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Physicians' Education Resource®, LLC, designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
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This activity is supported by an educational grant from GlaxoSmithKline.
Medical Summaries and Commentaries™: Update from San Francisco: Interpreting Therapeutic Advancements for Severe Asthma
Release Date: March 29, 2019
Expiration Date: March 29, 2020
Media: Internet - based
This online activity is designed to update physicians on data presented at the American Academy of Allergy, Asthma, & Immunology (AAAAI) Annual Meeting, held in February 2019 in San Francisco, CA. PER’s Medical Summaries and Commentaries™: Update from San Francisco: Interpreting Therapeutic Advancements for Severe Asthma online CME activity facilitates critical assessment and clinical integration of new evidence when appropriate. The activity reviews 8 abstracts with some of the most compelling and clinically relevant severe asthma presentations from the meeting. For each abstract, a short summary of key clinical data is accompanied by expert perspective that provides insight into how clinicians can apply these findings to their clinical practice to improve patient care.
Benefits of Participation
- Learn about emerging treatments for the management of severe asthma
- Hear about digital asthma programs that may improve management of severe asthma
- Learn about new research findings with approved biologic treatments for severe asthma
- Explore future directions for the prevention and management of exacerbations in severe asthma
- Be informed about recent clinical trials in severe asthma and their impact on clinical practice decisions
Acknowledgement of Commercial Support
This activity is supported by an educational grant from GlaxoSmithKline.
Instructions for This Activity and Receiving Credit
This activity is directed toward healthcare professionals specializing in immunology, allergy, pulmonology, primary care, and others interested in the care of patients with asthma.
After successful completion of this activity, you should be better prepared to:
- Explain recent clinical trial findings on burden and phenotypes of asthma
- Integrate evidence-based diagnostic and therapeutic recommendations and therapeutic implications of new and emerging data into practice
- Incorporate best practices for effective management of patients with uncontrolled asthma based on new and emerging data
Faculty, Staff, and Planners' Disclosures
Michael S. Blaiss, MD
Clinical Professor of Pediatrics
Medical College of Georgia at Augusta University
Disclosures: Consultant: Sanofi/Regeneron
Lila Kertz, MSN, RN, CPNP, AE-C
Pediatric Nurse Practitioner
Clinical Director, Severe Asthma Clinic for Kids
Pediatric Allergy, Immunology, and Pulmonary Medicine
Washington University School of Medicine
Saint Louis Children’s Hospital
St. Louis, MO
Disclosures: Speakers Bureau: Sanofi, AstraZeneca
The staff of PER® have no relevant financial relationships with commercial interests to disclose.
Disclosure Policy and Resolution of Conflicts of Interest (COI)
As a sponsor accredited by the ACCME, it is the policy of PER® to ensure fair balance, independence, objectivity, and scientific rigor in all of its CME/Ce activities. In compliance with ACCME guidelines, PER® requires everyone who is in a position to control the content of a CME/CE activity to disclose all relevant financial relationships with commercial interests. The ACCME defines “relevant financial relationships” as financial relationships in any amount occurring within the past 12 months that creates a COI.
Additionally, PER® is required by ACCME to resolve all COI. PER® has identified and resolved all COI prior to the start of this activity by using a multistep process.
Off-Label Disclosure and Disclaimer
This CME activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME activity is for continuing medical and nursing education purposes only, and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of PER® or any of the companies that provided commercial support for this activity.
PER Pulse™ Recaps
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Recent Data for Dose-Weight Adjustments When Prescribing Mepolizumab for Severe Asthma
Despite treatment with glucocorticoids, some patients with severe asthma have frequent exacerbations associated with persistent eosinophilic inflammation. Several novel biologic therapies that target specific pathways underlying asthma have been approved, including mepolizumab. Mepolizumab is a humanized monoclonal antibody against interleukin (IL)-5 that selectively inhibits eosinophilic inflammation and reduces eosinophils in sputum and blood.1-6 Mepolizumab is FDA-approved for use in combination with other asthma medications for maintenance treatment of severe eosinophilic asthma (SEA) in patients 12 years or older.
