Asthma is considered “difficult-to-treat” when it remains uncontrolled despite medium- or high-dose inhaled corticosteroid (ICS) with a long-acting β₂ agonist (LABA) or oral corticosteroids (OCS). In many cases, asthma may appear difficult-to-treat because of modifiable factors such as poor adherence, smoking, incorrect inhaler use, comorbidities, or incorrect diagnosis.¹

“Severe” asthma can be considered a subset of “difficult-to-treat” asthma where patients remain uncontrolled even with adherence to optimised high-dose ICS/LABA treatment.¹ Patients are assessed at this point for their eligibility for biologic therapies, such as the anti-IgE omalizumab, the anti-IL5s mepolizumab and reslizumab, anti-IL5R benralizumab, or the anti-IL4R dupilumab.¹

Dr Joy Lee, Respiratory and Sleep Physician and Consultant at the Allergy, Asthma and Clinical Immunology department at the Alfred Hospital, Melbourne, manages difficult-to-treat and severe asthma. “After you’ve differentiated the patient with difficult-to-treat from severe asthma, you’ve ruled out that it’s not lack of adherence or other factors contributing to poor asthma control, it’s likely that they have severe asthma,” she said.

The proportion of adult patients who have difficult-to-treat or severe asthma is relatively low, at 17% and 3.7%, respectively.¹ However, patients with severe asthma experience a heavy burden of symptoms, exacerbations, medication side effects and comorbidities, and this has traditionally made management challenging.¹

“Phenotyping” in severe asthma diagnosis informs treatment decisions

Once a patient has been diagnosed with severe asthma, the next step is to assess the phenotype of their disease and factors contributing to symptoms and exacerbations.¹ Dr Lee described her patient assessment approach: “When we consider the phenotype of the patient’s asthma, we like to assess things like the age of onset (whether it’s childhood- or adult-onset), and then we look at whether we’re dealing with Type 2 high, which includes allergic-type asthma or non-allergic or Type 2 low asthma,” she said.

The tests required for identifying Type 2 inflammation in asthma aim at identifying markers of airway inflammation and include blood eosinophil count (≥150 per µL) and/or FeNO ≥20 ppb, and/or sputum eosinophils ≥2%.¹ Skin-prick testing or IgE testing for specific environmental allergens is also conducted at this stage.¹

If Type 2 airway inflammation is identified, the next step is to consider which add-on biologic to commence first: anti-IgE, anti-IL5/anti-IL5R or anti-IL4R. “With biologic therapies, we’re looking at using very targeted treatments now. One size does not fit all in severe asthma and there are several options. So, for each individual patient, we try to identify the factors that are causing their disease, and then we treat those specific factors – a ‘treatable traits’ approach,” Dr Lee said.

For PBS-listed omalizumab (indicated in children aged 6–12 years and adolescents and adults ≥12 years), patients must be diagnosed with uncontrolled severe asthma and meet a number of additional eligibility criteria.³ Patient eligibility is based on sensitisation to inhaled allergens on skin-prick testing or specific IgE, total serum IgE ≥30 IU/mL, and presence of uncontrolled asthma even with optimised asthma therapy despite formal assessment of and adherence to correct inhaler technique (which must be documented).²

Omalizumab significantly reduces asthma exacerbations in Type-2 severe asthma

Omalizumab is a recombinant DNA-derived humanised monoclonal antibody that binds selectively to human IgE.² In adults with allergic asthma, several clinical studies have shown that omalizumab reduced serum free IgE levels by 84–99% from baseline within 2 hours of dosing, resulting in significant reductions in annualised asthma exacerbations vs. placebo (p<0.0001 to p=0.039).² Omalizumab has also been shown to result in clinically meaningful improvements in patient quality of life in the majority of studies (p<0.05 for adults; p = 0.30 for children), an important endpoint in considering the heavy burden of disease of severe asthma.²

Dr Lee has extensive experience with omalizumab and other biologics. “I started treating severe asthma at about the time that biologics became available in Australia, including in clinical trial settings,” she said.

Certain criteria can be used (such as IgE ≥30 IU/mL) to assess which patients are most likely to respond well to omalizumab therapy, but in practice Dr Lee also assesses potential response based on a range of factors: “We also look at the patient’s asthma history and whether they have an allergic phenotype, whether they’re sensitised to dust mite or grass pollens for example, and whether there’s a history of child-onset asthma,” she explained.

