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Francesco Menzella, Mirco Lusuardi, Carla Galeone, Nicola Facciolongo, Luigi Zucchi
Despite several therapeutic choices, 10-20% of patients with severe uncontrolled asthma do not respond to maximal best standard treatments, leading to a healthcare expenditure of up to 80% of overall costs for asthma. Today, there are new important therapeutic strategies, both pharmacological and interventional, that can result in improvement of severe asthma management, such as omalizumab, bronchial thermoplasty and other biological drugs, for example, mepolizumab, reslizumab and benralizumab. The availability of these new treatments and the increasing knowledge of the different asthmatic phenotypes and endotypes makes correct patient selection increasingly complex and important...
September 9, 2016: Therapeutic Advances in Respiratory Disease
Eugene R Bleecker, J Mark FitzGerald, Pascal Chanez, Alberto Papi, Steven F Weinstein, Peter Barker, Stephanie Sproule, Geoffrey Gilmartin, Magnus Aurivillius, Viktoria Werkström, Mitchell Goldman
BACKGROUND: Eosinophilia is associated with worsening asthma severity and decreased lung function, with increased exacerbation frequency. We assessed the safety and efficacy of benralizumab, a monoclonal antibody against interleukin-5 receptor α that depletes eosinophils by antibody-dependent cell-mediated cytotoxicity, for patients with severe, uncontrolled asthma with eosinophilia. METHODS: We did a randomised, double-blind, parallel-group, placebo-controlled phase 3 study at 374 sites in 17 countries...
September 2, 2016: Lancet
J Mark FitzGerald, Eugene R Bleecker, Parameswaran Nair, Stephanie Korn, Ken Ohta, Marek Lommatzsch, Gary T Ferguson, William W Busse, Peter Barker, Stephanie Sproule, Geoffrey Gilmartin, Viktoria Werkström, Magnus Aurivillius, Mitchell Goldman
BACKGROUND: Benralizumab is a humanised, afucosylated, anti-interleukin-5 receptor α monoclonal antibody that induces direct, rapid, and nearly complete depletion of eosinophils. We aimed to assess the efficacy and safety of benralizumab as add-on therapy for patients with severe, uncontrolled asthma and elevated blood eosinophil counts. METHODS: In this randomised, double-blind, parallel-group, placebo-controlled, phase 3 study (CALIMA) undertaken at 303 sites in 11 countries, we enrolled patients aged 12-75 years with severe asthma uncontrolled by medium-dosage to high-dosage inhaled corticosteroids plus long-acting β₂-agonists (ICS plus LABA) and a history of two or more exacerbations in the previous year...
September 5, 2016: Lancet
Ibrahim Sulaiman, Jonathan Chee Woei Lim, Hon Liong Soo, Johnson Stanslas
Extensive research into the therapeutics of asthma has yielded numerous effective interventions over the past few decades. However, adverse effects and ineffectiveness of most of these medications especially in the management of steroid resistant severe asthma necessitate the development of better medications. Numerous drug targets with inherent airway smooth muscle tone modulatory role have been identified for asthma therapy. This article reviews the latest understanding of underlying molecular aetiology of asthma towards design and development of better antiasthma drugs...
October 2016: Pulmonary Pharmacology & Therapeutics
Marek Lommatzsch
Current guidelines of the global initiative for asthma (GINA) recommend the addition of biologics in step 5 of the stepwise asthma treatment approach. This review gives an overview on the effects and the clinical role of antibodies targeting immunoglobulin E, IgE (Omalizumab), Interleukin-5, IL-5 (Mepolizumab, Reslizumab) or the IL-5 receptor (Benralizumab). In addition, potential future treatment options of refractory asthma with antibodies (for instance Dupilumab) are discussed.
June 2016: Deutsche Medizinische Wochenschrift
MirHojjat Khorasanizadeh, Mahsa Eskian, Amal H Assa'ad, Carlos A Camargo, Nima Rezaei
Nonresponders to maximal guideline-based therapies of asthma account for most of the morbidity, mortality, and economic burden of the disease. Because eosinophils are key effector cells in asthmatic airway inflammation, blocking IL-5, the main cytokine responsible for its survival and activation, seems to be a rational strategy. While previous monoclonal antibodies against the IL-5 ligand resulted in inconsistent improvements in asthma outcomes, benralizumab has shown promise. Benralizumab is a monoclonal antibody against IL-5 receptor, and has an enhanced antibody dependent cell-mediated cytotoxicity function...
