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Pulmonary – Treatable traits
Published in Vibeke Backer, Peter G. Gibson, Ian D. Pavord, The Asthmas, 2023
Vibeke Backer, Peter G. Gibson, Ian D. Pavord
The peripheral blood eosinophil counts have been extensively studied as a potential biomarker for asthma. Eosinophils are important drivers of severe exacerbations in asthma, and blood eosinophil counts are useful in the early detection of exacerbations and the regulation of steroid dosage. Mepolizumab, a humanised monoclonal antibody against IL-5, is a selective and effective inhibitor of eosinophilic inflammation which significantly decreases the frequency of asthma attacks in patients with severe asthma and evidence of eosinophilic airway inflammation, despite treatment with high doses of corticosteroids. The benefits of treatment are closely associated with the blood eosinophil count, and the clinical response is marked in patients with pre-treatment eosinophilia and absent in patients with a count <150/μL. This is also the case for other biologics that reduce type-2 airway inflammation by targeting alternative targets (i.e. Dupilumab and Omalizumab).
The Pharmacotherapy of Rhinitis and Asthma
Published in Pudupakkam K Vedanthan, Harold S Nelson, Shripad N Agashe, PA Mahesh, Rohit Katial, Textbook of Allergy for the Clinician, 2021
Amanda Grippen Goddard, Harold S. Nelson, Rohit Katial, Flavia Hoyte
Since 2015, there have been three anti-IL-5 therapies (mepolizumab, reslizumab and benralizumab) approved for add-on maintenance treatment for patients with severe eosinophilic asthma. Mepolizumab is a recombinant, humanized IgG1κ monoclonal antibody against IL-5 that inhibits IL-5 from binding to the α-subunit of the IL-5 receptor complex expressed on the eosinophil cell surface. There is a small risk for hypersensitivity reactions and herpes zoster infections with mepolizumab. Reslizumab is a humanized IgG4κ monoclonal anti-IL-5 antibody that also inhibits binding of IL-5 to its receptor. As opposed to mepolizumab that is given subcutaneously, reslizumab is given intravenously. There are small risks for developing anaphylaxis and elevated creatinine phosphokinase levels with reslizumab. Both mepolizumab and reslizumab inhibit the growth, differentiation, recruitment, activation and survival of eosinophils. Benralizumab is a humanized afucosylated recombinant IgG1κ monoclonal antibody that binds with high affinity to the α-subunit of the IL-5 receptor. By doing so, benralizumab inhibits the proliferation and activation of eosinophils by blocking the same IL-5-mediated eosinophil properties that are blocked by mepolizumab and reslizumab. In addition, the Fc portion of benralizumab binds to Fc receptors on immune effector cells, such as natural killer cells, which then deplete existing eosinophils and precursors in the bone marrow by inducing apoptosis through antibody-dependent cell-mediated cytotoxicity (Assaf and Hanania 2019, Katial et al. 2017).
Biologics in allergic disease
Published in Richard F. Lockey, Dennis K. Ledford, Allergens and Allergen Immunotherapy, 2020
Tara V. Saco, Farnaz Tabatabaian
Eosinophils are an integral part of Th2 asthma. Elevated sputum and peripheral eosinophils correlate with increased asthma exacerbations and poorly controlled asthma [1,14,15]. IL-5 is necessary for eosinophil growth, differentiation, and migration into the airways [1,16]. Mepolizumab, reslizumab, and benralizumab are three monoclonal antibodies that target IL-5. Mepolizumab and reslizumab directly bind to the IL-5 cytokine and prevent its downstream binding to the IL-5 receptor [14,17–19]. Benralizumab binds to the alpha (α) chain of IL-5 receptor, thus enhancing the antibody-dependent cell-mediated cytotoxicity causing apoptosis of eosinophils, basophils, and eosinophil progenitor cells [20]. Mepolizumab is the first IL-5 inhibitor approved by the FDA as an add-on therapy for severe persistent asthma in the 12 years and older age group. It is administered as a 100 mg subcutaneous injection every 4 weeks [21]. Mepolizumab shows improvement in the quality-of-life scores with decreased emergency room (ER) visits and hospitalizations, a 53% decrease in asthma exacerbation, an improvement of 100 mL in FEV1, and 50% reduced oral glucocorticoid use in phase 3 studies [22,23]. Subjects with higher levels of peripheral eosinophilia experience greatest benefit. Mepolizumab, 300 mg sub-Q, is FDA approved for eosinophilic granulomatosis with polyangiitis [22].
