The effectiveness of Reslizumab in severe asthma treatment: a real-world experience

Abstract Background Increased numbers of blood and sputum eosinophils are associated with higher exacerbation frequency and increased asthma severity. In clinical trials, targeting Interleukin-5 has been shown to be a useful therapeutic strategy for patients with severe eosinophilic asthma. Methods Twenty-six patients have been commenced on Reslizumab in our institution since early 2017. Safety and clinical efficacy parameters were recorded at regular intervals. Results Mean ACQ-6 score at the start of treatment was 3.5. The average number of exacerbations in the year preceding treatment was 8.3 per person. 30% of patients had been admitted to hospital at least once over the 12 months preceding therapy. 54% of our patients were on long term oral steroid. Our data showed sustained improvement of Asthma control (Mean improvement in ACQ-6 was 1.7 at 1 year, and 2.0 at 2 years, P = 0.0001). Of the patients who were on long term systemic steroids, 35.7% discontinued steroids completely, with a mean reduction of prednisolone dose of 5.2 mg at 1 year. There was a 79% reduction in the annual exacerbation frequency at 1 year, and 88% at 2 years (P = < 0.0001). Modest, albeit statistically significant increases in creatine kinase which seemed to plateau by 1 year were noted. Conclusions Overall, Reslizumab was well tolerated with discontinuation of treatment due to side effects recorded in only one patient. Our data confirm the utility of anti-IL5 therapy in a carefully selected phenotype of severe asthma with evidence of eosinophilic airway inflammation.

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Severe eosinophilic bronchial asthma: new therapeutic options

Medical Council ◽

10.21518/2079-701x-2018-15-44-52 ◽

2018 ◽

pp. 44-52 ◽

Cited By ~ 2

Author(s):

N. M. Nenasheva

Keyword(s):

Monoclonal Antibodies ◽

Severe Asthma ◽

Bronchial Asthma ◽

Biological Agents ◽

Therapeutic Options ◽

Clinical Use ◽

Eosinophilic Asthma ◽

Interleukin 5 ◽

Severe Eosinophilic Asthma

Eosinophilic asthma is a common phenotype of severe asthma, occurring in at least half of patients. In recent years, there have been significant changes in the approaches to the treatment of severe bronchial asthma and, above all, eosinophilic asthma. The article discusses the role of eosinophils in the pathogenesis of severe asthma, the detection of the phenotype of severe eosinophilic asthma, and modern approaches to targeting severe asthma with an eosinophilic phenotype using biological agents. A special emphasis is placed on preparations of monoclonal antibodies to interleukin-5, in particular, mepolizumab, recently approved for clinical use in our country.

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Biologics for oral corticosteroid-dependent asthma

Allergy and Asthma Proceedings ◽

10.2500/aap.2020.41.200015 ◽

2020 ◽

Vol 41 (3) ◽

pp. 151-157

Author(s):

İnsu Yılmaz

Keyword(s):

Severe Asthma ◽

Oral Corticosteroid ◽

Real Life ◽

Severe Atopic Dermatitis ◽

Double Blind ◽

Eosinophilic Asthma ◽

Asthma Phenotype ◽

Severe Eosinophilic Asthma ◽

Term Administration

Background: Oral corticosteroid (OCS) dependent asthma is one of the severe asthma phenotypes that requires personalized treatment. Objective: To review the role of biologic treatments in OCS-dependent asthma. Methods: A nonsystematic review was performed of emerging multiple novel biologics for potential treatment of OCS-dependent asthma. Results: The serious adverse effects of OCS can be seen as a result of their regular long-term administration. Anti‐interleukin (IL) 5 (mepolizumab), anti‐IL-5R (benralizumab), and anti‐IL-4Rα (dupilumab) are the therapies of choice for OCS-dependent severe asthma. Results of studies showed the efficacy of mepolizumab, benralizumab, and dupilumab, especially in patients with the OCS-dependent severe eosinophilic asthma phenotype and with nasal polyps. Dupilumab may be the therapy of choice of monoclonal antibodies in cases of moderate-severe atopic dermatitis accompanied by OCS-dependent severe asthma. For reslizumab and omalizumab, placebo controlled double-blind studies conducted with OCS-dependent patient populations are needed. Conclusion: Biologics are effective in the “OCS-dependent asthma” phenotype as add-on therapy. It seems that chronic OCS use in OCS-dependent asthma will be replaced by biologic agents that specifically target type 2 inflammation, along with a much better safety profile. However, real-life studies that compare these biologics in OCS-dependent severe asthma are urgently needed.