Important phase 3 clinical trials of mepolizumab leading to its approval include Dose Ranging Efficacy and Safety with Mepolizumab (DREAM) and Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma (MENSA).7-8 The DREAM study was significant because it identified eosinophilic asthma as the phenotype that responds to intravenous (IV) mepolizumab.7 The goal of the MENSA study was to compare the efficacy of subcutaneous versus IV administration of mepolizumab in an attempt to relieve the cost and time burden required with IV dosing.8 Patients with eosinophilic asthma, defined by a peripheral eosinophil count of at least 300 cells/µL, and who were taking high-dose inhaled corticosteroids with or without oral corticosteroid use, were eligible for the study. Data showed that both IV and subcutaneous dosing of mepolizumab reduced asthma exacerbations by 50% compared with placebo, and no significant differences in adverse events were seen.8
Another study, the Efficacy of Mepolizumab Add-On Therapy on Health-Related Quality of Life and Markers of Asthma Control in Severe Eosinophilic Asthma (MUSCA) trial, a phase 3b multicenter study in patients with SEA and a history of ≥2 exacerbations in the previous year despite regular high-dose inhaled glucocorticoids plus asthma medication, aimed to assess the effect of SEA on health-related quality of life.9 Patients with SEA who received mepolizumab 100 mg every 4 weeks for 24 weeks had significant improvements in health and asthma control, and the drug had a safety profile similar to that of placebo.
When prescribing mepolizumab or any other biologic treatment for severe asthma, body weight may affect treatment efficacy and dose-weight adjustments may need to be considered. A recent post hoc meta-analysis of 936 patients who participated in the MENSA and MUSCA trials investigated the influence of body weight and body mass index (BMI) on the efficacy of mepolizumab in severe eosinophilic asthma.10 The analysis found that mepolizumab was effective at significantly reducing clinically significant exacerbations across all weight and BMI categories with a simple fixed-dose regimen, suggesting that dose-weight adjustments may not be necessary.Key Points
- An anti–IL-5 monoclonal antibody, mepolizumab, reduces asthma exacerbations in SEA
- Mepolizumab improves asthma control and health-related quality of life
- A fixed-dose regimen of mepolizumab was shown to be effective at reducing clinically significant exacerbations despite body weight and BMI
- Flood-Page P, Menzies-Gow A, Phipps, et al. Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics. J Clin Invest. 2003;112(7):1029-1036.
- Menzies-Gow A, Flood-Page P, Sehmi R, et al. Anti-IL-5 (mepolizumab) therapy induces bone marrow eosinophil maturational arrest and decreases eosinophil progenitors in the bronchial mucosa of atopic asthmatics. J Allergy Clin Immunol. 2003;111(4):714-719.
- Flood-Page P, Swenson C, Faiferman I, et al; International Mepolizumab Study Group. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med. 2007;176(11):1062-1071. doi: 10.2264/rccm.200701-085OC.
- Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009;360(10):973-984. doi: 10.1056/NEJMoa0808991.
- Nair P, Pizzichini MM, Kjarsgaard M, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009;360(10):985-993. doi: 10.1056/NEJMoa0805435.
- Leckie MJ, ten Brinke A, Khan J, et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet. 2000;356(9248):2144-2148.
- Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012;380(9842):651-659. doi: 10.1016/S0140-6736(12)60988-X.
- Ortega HG, Liu MC, Pavord ID, et al; MENSA Investigators. Mepolizumab treatment in patients with severe eosinophilic asthma [published correction appears in N Engl J Med. 2015;372(18):1777]. N Engl J Med. 2014;371(13):1198-1207. doi: 10.1056/NEJMoa1403290.
- Chupp GL, Bradford ES, Albers FC, et al. Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial. Lancet Respir Med. 2017;5(5):390-400. doi: 10.1016/S2213-2600(17)30125-X.
- Bradford ES, Taillé C, Bratton DJ, et al. Efficacy of 100 mg SC mepolizumab for severe eosinophilic asthma (SEA) across body weight: meta-analysis. J Allergy Clin Immunol. 2019;143(2 suppl):AB102. doi: 10.1016/j.jaci.2018.12.309.
