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Biologic Therapeutics for Type 2 Asthma

Eileen Wang, MD, MPH

Assistant Professor
Division of Allergy and Immunology
Department of Medicine
National Jewish Health
University of Colorado School of Medicine
Denver and Aurora, Colorado

Eileen Wang, MD, MPH has disclosed that she has received fees for non-CME/CE services from AstraZeneca and funds for research support from Genentech and GlaxoSmithKline.

View ClinicalThoughts from this Author

Released: September 21, 2020

Treatment of poorly controlled asthma or systemic corticosteroid-dependent asthma has made great advances in recent years with the development of biologic therapeutics. FDA-approved biologic therapeutics for asthma target type 2 inflammatory pathways, which are associated with eosinophilic and/or allergic inflammation driven by the activation of T-helper 2 cells and innate lymphoid cells 2. These biologic agents act by targeting immunoglobulin E (IgE), interleukin (IL)-5, or IL-4 and IL-13 pathways.

Anti-IgE: Omalizumab
Omalizumab targets IgE and is administered subcutaneously. It is currently approved for moderate to severe asthma in patients 6 years of age and older who have evidence of allergic sensitization to a perennial environmental allergen. Administered every 2 or 4 weeks, dosing is based upon weight, total serum IgE levels, and age.

Because of a low but increased risk of hypersensitivity reactions, omalizumab should be given in an observed clinical setting equipped to handle anaphylaxis. More common adverse effects include joint pain, fatigue, headaches, and nasopharyngitis.

In 2014, omalizumab was also approved for chronic spontaneous urticaria (CSU), also known as chronic idiopathic urticaria. As a result, in a patient with allergic asthma and comorbid CSU, omalizumab can be a prime choice to address both conditions. In fact, in our online decision support tool, “Managing Severe Asthma,” all experts chose omalizumab for patients with severe allergic asthma and comorbid chronic urticaria.

Anti-IL-5 and Anti-IL-5 Receptor: Mepolizumab, Reslizumab, Benralizumab
IL-5 is a key mediator of eosinophil maturation and proliferation. Anti-IL-5/5R biologics are effective treatments for severe asthma in which eosinophilic inflammation is thought to be the primary driver (supported by detection of peripheral and/or pulmonary eosinophilia in sputum, bronchoalveolar lavage, lung tissue).

Mepolizumab targets IL-5 and is given subcutaneously. It is approved for patients aged 6 years and older with eosinophilic asthma, has fixed dosing every 4 weeks, and can be given in the clinic or at home (autoinjector and prefilled syringe are for individuals aged 12 years and older).

More common adverse effects include headache, injection site reaction, and fatigue. In clinical trials, a small number of patients receiving mepolizumab developed herpes zoster. Thus, for those aged 50 years and older, consider vaccination for herpes zoster.

Reslizumab is indicated for adults with severe eosinophilic asthma. It targets IL-5 and is administered intravenously.

As the only weight-based agent in this class, reslizumab is frequently considered in obese patients, particularly if there is incomplete clinical response after initiation of other anti-IL5/5R biologics. More common adverse effects include headache, pharyngitis, and pyrexia.

Benralizumab targets the alpha subunit of the IL-5 receptor, has fixed dosing subcutaneously every 4 weeks for 3 doses, then subsequently every 8 weeks, and is approved in patients ages 12 years and older. Benralizumab can be given in the clinic or at home with a prefilled autoinjector. More common adverse effects include headache, pharyngitis, and pyrexia.

Anti-IL-4 and IL-13: Dupilumab
Dupilumab binds the alpha subunit of the IL-4 receptor, thereby inhibiting both IL-4 and IL-13 signaling. It has 3 indications: Moderate to severe eosinophilic or oral corticosteroid-dependent asthma in patients ages 12 years and older, moderate to severe atopic dermatitis in patients ages 6 years and older, and adults with chronic rhinosinusitis with nasal polyposis. Thus, dupilumab should be considered when these comorbidities are uncontrolled. Indeed, in our online decision support tool, “Managing Severe Asthma,” most experts added an anti–IL-4 receptor biologic in patients with severe asthma and comorbid atopic dermatitis or chronic rhinosinusitis with nasal polyposis.

More common adverse effects include conjunctivitis and injection site reactions. Increased systemic eosinophilia, typically transient, has been associated with dupilumab. There have been a few cases of eosinophilic pneumonia reported. As a result, consider alternative biologics or close monitoring of those with very high baseline absolute eosinophil counts. This potential risk should be balanced with the expected benefit of dupilumab over alternative agents. Consistent with this, in our online decision support tool, most experts—but not all—chose a non-dupilumab agent as their first choice for a patient with high eosinophils.

Special Considerations
None of these biologics have great data on malignancy or pregnancy. For malignancy, during the clinical trials for omalizumab, there was an increased rate of malignancy in those treated with omalizumab (0.5%) vs placebo (0.2%). However, a separate 5-year observational study found no increased risk of malignancy for omalizumab.

Regarding pregnancy, the prospective, observational EXPECT study evaluated safety outcomes in pregnant women exposed to at least 1 dose of omalizumab and found no increase in the prevalence of congenital anomalies vs historical findings in asthmatic populations. With the noted potential adverse effects of hypersensitivity reactions, it is not recommended to start omalizumab in pregnant women. However, continuation of omalizumab in pregnancy, after balancing risks vs benefits, is generally considered safe.

The other biologics have no published human data, but there are some ongoing observational registries. All require discussions with the patient about potential risks and benefits during pregnancy with the primary goal of maintaining or achieving good disease control.

Your Thoughts?
For customized expert advice, I encourage you to visit the online decision support tool, “Managing Severe Asthma,” which I developed with my colleagues, Bradley E. Chipps, MDFAAP, FACAAI, FAAAAI, FCCP; Nicola Alexander Hanania, MD, MS; Linda Rogers, MD; and Michael E. Wechsler, MD, MMSc. In this decision support tool, you can enter the details of your patient and learn how 5 experts would proceed.
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This activity is supported by educational grants from
Novartis Pharmaceuticals Corporation
Sanofi Genzyme and Regeneron Pharmaceuticals

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