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Corticosteroid tapering with benralizumab treatment for eosinophilic asthma: PONENTE Trial

ERJ Open Research ◽

10.1183/23120541.00009-2019 ◽

2019 ◽

Vol 5 (3) ◽

pp. 00009-2019 ◽

Cited By ~ 1

Author(s):

Andrew Menzies-Gow ◽

Jonathan Corren ◽

Elisabeth H. Bel ◽

Jorge Maspero ◽

Liam G. Heaney ◽

...

Keyword(s):

Adrenal Insufficiency ◽

Asthma Control ◽

Severe Asthma ◽

Maintenance Phase ◽

Phase Iii ◽

Eosinophilic Asthma ◽

Interleukin 5 ◽

Severe Eosinophilic Asthma ◽

Link Type ◽

Related Quality

Benralizumab is an interleukin-5 receptor α-directed cytolytic monoclonal antibody approved in several countries for the add-on maintenance treatment of patients with severe eosinophilic asthma aged 12 years and older. In the 28-week Phase III ZONDA trial (ClinicalTrials.gov identifier: NCT02075255), benralizumab produced a median 75% reduction from baseline in oral corticosteroid (OCS) dosage (versus 25% for placebo) while maintaining asthma control for patients with OCS-dependent severe asthma. This manuscript presents the detailed protocol for the Phase IIIb PONENTE (ClinicalTrials.gov identifier: NCT03557307), a study that will build on the findings from ZONDA.As the largest steroid-sparing study undertaken in severe asthma, PONENTE has a faster steroid tapering schedule for prednisone dosages ≥7.5 mg·day−1 than previous studies, and it includes an evaluation of adrenal insufficiency and an algorithm to taper OCS dosage when prednisone dosage is ≤5 mg·day−1. It also has a longer maintenance phase to assess asthma control for up to 6 months after completion of OCS tapering.The two primary endpoints are whether patients achieve 100% reduction in daily OCS use and whether patients achieve 100% reduction in daily OCS or achieve OCS dosage ≤5 mg·day−1, if adrenal insufficiency prevented further reduction, both sustained over ≥4 weeks without worsening of asthma. Safety and change from baseline in health-related quality of life will also be assessed.PONENTE should provide valuable guidance for clinicians on tapering OCS dosage, including the management of adrenal insufficiency, following benralizumab initiation for the treatment of patients who are OCS-dependent with severe, uncontrolled eosinophilic asthma.

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Health outcomes after stopping long-term mepolizumab in severe eosinophilic asthma: COMET

ERJ Open Research ◽

10.1183/23120541.00419-2021 ◽

2021 ◽

pp. 00419-2021

Author(s):

Mark C Liu ◽

Elisabeth H Bel ◽

Oliver Kornmann ◽

Wendy C Moore ◽

Norihiro Kaneko ◽

...

Keyword(s):

Health Outcomes ◽

Healthcare Resource ◽

Asthma Severity ◽

Response To Therapy ◽

Open Label ◽

Eosinophilic Asthma ◽

Severe Eosinophilic Asthma ◽

Link Type ◽

Increased Risk

AbstractAsthma 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 four weeks or 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 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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Stopping versus continuing long-term mepolizumab treatment in severe eosinophilic asthma (COMET study)

European Respiratory Journal ◽

10.1183/13993003.00396-2021 ◽

2021 ◽

pp. 2100396

Author(s):

Wendy C. Moore ◽

Oliver Kornmann ◽

Marc Humbert ◽

Claude Poirier ◽

Elisabeth H. Bel ◽

...

Keyword(s):