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Predicting Efficacy of Omalizumab by Blood Eosinophil Count
Allergic asthma (AA) results from an immunoglobulin E (IgE) antibody–mediated response to allergens. Omalizumab is a targeted anti-IgE monoclonal antibody that effectively blocks IgE-receptor binding on antigen-presenting cells, mast cells, and basophils.1-3 It is FDA-approved in adults and adolescents as add-on therapy for the treatment of moderate-to-severe persistent AA that is uncontrolled despite high-dose inhaled corticosteroids and other controller medications.
It is known that biologic therapies that target interleukin-5, such as mepolizumab and reslizumab, are more efficacious in patients with a high blood eosinophil count; they are specifically restricted to adults with refractory severe eosinophilic asthma, characterized by having a blood eosinophil count ≥300 cells/µL over 12 months. A large number of patients with severe allergic asthma also have a blood eosinophil count ≥300 cells/µL.4,5 Data from three phase 3 clinical trials were recently used in a post hoc analysis examining the effects of omalizumab-associated changes in eosinophil levels.
The INNOVATE study sought to determine the benefits of omalizumab as add-on therapy in patients aged 12 to 75 years with severe persistent asthma inadequately controlled despite best available therapy. The study found that after 28 weeks, omalizumab significantly improved asthma-related quality of life, morning peak expiratory flow, and asthma symptom scores, and adverse events were similar between treatment groups.6 Similar results were reported in the IA05 study, which evaluated add-on omalizumab in children aged 6 to <12 years with perennial allergen sensitivity and history of exacerbations and asthma symptoms despite treatment.7 Finally, the EXTRA study explored 3 biomarkers of T-helper 2–driven inflammation—fractional exhaled nitric oxide, peripheral blood eosinophils, and serum periostin—as predictors of which patients will have the greatest response to omalizumab therapy.8
The analysis of these studies showed modest reductions in eosinophil levels, although responses were larger than those experienced with placebo in both severe and less-severe patient populations, with the greatest reductions in patients with the highest eosinophil levels.9Key Points
- Omalizumab improves asthma-related quality of life as add-on therapy in patients with AA
- Data with omalizumab show modest reductions in eosinophil levels compared with baseline
- More studies are needed to determine if omalizumab reduces eosinophil levels independent of other therapy
- MacGlashan DW Jr, Bochner BS, Adelman DC, et al. Down-regulation of FϲεRI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J Immunol. 1997;158(3):1438-1445.
- Holgate S, Casale T, Wenzel S, Bousquet J, Deniz Y, Reisner C. The anti-inflammatory effects of omalizumab confirm the central role of IgE in allergic inflammation. J Allergy Clin Immunol. 2005;115(3):459-465.
- Djukanović SJ, Wilson SJ, Kraft M, et al. Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma. Am J Respir Crit Care Med. 2004;170(6):583-593.
- Buhl R, Humbert M, Bjermer L, et al; expert group of the European Consensus Meeting for Severe Eosinophilic Asthma. Severe eosinophilic asthma: a roadmap to consensus. Eur Respir J. 2017;49(5):1700634. doi: 10.1183/13993003.00634-2017.
- Tran TN, Zeiger RS, Peters SP, et al. Overlap of atopic, eosinophilic, and TH2-high asthma phenotypes in a general population with current asthma. Ann Allergy Asthma Immunol. 2016;116(1):37-42. doi: 10.1016/j.anai.2015.10.027.
- Humbert M, Beasley R, Ayres J, et al. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy. 2005;60(3):309-316.
- Lanier B, Bridges T, Kulus M, Taylor AF, Berhane I, Vidaurre CF. Omalizumab for the treatment of exacerbations in children with inadequately controlled allergic (IgE-mediated) asthma. J Allergy Clin Immunol. 2009;124(6):1210-1216. doi: 10.1016/j.jaci.2009.09.021.
- Hanania NA, Wenzel S, Rosén K, et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med. 2013;187(8):804-811. doi: 10.1164/rccm.201208-1414OC.
