Asthma, a chronic lung disease characterized by spasms and secretions in the bronchi, results in varying degrees of airway obstruction. The condition is estimated to have affected about 262 million people around the world and resulted in 461,000 deaths in 2019. Although the prevalence of asthma is higher in countries with high sociodemographic development, countries with low and middle levels of sociodemographic development have more asthma-related deaths.1 In the United States, roughly 25 million people had asthma in 2021 (Figure 1).2
Heterogenous Pathologies and Implications for Treatment
Asthma is an umbrella diagnosis covering a number of heterogeneous inflammatory pathways. In the past, excessive T-helper cell type 2 (Th2) response and immunoglobulin E (IgE) sensitivity were thought to solely drive asthma-related bronchial inflammation. Although these pathways do play a dominant role in allergic asthma, several distinct asthma endotypes have now been identified.3 In fact, a recent computational study that analyzed molecular and cellular patterns of asthma from a database containing over 151 million people identified 22 possibly distinct asthma endotypes, indicating that much remains to be elucidated regarding asthma’s pathophysiology.4
The heterogeneous pathophysiology underlying asthma has clinical implications for the severity of the disease and treatment responsiveness. The primary goals of asthma management include achieving symptom control, minimizing exacerbation, relieving airflow limitation, and managing treatment-related side effects when they arise. To this end, a personalized and multipronged approach encompassing risk-factor modification, pharmacological treatment, nonpharmacological strategies, education, and skills training should be employed. The primary therapeutics used in asthma management are characterized as “controllers,” which include therapies aimed at reducing inflammation, controlling symptoms, and reducing the risk of exacerbations, such as inhaled corticosteroids (ICS) and long-acting beta-agonists (LABA); “relievers,” which are rapid-onset bronchodilators that are used as needed, such as short-acting beta 2-agonists (SABA); and “add-on therapies,” which are additional therapies mainly used for patients with asthma that is difficult to treat, including drugs such as long-acting muscarinic antagonists (LAMA) and biologic therapies such as benralizumab, dupilumab, mepolizumab, reslizumab, tezepelumab, and omalizumab.5
An estimated 5% to 10% of patients with asthma develop severe asthma, which is defined as asthma that requires the use of high-intensity ICS and a secondary controller to prevent it from being uncontrolled, or asthma that remains uncontrolled despite this therapy regimen.6 For these patients, biologic therapies may be necessary. This review presents the US Food and Drug Administration (FDA)-approved biologics available to control symptoms and prevent exacerbations in patients with severe asthma.
Targeting IgE: Omalizumab
Circulating IgE plays a vital role in the pathogenesis of asthma; when sensitized by allergens, IgE binds to the high-affinity receptors on mast cells and basophils to induce an allergic reaction, resulting in the secretion of mediators such as histamine, tryptase, and arachidonic acid metabolites. Omalizumab, which binds to and reduces levels of circulating IgE, is a valuable treatment option for patients with moderate to severe asthma.7
Omalizumab has demonstrated reductions in the exacerbation rate of asthma symptoms across age groups.8 Children and adults with severe asthma taking subcutaneous omalizumab as an adjunct to corticosteroids were more likely to be able to completely discontinue corticosteroids compared with patients not taking omalizumab.9 A meta-analysis of observational studies has corroborated the benefits of omalizumab demonstrated in randomized controlled trials, including reductions in exacerbations and oral corticosteroid use and improvements in treatment effectiveness, lung function, and patient-reported outcomes.10 Long-term treatment with omalizumab has been found to be safe and well tolerated, and patients with severe asthma may continue to see improvements in controlling their symptoms even after 9 years of treatment with omalizumab.11
Currently, omalizumab is indicated for moderate to severe persistent asthma in adults and pediatric patients older than 6 years of age with a positive skin test or in vitro reactivity to a perennial aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids. In adults and adolescents aged 12 years and older, arthralgia, fatigue, dizziness, fracture, pruritis, dermatitis, general pain, leg and arm pain, and earache are the most common adverse events associated with omalizumab. In patients aged 6 to 11 years, the most common adverse reactions are nasopharyngitis, headache, pyrexia, upper abdominal pain, pharyngitis streptococcal, otitis media, viral gastroenteritis, arthropod bites, and epistaxis.12