April 27, 2016: International Reviews of Immunology
Laren D Tan, Jennifer M Bratt, Dorottya Godor, Samuel Louie, Nicholas J Kenyon
The presence of eosinophilic inflammation is a characteristic feature of chronic and acute inflammation in asthma. An estimated 5%-10% of the 300 million people worldwide who suffer from asthma have a severe form. Patients with eosinophilic airway inflammation represent approximately 40%-60% of this severe asthmatic population. This form of asthma is often uncontrolled, marked by refractoriness to standard therapy, and shows persistent airway eosinophilia despite glucocorticoid therapy. This paper reviews personalized novel therapies, more specifically benralizumab, a humanized anti-IL-5Rα antibody, while also being the first to provide an algorithm for potential candidates who may benefit from anti-IL-5Rα therapy...
2016: Journal of Asthma and Allergy
Hae-Sim Park, Mi-Kyeong Kim, Nobuyuki Imai, Tsutomu Nakanishi, Mitsuru Adachi, Ken Ohta, Yuji Tohda
BACKGROUND: Airway eosinophils are considered to play an important role in the pathogenesis of asthma. Interleukin-5 is believed to be a key cytokine for the development, proliferation and activation of eosinophils. Benralizumab is an anti-interleukin-5 receptor α monoclonal antibody that depletes blood and airway eosinophils. We conducted a phase 2a study in South Korea and Japan to evaluate the effect of benralizumab in an East Asian population. The primary objective was to evaluate the effect of benralizumab in adults with uncontrolled eosinophilic asthma with 2-6 incidences of exacerbations in the past year using a medium/high dose of inhaled corticosteroids and long-acting β2-agonists...
2016: International Archives of Allergy and Immunology
Gilda Varricchi, Diego Bagnasco, Francesco Borriello, Enrico Heffler, Giorgio W Canonica
PURPOSE OF REVIEW: Human eosinophils were first identified and named by Paul Ehrlich in 1879 on the basis of the cell's granular uptake of eosin. Although eosinophils represent approximately 1% of peripheral blood leukocytes, they have the propensity to leave the blood stream and migrate into inflamed tissues. Eosinophils and their mediators are critical effectors to asthma and eosinophilic granulomatosis with polyangiitis (EGPA). Eosinophils are equipped with a large number of cell-surface receptors and produce specific cytokines and chemokines...
April 2016: Current Opinion in Allergy and Clinical Immunology
Stephanie S Eng, Magee L DeFelice
The eosinophil is a fully delineated granulocyte that disseminates throughout the bloodstream to end-organs after complete maturation in the bone marrow. While the presence of eosinophils is not uncommon even in healthy individuals, these granulocytes play a central role in inflammation and allergic processes. Normally appearing in smaller numbers, higher levels of eosinophils in the peripheral blood or certain tissues typically signal a pathologic process. Eosinophils confer a beneficial effect on the host by enhancing immunity against molds and viruses...
April 2016: Clinical Reviews in Allergy & Immunology
Tuyet-Hang Pham, Gautam Damera, Paul Newbold, Koustubh Ranade
BACKGROUND: Eosinophilic inflammation is frequently associated with increased asthma severity. Benralizumab is a humanized, afucosylated, anti-interleukin-5Rα monoclonal antibody that selectively depletes eosinophils and basophils through enhanced antibody-dependent cell-mediated cytotoxicity. OBJECTIVE: To study effects of benralizumab on eosinophil counts and activity following administration to asthma patients. METHODS: Sera were collected from asthma patients enrolled in two clinical studies...
February 2016: Respiratory Medicine
Janice M Reichert
The number of novel antibody therapeutics that received first marketing approvals in 2015 met expectations, with 6 (alirocumab (Praluent®), evolocumab (Repatha®), daratumumab (Darzalex®), dinutuximab (Unituxin®), idarucizumab (Praxbind®), mepolizumab (Nucala®)) granted first approvals as of mid-November*. Seven novel antibody therapeutics (begelomab, brodalumab, elotuzumab, ixekizumab, necitumumab, obiltoxaximab, reslizumab) are in regulatory review, and thus a similar number, if not more, are projected to gain first approvals in 2016...
2016: MAbs
Megan F Patterson, Larry Borish, Joshua L Kennedy
Asthma is a heterogeneous syndrome that might be better described as a constellation of phenotypes or endotypes, each with distinct cellular and molecular mechanisms, rather than as a singular disease. One of these phenotypes is eosinophilic asthma. As the development of eosinophilic inflammation is categorically dependent on the biological activity of Interleukin (IL)-5, IL-5 antagonism became an obvious target for therapy in this phenotype. Early trials of monoclonal antibodies targeting the biological activity of IL-5, including reslizumab, mepolizumab, and benralizumab, were performed on asthmatics with no concern for evidence of eosinophilia...