Emergency Department ◽

Asthma Control ◽

Emergency Department Visit ◽

Hazard Ratio ◽

Blood Eosinophil ◽

Eosinophilic Asthma ◽

Severe Eosinophilic Asthma ◽

Link Type ◽

Clinically Significant

The long-term efficacy and safety of mepolizumab for treatment of severe eosinophilic asthma are well established. Here, we examine the clinical impact of stopping mepolizumab after long-term use.COMET (NCT02555371) was a randomised, double-blind, placebo-controlled, parallel-group, multicenter study. Patients who had completed COLUMBA (NCT01691859) or COSMEX (NCT02135692) and received continuous mepolizumab treatment for ≥3 years were randomised 1:1 to stop (switch to placebo) or continue subcutaneous mepolizumab 100 mg every 4 weeks for 52 weeks. Primary endpoint: time to first clinically significant exacerbation; secondary endpoints: time to first exacerbation requiring hospitalisation/emergency department visit, time to decrease in asthma control (≥0.5-point increase in Asthma Control Questionnaire-5 score from COMET baseline), and blood eosinophil count ratio to COMET baseline. Safety was assessed.Patients stopping (n=151) versus continuing (n=144) mepolizumab had significantly shorter times to first clinically significant exacerbation (hazard ratio: 1.61 [95% confidence interval: 1.17,2.22]; p=0.004) and decrease in asthma control (hazard ratio: 1.52 [1.13,2.02]; p=0.005), and higher blood eosinophil counts at Week 52 (270 versus 40 cells·µL−1; ratio [stopping versus continuing]: 6.19 [4.89, 7.83]; p<0.001). Differences in efficacy outcomes between groups were observed when assessed from Week 12 (16 weeks after last mepolizumab dose). Exacerbations requiring hospitalisation/emergency department visit were rare. Adverse events in patients continuing mepolizumab were consistent with previous studies. For patients who stopped mepolizumab, the safety profile was consistent with other eosinophilic asthma populations.Patients who stopped mepolizumab had an increase in exacerbations and reduced asthma control versus those who continued.

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Precision medicine applications for severe asthma

LymphoSign Journal ◽

10.14785/lymphosign-2019-0017 ◽

2019 ◽

Vol 6 (4) ◽

pp. 117-135

Author(s):

Orit Gourgy Hacohen ◽

Shai Cohen

Keyword(s):

Precision Medicine ◽

Severe Asthma ◽

Oral Corticosteroid ◽

Treatment Options ◽

Current Evidence ◽

Blood Eosinophil ◽

Eosinophilic Asthma ◽

Severe Eosinophilic Asthma ◽

Beneficial Effects ◽

New Treatment

Asthma is a heterogeneous condition in which multiple pathological pathways manifest with similar symptoms. Severe asthma (SA) is challenging to manage and comprises a significant health and economic burden. Many studies have been conducted in an attempt to define different clinical phenotypes that translate into biological endotypes, with the goal of tailoring treatment based on precision medicine. This review summarizes the current evidence for the treatments of SA, and in particular, the biologic treatments that are currently available: omalizumab, mepolizumab, reslizumab, benralizumab and dupilumab. We found only limited high-quality direct evidence regarding treatment with anti-IgE (omalizumab) in SA patients. Data regarding anti-interleukin (IL)-5 (mepolizumab, reslizumab and benralizumab) showed beneficial effects in severe eosinophilic asthma (SEA) with different levels of blood eosinophils used in clinical trials. Dupilumab, anti-IL-4/IL-13, was shown to be effective in SEA and is the only agent currently FDA-approved for the indication of oral corticosteroid dependent asthma, regardless of the blood eosinophil level. This review also summarizes the existing knowledge regarding the characteristics of the patient who may respond to the different therapies. As of today, more studies are needed to better understand the diverse mechanisms that underlie SA phenotypes. We have not yet adequately reached the goal of precision medicine. Additional studies are necessary in order to find novel surrogate markers that can predict the response to a specific biologic therapy, especially in patients who are oral corticosteroid dependent. In addition, efforts must be invested into research looking for new treatment options for patients with non-type-2 inflammation SA. Statement of novelty: we review the current evidence regarding tailored treatment therapies in SA, with a particular focus on the knowledge regarding patient selection for specific biologic treatments.

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Efficacy of mepolizumab for patients with severe asthma and eosinophilic chronic rhinosinusitis

BMC Pulmonary Medicine ◽

10.1186/s12890-019-0952-1 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 11

Author(s):

Takanori Numata ◽

Katsutoshi Nakayama ◽

Hirofumi Utsumi ◽

Kenji Kobayashi ◽

Haruhiko Yanagisawa ◽

...