Targeting Interleukin-5: Mepolizumab, Reslizumab, and Benralizumab
Interleukin-5 (IL-5) is a cytokine implicated in the pathogenesis of Th2-high asthma due to its crucial role in the differentiation, growth, activation, and survival of eosinophils, making it a valuable target for biologic therapies seeking to treat patients with moderate to severe asthma that is resistant to ICS.13
Mepolizumab, which is indicated for use in severe asthma for both adult and pediatric patients aged older than 6 years, is a monoclonal antibody that binds to IL-5 to block its interaction with the alpha chain of its receptor complex (IL-5Rα) expressed on eosinophil cell surfaces.14 Mepolizumab has been shown to reduce exacerbations in patients with recurrent severe eosinophilic asthma.15 A randomized controlled trial of 576 patients with recurrent asthma exacerbations found that intravenous mepolizumab resulted in rates of exacerbations being reduced by 47% and that subcutaneous mepolizumab reduced exacerbations by 53%.16 Another randomized controlled trial found that treatment with mepolizumab increased the likelihood that a patient could reduce their glucocorticoid use by 2.39 times and that, despite lower glucocorticoid use, patients treated with mepolizumab experienced a relative reduction of 32% in their annualized rate of exacerbations.17 The most common adverse reactions experienced by patients taking mepolizumab are headache, injection site reaction, back pain, and fatigue.14
Reslizumab, which is indicated for use as an add-on maintenance treatment for patients aged 18 years and older with severe eosinophilic asthma, is a monoclonal antibody that binds to IL-5 and inhibits its signaling, reducing the production and survival of eosinophils.18 In 2 duplicate multicenter randomized controlled trials that enrolled patients aged 12 to 75 years with moderate to severe asthma, an eosinophil count exceeding 400 cells per μL, and 1 or more exacerbations in the past year, intravenous reslizumab was found to result in a significant reduction in the frequency of asthma exacerbations.19 Furthermore, reslizumab has been shown to be effective in minimizing exacerbations in patients with severe eosinophilic asthma who have failed to respond to omalizumab.20
The most common treatment-related adverse event with reslizumab is oropharyngeal pain. However, reslizumab carries a boxed warning for anaphylaxis, which was experienced by 0.3% of patients in placebo-controlled studies, and patients should be observed for an appropriate amount of time after receiving a reslizumab infusion, which should be discontinued immediately if they experience anaphylaxis.18
Like reslizumab and mepolizumab, benralizumab is a monoclonal antibody targeting IL-5. However, the drug has a dual mechanism of action; benralizumab interacts with an extracellular IL-5Rα epitope in close proximity to the IL-5 binding site, impeding IL-5 binding while also binding to the FcγRIIIa receptor found on the surface of natural killer (NK) cells, making it a potent inducer of the eosinophil apoptosis operated by NK cells.21
Benralizumab is indicated as an add-on or maintenance treatment for patients aged 12 years and older with severe eosinophilic asthma. Common adverse reactions to benralizumab include headache and pharyngitis.22 The pooled results of 2 phase 3 studies of patients aged 12 to 75 years with severe uncontrolled asthma who were also taking high-dosage ICS and LABA revealed that patients experienced a 46% reduction in exacerbations and improved lung function when given add-on benralizumab injections every 8 weeks; this was true regardless of their serum IgE concentrations or atopy status.23
Targeting IL-4 and IL-13: Dupilumab
Dupilumab, which is indicated for use as an add-on maintenance therapy for patients aged 6 years and older with moderate to severe eosinophilic asthma or with oral corticosteroid-dependent asthma, is a monoclonal antibody that binds to the IL-4 receptor alpha (IL-4Rα), inhibiting IL-4 and IL-13 signaling.24 IL-4 mediates several proinflammatory functions implicated in allergic asthma. IL-4 is associated with the secretion of IgE by B lymphocytes; by upregulating IgE receptors on cell surfaces, IL-4 enhances IgE-mediated immune responses. IL-4 also contributes to the hypersecretion of mucus, induces the vascular cell adhesion molecule (VCAM)-1 on the vascular endothelium, and inhibits eosinophil apoptosis.25 IL-13 contributes to allergic inflammation by promoting the survival, activation, and recruitment of eosinophils.26 By binding to and blocking IL-4Rα, which is shared by the IL-4 and IL-13 receptor complexes, dupilumab inhibits IL-4 and IL-13 signaling, reducing IL-4- and IL-13-mediated inflammatory processes.24
