Our evolving understanding of severe asthma

This is the first of three features in the limbic reporting on the ADVENT Advances in Type 2 Inflammatory Diseases medical education series run by Sanofi Genzyme.

Previously, asthma was considered a homogenous disorder. Now, asthma is recognized by the Global Initiative for Asthma (GINA) Guidelines as a heterogenous disease, usually characterised by chronic airway inflammation.¹ Severe asthma is defined as:

“asthma that is uncontrolled despite adherence with maximal optimized therapy and treatment of contributary factors [such as inhaler technique and adherence], or that worsens when high dose treatment is decreased.” ¹

GINA Guidelines, 2020.

Evaluate the phenotype

When assessing severe asthma, it is important to evaluate the patient’s inflammatory phenotype – whether they have type 2 inflammation or not.¹ Our understanding of type 2 inflammation and its link to the physiology of asthma have both evolved over the past few decades. Now, type 2 inflammation can be found in approximately half the population of people with severe asthma.¹

Type 2 inflammation is driven by both the innate (ILC2) and adaptive (Th2) arms of the immune system.^2–5 Both of these cell types produce the key cytokines of type 2 inflammation: IL-4, IL-13 and IL-5. Innate cells downstream from Th2 cells (e.g. mast cells and basophils) can amplify the type 2 inflammatory response as they are activated by antigen-bound IgE, which can form crosslinks resulting in the release of several inflammatory mediators, including IL-4 and IL-13.⁵ These cytokines are key drivers in the pathophysiology of asthma.^2,5–12

Currently, it is recognised that there are many clinical phenotypes. It should be noted that the majority of patients have mixed phenotypes; patients with allergic asthma also have eosinophilic airway inflammation.¹

Match the treatment to the phenotype

Patients with severe asthma and a type 2 inflammatory phenotype may not respond to high dose ICS.¹ Hence the need to understand their inflammatory phenotype to be able to tailor treatment to each patient’s needs. According to the GINA Guidelines, when type 2 inflammation is suspected the following should be checked:¹

• Blood eosinophils ≥150µl and/or
• FeNO ≥20 ppb and/or
  • Repeat blood eosinophils and FeNO up to 3x on lowest possible OCS dose
• Sputum eosinophils ≥2% and/or
• Presence of allergens driving symptoms and/or
• Need for maintenance OCS

“We can measure [type 2 inflammation]. We can use both airway eosinophils, blood eosinophilia and elevated levels of exhaled nitric oxide at least in part to identify type 2 [inflammation]”

Professor Peter Wark. ADVENT Advances in Type 2 Inflammatory Diseases. August 2020

Consider if an add-on biologic targeting the type 2 inflammation pathway would be beneficial. A range of biologic agents are now registered in Australia to treat severe asthma. These cover a variety of options targeting different components of asthma physiology, including anti-IgE for moderate to severe allergic asthma (omalizumab), anti-IL-5 (mepolizumab) or anti-IL-5Ra (benralizumab) for severe eosinophilic asthma and anti-IL-4Ra (dupilumab) for moderate to severe asthma with type 2 inflammation.^13–16 It is important to note that just because IgE, eosinophils or FeNO levels are high in an individual patient with severe asthma, it does not necessarily mean that these cells and molecules are the principle drivers of disease activity. Refer to the GINA 2020 Guidelines for advice on how to choose which biologic to start with.¹

“It’s worth looking harder for phenotyping your patient … I think this is now essential so that we [can] start targeting treatments and monoclonal antibody therapies and then looking for auxiliary treatments”

Professor Peter Wark. ADVENT Advances in Type 2 Inflammatory Diseases. August 2020.

Assess if the therapy is having the expected effect

Traditionally, clinicians who manage severe asthma have been interested in biomarkers as a way of selecting patients for targeted therapy. Less attention has been paid to how biomarkers change after therapy has started. However, biomarkers can help clinicians determine if a treatment is working. Below are some examples of biologics available and the biomarkers worth considering when assessing treatment efficacy.

Anti-IgE monoclonal antibody (omalizumab) bind to Fc component of free IgE, preventing the binding of IgE to FcεRI receptors therefore reducing levels of free IgE and reducing the expression of the receptors.^1,13 To assess effectiveness of treatment with omalizumab consider monitoring serum free IgE levels (if available), exhaled FeNO and blood eosinophil levels.

Anti-IL-5 monoclonal antibodies (mepolizumab and benralizumab) bind to circulating IL-5. Benralizumab binds to the alpha subunit of the IL-5 receptor (IL-5Rα) on eosinophils and basophils, leading to apoptosis of these cells.^1,15 Mepolizumab inhibits IL-5 signalling by blocking the binding of IL-5 to its receptors on eosinophil cell surfaces, reducing the production and survival of these cells.^1,14 To assess the efficacy of these treatments consider monitoring blood eosinophils rather than exhaled FeNO levels.

Anti-IL-4Ra monoclonal antibody (dupilumab) inhibits both IL-4 and IL-13 signalling. The IL-4Rα subunit is shared by both IL-4 and IL-13 receptor complexes, and by binding to this subunit dupilumab blocks both signalling pathways, thus preventing activation of multiple cell types as well as multiple mediators of type 2 inflammation.^1,16 When assessing efficacy of dupilumab consider monitoring exhaled FeNO and total serum IgE.

“Where I think looking at these biomarkers really comes into its own is trying to troubleshoot the patient who’s doing poorly after starting on a biological agent. This failure to respond might be initially right from the get-go or might be …[a patient] who did well for the first nine months and started to deteriorate later on. But I think one of the really important questions in sorting out this sort of situation is asking yourself is the monoclonal antibody having the expected biological effect or not?”

Professor John Upham. ADVENT Advances in Type 2 Inflammatory Diseases. August 2020.

Please click here for a copy of the currently approved Dupixent product information in Australia.

References:

1. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2020. Available from: ginasthma.org (accessed September 2020).
2. Israel E, Reddel HK. N Engl J Med. 2017;377:965-976.
3. Fahy JV. Nat Rev Immunol. 2015;15:57-65.
4. Chung KF. Lancet. 2015;386:1086-1096.
5. Gandhi NA, et al. Nat Rev Drug Discov. 2016;15:35-50.
6. McGregor MC, et al. Am J Respir Crit Care Med. 2019;199:433-445.
7. Fajt ML, et al. Allergy Asthma Immunol Res. 2017;9:3-14.
8. Brusselle GG, et al. Nat Med. 2013;19:977-979.
9. Santini G, et al. Expert Opin Investig Drugs. 2017;26:357-366.
10. Paul WE, et al. Nat Rev Immunol. 2010;10:225-235.
11. McLeod J, et al. Cytokine. 2015;75:57-61.
12. Le Floc’hA, et al. Allergy. 2020; 75: 1188–120.
13. Australian Product Information Xolair (omalizumab), 2020.
14. Australian Product Information Nucala (mepolizumab) 2019.
15. Australian Product Information Fasenra (benralizumab) January 2020.
16. Australian Product Information Dupixent (dupilumab) June 2020.

Sanofi-aventis Australia Pty ltd trading as Sanofi Genzyme, ABN 31 008 558 807. Talavera Corporate Centre, Building D, 12-24 Talavera Rd, Macquarie Park, NSW 2113. www.sanofi.com.au MAT-AU-2001127 First Issued September 2020.