Keyword(s):

Chronic Rhinosinusitis ◽

Severe Asthma ◽

Predictive Factors ◽

Systemic Corticosteroid ◽

Multivariate Logistic Regression Analysis ◽

Patient Characteristics ◽

Blood Eosinophil ◽

Eosinophilic Asthma ◽

Severe Eosinophilic Asthma ◽

Eosinophilic Chronic Rhinosinusitis

Abstract Background Several major randomized control studies have demonstrated that mepolizumab, an anti-IL-5 monoclonal antibody, is effective for patients with severe eosinophilic asthma who show exacerbation or require systemic corticosteroid maintenance therapy. However, the predictive factors of the response to mepolizumab other than blood eosinophil count are unclear in clinical practice. Objective To elucidate the predictive factors of the response to mepolizumab for patients with severe eosinophilic asthma. Methods From July 2016 to December 2017, 28 patients with severe asthma received mepolizumab in our hospital. To determine the predictive factors, we retrospectively evaluated patient characteristics, comorbidities, biomarkers, pulmonary function, maintenance dose of systemic corticosteroids and number of exacerbations. Results The response rate to mepolizumab treatment was 70% (19/27; one pregnant woman was excluded from analysis). Compared with 11 patients without eosinophilic chronic rhinosinusitis (ECRS), 16 patients with ECRS showed significantly improved systemic corticosteroid-sparing effects [− 71.3 ± 37.0% vs − 10.7 ± 20.1%, P = 0.006], change from baseline FeNO [− 19 ± 57 (%) vs 30 ± 77 (%), P = 0.023] and symptoms [14 patients (88%) vs five patients (45%), P = 0.033]. ECRS was identified as a predictive factor of the response to mepolizumab in a multivariate logistic regression analysis [odds ratio = 22.5, 95% CI (1.5–336), P = 0.024]. Of the eight patients previously administered omalizumab, five responded to mepolizumab. Staphylococcus aureus enterotoxin B IgE results were negative in 80% of responders (P = 0.14). Conclusion Both groups showed improved symptom scores and a decreased number of exacerbations. Mepolizumab substantially improved the clinical variables of patients with eosinophilic asthma complicated with ECRS.

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Antibodies targeting the interleukin-5 signaling pathway used as add-on therapy for patients with severe eosinophilic asthma: a review of the mechanism of action, efficacy, and safety of the subcutaneously administered agents, mepolizumab and benralizumab

Expert Review of Respiratory Medicine ◽

10.1080/17476348.2020.1718495 ◽

2020 ◽

Vol 14 (4) ◽

pp. 353-365 ◽

Cited By ~ 6

Author(s):

Georgios Hillas ◽

Evangelia Fouka ◽

Andriana I Papaioannou

Keyword(s):

Signaling Pathway ◽

Mechanism Of Action ◽

Efficacy And Safety ◽

Eosinophilic Asthma ◽

Interleukin 5 ◽

Severe Eosinophilic Asthma

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Diagnosis and Management of Severe Asthma

Seminars in Respiratory and Critical Care Medicine ◽

10.1055/s-0037-1607391 ◽

2018 ◽

Vol 39 (01) ◽

pp. 091-099 ◽

Cited By ~ 5

Author(s):

Kian Fan Chung

Keyword(s):

Severe Asthma ◽

Inhaled Corticosteroids ◽

Immunoglobulin E ◽

High Dose ◽

Blood Eosinophil ◽

Exhaled Breath ◽

Eosinophilic Asthma ◽

Severe Eosinophilic Asthma ◽

Asthma Patients ◽

Long Acting

AbstractSevere therapy-resistant asthma has been defined as “asthma which requires treatment with high dose inhaled corticosteroids (ICSs) plus a second controller (and/or systemic corticosteroids) to prevent it from becoming ‘uncontrolled’ or which remains ‘uncontrolled’ despite this therapy”. Patients who usually present with ‘difficult-to-treat asthma’ should first be assessed to determine whether he/she has asthma with the exclusion of other diagnoses and if so, whether the asthma can be classified as severe therapy-resistant. This necessitates an assessment of adherence to medications, confounding factors, and comorbidities. Increasingly, management of severe therapy-resistant asthma will be helped by the determination of phenotypes to optimize responses to existing and new therapies. Severe asthma patients are usually on a combination of high dose ICS and long-acting β-agonist (LABA) and, in addition, are often on a maintenance dose of oral corticosteroids. Phenotyping can be informed by measuring blood eosinophil counts and the level of nitric oxide in exhaled breath, and the use of sputum granulocytic counts. Severe allergic asthma and severe eosinophilic asthma are two defined phenotypes for which there are efficacious targeted biologic therapies currently available, namely anti-immunoglobulin E (IgE) and anti-interleukin (IL)-5 antibodies, respectively. Further progress will be realized with the definition of noneosinophilic or non-T2 phenotypes. It will be important for patients with severe asthma to be ultimately investigated and managed in specialized severe asthma centers.

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