A systematic review of 3 randomized controlled trials that evaluated the use of dupilumab among patients aged over 12 years found that dupilumab reduced severe asthma exacerbations and the use of oral corticosteroids while improving patients’ asthma control, quality of life, and rescue medication use.27 A randomized controlled trial involving children aged 6 to 11 years with uncontrolled moderate to severe asthma found that those who received dupilumab experienced fewer exacerbations and better lung function and asthma control than those who received placebo.28 A multicenter randomized controlled trial evaluating the use of dupilumab in adult patients with uncontrolled asthma found that dupilumab increased lung function and reduced severe exacerbations in patients regardless of their eosinophil count.29 The most common side effects of dupilumab when used to treat asthma include injection site reactions, oropharyngeal pain, and eosinophilia.24
Targeting Thymic Stromal Lymphopoietin: Tezepelumab
While monoclonal antibody therapies have brought about significant advances in the treatment of asthma, their targeting of immunological pathways downstream of Th2 response makes them less effective for endotypes of asthma that are Th2-low. To address this gap, researchers began investigating drugs that target alarmins, a trio of epithelial cytokines — thymic stromal lymphopoietin (TSLP), IL-33, and IL-25 — that instigate inflammatory responses that may lead to asthma symptoms and exacerbations. TSLP specifically is a key instigator of the immune response to environmental irritants, and several studies have identified TSLP dysregulation in patients with asthma, making it an attractive target for drugs that seek to treat patients with Th2-low asthma.30
Tezepelumab is a monoclonal antibody that binds to TSLP, preventing it from interacting with the heterodimeric TSLP receptor. Tezepelumab is indicated for use as an add-on maintenance treatment for patients aged 12 years and older with severe asthma.31
In a phase 2b randomized controlled trial of adults with severe, uncontrolled asthma, tezepelumab was found to reduce the frequency of exacerbations and improve lung function when compared with placebo.32 In a phase 3 multicenter randomized controlled trial studying patients aged 12 to 80 years of age with severe uncontrolled asthma who had received medium- or high-dose ICS for least 1 year and at least 1 additional controller medication for at least 3 months, tezepelumab reduced exacerbations and improved lung function and health-related quality of life when compared with placebo.33 The most common treatment-related adverse effects of tezepelumab are pharyngitis, arthralgia, and back pain.31
A summary of the currently available FDA-approved biologic medications for the treatment of asthma is presented in Table 1.12,14,18,22,24,31
1. GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396(10258):1204-1222. doi:10.1016/S0140-6736(20)30925-9
2. Centers for Disease Control and Prevention. Most Recent National Asthma Data. Updated May 10, 2023. Accessed June 11, 2023. https://www.cdc.gov/asthma/most_recent_national_asthma_data.htm
3. Kuruvilla ME, Lee FEH, Lee GB. Understanding asthma phenotypes, endotypes, and mechanisms of disease. Clinic Rev Allerg Immunol. 2019;56(2):219-233. doi:10.1007/s12016-018-8712-1
4. Jia G, Zhong X, Im HK, et al. Discerning asthma endotypes through comorbidity mapping. Nat Commun. 2022;13(1):6712. doi:10.1038/s41467-022-33628-8
5. Reddel HK, Bacharier LB, Bateman ED, et al. Global Initiative for Asthma Strategy 2021: executive summary and rationale for key changes. Eur Respir J. 2021;59(1):2102730. doi:10.1183/13993003.02730-2021
6. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43(2):343-373. doi:10.1183/09031936.00202013
7. Thomson NC, Chaudhuri R. Omalizumab: clinical use for the management of asthma. Clin Med Insights Circ Respir Pulm Med. 2012;627-40. doi:10.4137/CCRPM.S7793
8. Henriksen DP, Bodtger U, Sidenius K, et al. Efficacy of omalizumab in children, adolescents, and adults with severe allergic asthma: a systematic review, meta-analysis, and call for new trials using current guidelines for assessment of severe asthma. Allergy Asthma Clin Immunol. 2020;16:49. doi:10.1186/s13223-020-00442-0