- Hanania NA, Corren J, Holweg C, et al. Effects of omalizumab on blood eosinophil numbers in patients with allergic asthma. J Allergy Clin Immunol. 2019;143(2 suppl):AB95. doi: 10.1016/j.jaci.2018.12.290.
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Gender Differences in Efficacy of Benralizumab
Benralizumab is a humanized, monoclonal antibody that targets the α subunit of the anti–interleukin-5 receptor, and it was recently approved as add-on therapy for the treatment of severe eosinophilic asthma (SEA). Two phase 3 clinical trials leading up to the approval of benralizumab investigated its efficacy and safety: Anti-Interleukin-5 Receptor α Monoclonal Antibody, as Add-On Treatment for Patients with Severe, Uncontrolled, Eosinophilic Asthma (CALIMA); and Efficacy and Safety of Benralizumab for Patients with Severe Asthma Uncontrolled With High-Dosage Inhaled Corticosteroids and Long-Acting β2-Agonists (SIROCCO).1-2 Patients who participated in the trials received either placebo or subcutaneous benralizumab 30 mg over a period of 48 weeks (SIROCCO) or 56 weeks (CALIMA). Both trials found that benralizumab in combination with high-dose inhaled corticosteroids and long-acting β2-agonists significantly reduces annual exacerbation rates and is generally well tolerated in individuals with SEA.
The sex-specific effects of benralizumab are not known but were recently examined in a post hoc analysis of the CALIMA and SIROCCO trials. Sex-related differences in asthma prevalence are well known and change throughout life.3 In childhood, boys have increased prevalence of asthma compared with girls, but that reverses during puberty and in adulthood, suggesting that sex hormones influence asthma pathogenesis and allergic disease.4 Since women are more prone to an asthma diagnosis in adulthood compared with men and are at risk for greater morbidity because of their diagnosis, knowledge of sex-hormone–regulated pathogenesis of asthma and of the hormonally affected differences on efficacy of biologic treatment of SEA in both sexes is necessary.5
The results of the post hoc analysis reported that both women and men who participated in the studies, with blood eosinophil counts of ≥300 cells/µL, shared similar baseline characteristics, including age and body mass index. Numerical differences were observed in immunoglobulin E (IgE), atopy, and the number of historical exacerbations.6 Studies focused on sex-related disparities in treatment of asthma are needed and are important in establishing individualized asthma management strategies for all patients with SEA.Key Points
- Major clinical trials leading to the approval of benralizumab, CALIMA and SIROCCO, reported its efficacy in reducing exacerbations and its favorable safety profile
- Post hoc analysis of sex-related differences of the participants in the CALIMA and SIROCCO trials were reported and included IgE, atopy, and number of exacerbations
- More studies focused on sex-related disparities in the treatment of benralizumab and other biologics are needed for effective treatment of SEA
- FitzGerald JM, Bleecker ER, Nair P, et al; CALIMA study investigators. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2128-2141. doi: 10.1016/S0140-6736(16)31322-8.
- Bleecker ER, FitzGerald JM, Chanez P, et al; SIROCCO study investigators. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2115-2127. doi: 10.1016/S0140-6736(16)31324-1.
- Chen Y, Stewart P, Johansen H, McRae L, Taylor G. Sex difference in hospitalization due to asthma in relation to age. J Clin Epidemiol. 2003;56(2):180-187.
- Shah R, Newcomb DC. Sex bias in asthma prevalence and pathogenesis. Front Immunol. 2018;9:2997. doi: 10.3389/fimmu.2019.02997.
- Kynyk JA, Mastronarde JG, McCallister JW. Asthma, the sex difference. Curr Opin Pulm Med. 2011;17(1):6-11. doi: 10.1097/MCP.0b013e3283410038.
- Ryan O, Bernstein D, Hirsch I, Kreindler J. Pooled baseline characteristics of women in phase III benralizumab asthma exacerbation studies (SIROCCO and CALIMA). J Allergy Clin Immunol. 2019;143(2):AB100. doi: 10.1016/j.jaci.2018.12.304.
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