2015: Journal of Asthma and Allergy
R Andrew McIvor
OBJECTIVE: Asthma is a chronic inflammatory disorder of the airways with increasing worldwide prevalence. Despite treatment according to guidelines, a considerable proportion of patients with asthma remain symptomatic. Different potential therapeutic options for the treatment of these patients are currently in development and undergoing clinical trials, and it is important to regularly review their status. DATA SOURCES: A search of was performed and supported by a PubMed literature search and restricted to the previous 10 years to ensure currency of data...
October 2015: Annals of Allergy, Asthma & Immunology
Yuling Wu, Jia J Li, Hyun Jun Kim, Xu Liu, Weiyi Liu, Ahmad Akhgar, Michael A Bowen, Susan Spitz, Xu-Rong Jiang, Lorin K Roskos, Wendy I White
Benralizumab is a humanized anti-IL5 receptor α (IL5Rα) monoclonal antibody (mAb) with enhanced (afucosylation) antibody-dependent cell-mediated cytotoxicity (ADCC) function. An ADCC reporter cell-based neutralizing antibody (NAb) assay was developed and characterized to detect NAb against benralizumab in human serum to support the clinical development of benralizumab. The optimal ratio of target cells to effector cells was 3:1. Neither parental benralizumab (fucosylated) nor benralizumab Fab resulted in ADCC activity, confirming the requirement for ADCC activity in the NAb assay...
November 2015: AAPS Journal
Bart Hilvering, Luzheng Xue, Ian D Pavord
Two recent phase III trials in patients with severe eosinophilic asthma have shown that anti-interleukin 5 (IL-5) therapy with mepolizumab reduces the frequency of asthma attacks, improves symptoms and allows patients to reduce oral glucocorticoid use without loss of control of asthma. An earlier large 616 patient Dose Ranging Efficacy And safety with Mepolizumab in severe asthma (DREAM) study had shown that the only variables associated with treatment efficacy were a prior history of asthma attacks and the peripheral blood eosinophil count...
August 2015: Therapeutic Advances in Respiratory Disease
Francesco Menzella, Mirco Lusuardi, Carla Galeone, Luigi Zucchi
Patients with severe asthma or COPD have often a suboptimal symptom control due to inadequate treatment. A better understanding of pathogenetic mechanisms, phenotypes, endotypes and the new technologies available in the fields of molecular biology and immunogenetics have made it possible to synthesize specific monoclonal antibodies virtually able to interact with any target antigen, or to open a way for new therapeutic target options. At the moment, the only biologic drug available in clinical practice is omalizumab...
2015: Multidisciplinary Respiratory Medicine
Richard M Nowak, Joseph M Parker, Robert A Silverman, Brian H Rowe, Howard Smithline, Faiz Khan, Jon P Fiening, Keunpyo Kim, Nestor A Molfino
BACKGROUND: Patients with frequent asthma exacerbations resulting in emergency department (ED) visits are at increased risk for future exacerbations. We examined the ability of 1 dose of benralizumab, an investigational antiinterleukin 5 receptor α monoclonal antibody, to reduce recurrence after acute asthma exacerbations. METHODS: In this randomized, double-blind, placebo-controlled study, eligible subjects presented to the ED with an asthma exacerbation, had partial response to treatment, and greater than or equal to 1 additional exacerbation within the previous year...
January 2015: American Journal of Emergency Medicine
Christopher E Brightling, Eugene R Bleecker, Reynold A Panettieri, Mona Bafadhel, Dewei She, Christine K Ward, Xiao Xu, Claire Birrell, René van der Merwe
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with eosinophilic airway inflammation in 10-20% of patients. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, depletes blood and sputum eosinophils. We aimed to establish whether benralizumab reduces acute exacerbations of COPD in patients with eosinophilia and COPD. METHODS: We did this randomised, double-blind, placebo-controlled, phase 2a study between Nov 18, 2010, and July 13, 2013, at 26 sites in the UK, Poland, Germany, Canada, the USA, Denmark, and Spain...
November 2014: Lancet Respiratory Medicine
Nathan Hambly, Parameswaran Nair
PURPOSE OF REVIEW: A small proportion of patients with asthma have severe disease characterized by persistent airflow obstruction, airway hyperresponsiveness and eosinophilic airway inflammation. This review focuses on the clinical efficacy of inhibiting T helper 2-cytokine-mediated inflammatory responses using monoclonal antibodies directed against immunoglobulin E (IgE), interleukin (IL)-5, and IL-4/IL-13 in patients with severe refractory asthma. RECENT FINDINGS: The heterogeneity of airway inflammation in severe asthma has led to the recognition of multiple pathophysiologically distinct severe asthma endotypes...
January 2014: Current Opinion in Pulmonary Medicine
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