9. Rodrigo GJ, Neffen H, Castro-Rodriguez JA. Efficacy and safety of subcutaneous omalizumab vs placebo as add-on therapy to corticosteroids for children and adults with asthma: a systematic review. Chest. 2011;139(1):28-35. doi:10.1378/chest.10-1194
10. Bousquet J, Humbert M, Gibson PG, et al. Real-world effectiveness of omalizumab in severe allergic asthma: a meta-analysis of observational studies. J Allergy Clin Immunol Pract. 2021;9(7):2702-2714. doi:10.1016/j.jaip.2021.01.011
11. Menzella F, Galeone C, Formisano D, et al. Real-life efficacy of omalizumab after 9 years of follow-up. Allergy Asthma Immunol Res. 2017;9(4):368-372. doi:10.4168/aair.2017.9.4.368
12. Xolair®. Prescribing information. Genentech, Inc. Accessed July 11, 2023. www.gene.com/download/pdf/xolair_prescribing.pdf
13. Pelaia C, Paoletti G, Puggioni F, et al. Interleukin-5 in the pathophysiology of severe asthma. Front Physiol. 2019;10:1514. doi:10.3389/fphys.2019.01514
14. Nucala. Prescribing information. GlaxoSmithKline LLC. Accessed July 12, 2023. http://www.gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Nucala/pdf/NUCALA-PI-PIL-IFU-COMBINED.PDF
15. 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
16. Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371(13):1198-1207. doi:10.1056/NEJMoa1403290
17. Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371(13):1189-1197. doi:10.1056/NEJMoa1403291
18. Cinqair®. Prescribing information. Teva Pharmaceutical Industries Ltd. Accessed July 12, 2023. www.accessdata.fda.gov/drugsatfda_docs/label/2016/761033lbl.pdf
19. Castro M, Zangrilli J, Wechsler ME, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015;3(5):355-366. doi:10.1016/S2213-2600(15)00042-9
20. Pérez de Llano LA, Cosío BG, Domingo C, et al. Efficacy and safety of reslizumab in patients with severe asthma with inadequate response to omalizumab: a multicenter, open-label pilot study. J Allergy Clin Immunol Pract. 2019;7(7):2277-2283.e2. doi:10.1016/j.jaip.2019.01.017
21. Pelaia C, Calabrese C, Vatrella A, et al. Benralizumab: from the basic mechanism of action to the potential use in the biological therapy of severe eosinophilic asthma. Biomed Res Int. 2018;2018:4839230. doi:10.1155/2018/4839230
22. Fasenra. Prescribing information. AstraZeneca Pharmaceuticals LP. Accessed July 12, 2023. www.accessdata.fda.gov/drugsatfda_docs/label/2017/761070s000lbl.pdf
23. Chipps BE, Newbold P, Hirsch I, Trudo F, Goldman M. Benralizumab efficacy by atopy status and serum immunoglobulin E for patients with severe, uncontrolled asthma. Ann Allergy Asthma Immunol. 2018;120(5):504-511.e4. doi:10.1016/j.anai.2018.01.030
24. Dupixent®. Prescribing information. Regeneron Pharmaceuticals, Inc. Accessed July 12, 2023. www.regeneron.com/downloads/dupixent_fpi.pdf
25. Steinke JW, Borish L. Th2 cytokines and asthma—interleukin-4: its role in the pathogenesis of asthma, and targeting it for asthma treatment with interleukin-4 receptor antagonists. Respir Res. 2001;2(2):66-70. doi:10.1186/rr40
26. Doran E, Cai F, Holweg CTJ, Wong K, Brumm J, Arron JR. Interleukin-13 in asthma and other eosinophilic disorders. Front Med (Lausanne). 2017;4:139. doi:10.3389/fmed.2017.00139
27. Agache I, Song Y, Rocha C, et al. Efficacy and safety of treatment with dupilumab for severe asthma: a systematic review of the EAACI guidelines—recommendations on the use of biologicals in severe asthma. Allergy. 2020;75(5):1058-1068. doi:10.1111/all.14268
28. Bacharier LB, Maspero JF, Katelaris CH, et al. Dupilumab in children with uncontrolled moderate-to-severe asthma. New Engl J Med. 2021;385(24):2230-2240. doi:10.1056/NEJMoa2106567
29. Wenzel S, Castro M, Corren J, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet. 2016;388(10039):31-44. doi:10.1016/S0140-6736(16)30307-5
30. Gauvreau GM, Sehmi R, Ambrose CS, Griffiths JM. Thymic stromal lymphopoietin: its role and potential as a therapeutic target in asthma. Expert Opin Ther Targets. 2020;24(8):777-792. doi:10.1080/14728222.2020.1783242
31. TezspireTM. Prescribing information. AstraZeneca Pharmaceuticals, LP. Accessed January 12, 2023. www.accessdata.fda.gov/drugsatfda_docs/label/2021/761224s000lbl.pdf
32. Corren J, Ambrose CS, Sałapa K, et al. Efficacy of tezepelumab in patients with severe, uncontrolled asthma and perennial allergy. J Allergy Clin Immunol Pract. 2021;9(12):4334-4342.E6. doi:10.1016/j.jaip.2021.07.045
33. Menzies-Gow A, Corren J, Bourdin A, et al. Tezepelumab in adults and adolescents with severe, uncontrolled asthma. N Engl J Med. 2021;384(19):1800-1809. doi:10.1056/NEJMoa2034975
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Reviewed August 2023