Mepolizumab prefilled syringe for the treatment of severe eosinophilic asthma: focus on the pediatric population
Published in Expert Review of Respiratory Medicine, 2022
Michelle Dilley Revier, Bob Geng
Asthma affects a significant number of children worldwide, and having efficacious, tolerable, targeted precision therapies for this population is crucial. Mepolizumab remains the only targeted anti-IL-5 therapy approved for pediatric asthma down to 6 years of age. For pediatric patients, the ability to dose less frequently and conveniently is often of significant relevance. Monthly therapy in this population may be preferred by patients and parents over therapies that are twice a month. Having a safety profile that does not necessitate co-prescription of epinephrine and mandatory initial observation also provides a greater level of reassurance and reduces the degree of complexity in starting therapy. However, up until recently the need for in-office administration has continued to add to the challenge of adoption of this therapy for pediatric patients. The innovation of the prefilled syringe will enable home administration, which would decrease the time and effort of families and ultimately reduce the burden of treatment. However, one of the advantages of in-office administration is the continued reminder from clinic staff to enforce and track medication compliance. While the science of mepolizumab has been presented throughout this review, the adoption on an individual basis of the 40 mg prefilled syringe will still rely on the art of medicine through informed-decision making between the provider and the patient/caretaker to determine the best path forward to yield the greatest adherence to therapy leading to the best potential outcome.
Results in clinical practice in the treatment of severe eosinophilic asthma with mepolizumab: a real-life study
Published in Journal of Asthma, 2022
Ana Isabel Enríquez-Rodríguez, Tamara Hermida Valverde, Pedro Romero Álvarez, Francisco Julián López-González, Jose Antonio Gullón Blanco, Ana Rosa Expósito Villegas, María José Escobar Fernández, Ana María Beristáin Urquiza, Miguel Ángel Alonso Fernández, Margarita Gutiérrez Rodríguez, Gema Castaño De las Pozas, Jennifer Jiménez Pérez, Roberto Fernández Mellado, Marta María García Clemente, Pere Casan Clara
Asthma is a chronic respiratory disease characterized by the presence of inflammation, variable airway obstruction, and bronchial hyperresponsiveness (1). Severe asthma patients require treatment with high dose inhaled corticosteroids (IC) in combination with long acting beta-agonists (LABA) and additional controllers (2). Patients with high levels of blood and/or sputum eosinophils are defined as severe asthma patients with an eosinophilic phenotype. International asthma guidelines recommend add-on biological therapy for severe eosinophilic asthma patients that remain uncontrolled despite maximal dose of an inhaled corticosteroids/long acting beta-2 agonists combination (ICS-LABA) and/or OCS. Interleukin-5 (IL-5) is the major cytokine responsible for the growth, differentiation, recruitment, activation, and survival of eosinophils. Mepolizumab, a humanized monoclonal antibody, blocks IL-5 reducing eosinophil production and survival in the airways (3,4). Mepolizumab reduced the number of exacerbations, the need of OCS and increased asthma control, health-related quality of life (HRQoL), and lung function in a population of uncontrolled severe eosinophilic asthma in clinical trials and real-life studies (5–13).
An update on the role of chronic rhinosinusitis with nasal polyps as a co-morbidity in severe asthma
Published in Expert Review of Respiratory Medicine, 2020
Riccardo Castagnoli, Amelia Licari, Ilaria Brambilla, Mariangela Tosca, Giorgio Ciprandi, Gian Luigi Marseglia
Mepolizumab is currently indicated in severe eosinophilic asthma. The efficacy and safety of mepolizumab in CRSwNP have been investigated in a proof-of-concept study and a Phase 2 trial, which included patients with mild or moderate asthma [86,87]. In both studies, intravenous mepolizumab 750 mg every 4 weeks reduced NP size or the need for surgery. Still, no significant outcome related to asthma was achieved, except for a significant reduction in blood eosinophil counts [97,98]. Notably, this dose was much higher than the standard subcutaneous 100 mg every 4 weeks dose licensed for severe eosinophilic asthma. In this context, Chan et al. recently reported an observed disconnect in mepolizumab response between upper and lower airways in a cohort of patients with uncontrolled severe eosinophilic asthma with concomitant CRSwNP. In particular, standard doses of mepolizumab significantly improved asthma control but not NP [99]. At present, mepolizumab at the standard 100-mg subcutaneous dose completed a Phase 3 trial as add-on maintenance in patients with severe, recurrent bilateral NP [100]. The safety profile of mepolizumab was comparable to clinical studies in severe asthma patients, with headache, injection site reactions, back pain, and fatigue occurring in ≥5% of patients [97,98].