Blood eosinophil count ≥260 cells per µL is also a predictor of response to omalizumab in the GINA guidelines,¹ but Dr Lee commented that the jury is still out: “There were two studies that looked at whether high biomarker levels, like eosinophil count, were predictors of clinical response [PROSPERO⁴ and STELLAIR⁵], but they produced conflicting results,” she said.

Real-world evidence from PROSPERO⁴ suggested a correlation with omalizumab effectiveness and high baseline eosinophil count (≥300 cells/µL),⁴ but the STELLAIR⁵ study found that omalizumab demonstrated similar effectiveness in both high and low eosinophil groups (≥300 and <300 cells/µL, respectively).⁵

The possibility of at-home dosing can make a difference to severe asthma patients

Dr Lee said treatment of severe asthma with omalizumab has come a long way since she started using it. “We are now more experienced with omalizumab, and also have information on its use in pregnancy with the publication of the EXPECT registry findings,⁶” she noted. EXPECT was a prospective, observational study of 250 pregnant women exposed to one or more doses of omalizumab during pregnancy and within 8 weeks prior to conception. An analysis comparing the outcomes from the registry with those from a disease-matched population not treated with omalizumab showed no evidence of an increased risk of major congenital anomalies in those treated with omalizumab.⁷

 “Omalizumab now also comes in a pre-filled syringe, and we’re teaching patients how to use it themselves for home administration, which has made a huge difference to them given the fortnightly dosing schedule,” she said.

When asked about managing the risk of anaphylaxis with omalizumab,² Dr Lee explained “We used to prescribe the EPIPEN because of reports from the early studies around anaphylaxis, but we haven’t seen that play out over time.^1,2 I think it’s up to the clinician’s discretion whether you want to continue doing that, but I don’t think it’s standard practice anymore. What we do in our practice now is give the first doses supervised in the clinic or hospital setting and observe them for 2 hours in case of a reaction. In terms of side effects, some patients do experience joint aches and pains, headaches and injection-site reactions, but I would say omalizumab is pretty well tolerated in about 90% of the patients we use it in.” The clinical trials in allergic asthma found the most commonly associated adverse drug reactions to be injection site reactions and headaches.² In children 6 to <12 years of age, the most commonly reported adverse reactions were headache, pyrexia, and upper abdominal pain. Most of these events were mild or moderate in severity.²

The approved product information for Xolair notes that local or systemic allergic reactions, including anaphylaxis, may occur, and that anaphylactic reactions were rare in clinical trials.² It is recommended that patients with a known history of anaphylaxis have each dose of Xolair administered in a setting where there is treatment for anaphylaxis available. Patients should also be advised that such reactions are possible and to seek prompt medical attention if allergic reactions occur.²

Omalizumab dosing is based on the patient’s total IgE prior to treatment and their body weight,² but Dr Lee insisted that this wasn’t as complicated as it sounds: “Online calculators and tables are freely available and can be used  to help determine the correct dose for your patient, and who might be suitable for monthly or fortnightly dosing,” she said.

Disclosure

This article was sponsored by Novartis. Any views expressed in the article are those of the expert alone and do not necessarily reflect the views of the sponsor. Before prescribing, please review the XOLAIR product information via the TGA website. Treatment decisions based on these data are the responsibility of the prescribing physician.

References:

1. Difficult-To-Treat & Severe Asthma in Adolescent and Adult Patients. Diagnosis and Management. Global Initiative For Asthma (GINA). April 2021
2. XOLAIR^® (omalizumab) Approved Product Information.
3. Pharmaceutical Benefits Scheme (PBS) Schedule: XOLAIR^® (omalizumab). Available at: https://www.pbs.gov.au. Accessed December 2021.
4. Casale TB et al. J Allergy Clin Immunol Pract. 2019 Jan;7(1):156–164.e1.
5. Humbert M et al. Eur Respir J. 2018 May 10;51(5):1702523.
6. Namazy J et al. J Allergy Clin Immunol. 2015 Feb;135(2):407–12
7. Namazy J et al. J Allergy Clin Immunol. 2020 Feb;145(2):528 – 536