (mepolizumab, reslizumab, and benralizumab), anti-IL-13 (lebrikizumab and tralokinumab), anti-IL-4 and anti-IL-13 (dupilumab), and anti-IgE (omalizumab) drugs. EDN over peripheral blood eosinophil count is recommended to monitor the asthma control status and to assess the efficacy of anti-IL-5 therapy in asthma.
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Project description:BackgroundEosinophils are crucial in allergic inflammation, and their correlation with asthma severity has made them a focal point in predicting treatment outcomes. Blood eosinophil count is a commonly utilized marker. However, its limitations have prompted alternative biomarker exploration, such as eosinophil-derived neurotoxin (EDN).ObjectiveThis research was conducted over 24 weeks on 56 patients with severe asthma treated with mepolizumab, reslizumab, and dupilumab. We aimed to evaluate the clinical significance of blood eosinophil count and their potential, including those of blood EDN levels and urine EDN values as biomarkers for predicting treatment response.MethodsThe analysis encompassed examining correlations between biomarkers and clinical features, including exacerbation rates and lung function, through ELISA assays and subsequent statistical analyses. The study protocol is registered at ClinicalTrials.gov (NCT05164939).ResultsThe findings underscore strong correlations between serum EDN levels, blood eosinophil counts, and treatment responses, with EDN demonstrating comparable predictive capabilities to blood eosinophil counts to determine treatment responses. Different biologics exhibited varying efficacy regarding baseline eosinophil counts and EDN levels.ConclusionsBlood eosinophil counts and EDN levels show potential as predictive markers for treatment responses in patients with severe asthma undergoing biologic therapies. However, further comprehensive studies are warranted to enhance the reliability and applicability of EDN as an effective asthma treatment biomarker.
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Project description:Severe asthma is burdened by frequent exacerbations and use of oral corticosteroids (OCS), which worsen patients' health and increase healthcare spending. The aim of this study was to assess the clinical and economic impact of switching from omalizumab (OMA) to mepolizumab (MEP) in patients eligible for both biologics, but not optimally controlled by omalizumab. We retrospectively enrolled uncontrolled severe asthmatic patients who switched from OMA to MEP during the last two years. Information included blood eosinophil count, asthma control test (ACT), spirometry, serum IgE, fractional exhaled nitric oxide (FeNO), OCS intake, drugs, exacerbations/hospitalizations, visits and diagnostic exams. Within the perspective of Italian National Health System, a pre- and post-MEP 12-month standardized total cost per patient was calculated. 33 patients were enrolled: five males, mean age 57 years, disease onset 24 years. At OMA discontinuation, 88% were OCS-dependent with annual mean rate of 4.0 clinically significant exacerbations, 0.30 exacerbations needing emergency room visits or hospitalization; absenteeism due to disease was 10.4 days per patient. Switch to MEP improved all clinical outcomes, reducing total exacerbation rate (RR = 0.06, 95% CI 0.03-0.14), OCS-dependent patients (OR = 0.02, 95% CI 0.005-0.08), and number of lost working days (Δ = - 7.9, 95% CI - 11.2 to - 4.6). Pulmonary function improved, serum IgE, FeNO and eosinophils decreased. Mean annual costs were €12,239 for OMA and €12,639 for MEP (Δ = €400, 95% CI - 1588-2389); the increment due to drug therapy (+ €1,581) was almost offset by savings regarding all other cost items (- €1,181). Patients with severe eosinophilic asthma, not controlled by OMA, experienced comprehensive benefits by switching to MEP with only slight increases in economic costs.
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Project description:Adolescents (12-17 years of age) with severe eosinophilic asthma experience frequent exacerbations and reduced lung function leading to poor health-related quality of life. Mepolizumab is approved for add-on maintenance therapy in patients with severe eosinophilic asthma ≥ 6 years of age in the EU and ≥ 12 years of age in other regions (including the USA), based on a Phase II/III program demonstrating reduced exacerbation rates with 4-weekly treatment. A total of 34 adolescent patients were recruited across the Phase III mepolizumab trials. Consistent with outcomes in the overall population, there was a reduction in the annual rate of clinically significant exacerbations, along with a reduction in blood eosinophil counts in response to mepolizumab in adolescent patients. The safety profile in adolescent patients was consistent with that seen in the overall population. Data from the Phase III clinical development program provide evidence for comparable efficacy and safety of mepolizumab between adolescents with severe eosinophilic asthma and the overall population. Clinical trial registration DREAM, NCT01000506 [MEA112997]; MENSA, NCT01691521 [MEA115588]; SIRIUS, NCT01691508 [MEA115575]; MUSCA, NCT02281318 [200862]; COSMOS, NCT01842607 [MEA115661].
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Project description:Eosinophilic esophagitis (EoE) is characterized by infiltration of eosinophils into esophageal epithelium. Blood levels of an eosinophil granule protein, eosinophil-derived neurotoxin (EDN), have been proposed as a biomarker for EoE. However, information regarding localization of EDN in the diseased tissues has not been available. The goal of this study was to evaluate the magnitude and distribution of EDN deposition in tissue specimens from the esophagus of EoE patients.We studied specimens from 10 adult EoE patients and eight histologically normal controls (three under age 17). Sections from mid-esophageal biopsy specimens were stained for EDN by immunofluorescence, using a polyclonal rabbit antibody to EDN. Cellular staining (i.e., infiltration of intact eosinophils) and extracellular staining (i.e., deposition of released EDN) were scored in a blinded manner on an established 7-point scale.Esophageal biopsy specimens from histologically normal controls showed no or few intact eosinophils and no or minimal extracellular EDN deposition. In contrast, EDN staining was clearly observed in specimens from all EoE patients. In some EoE patients, marked extracellular EDN deposition was observed despite relatively small numbers of intact eosinophils. Overall, there was no correlation between the eosinophil infiltration and the extracellular EDN staining scores.Marked tissue deposition of extracellular EDN is present in the esophagus of EoE patients. Tissue eosinophil counts may underestimate how extensively eosinophils are involved, particularly in individuals with marked eosinophil degranulation. Evaluation of EDN staining in esophageal biopsy specimens may be useful to diagnose and manage patients with EoE.
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