Unmet need in severe asthma

Overview of severe asthma

Asthma affects approximately 262 million people worldwide,² of whom ~5–10% have severe or uncontrolled asthma.³

Severe asthma is defined by the Global Initiative for Asthma (GINA) as a subset of difficult-to-treat asthma that remains uncontrolled despite adherence with maximal optimised high-dose inhaled corticosteroids (ICS) and long-acting β2-agonist (LABA) therapy and the treatment of contributory factors, or asthma that worsens when high-dose therapy is decreased.⁴

The long-term goals of severe asthma management include achieving good symptom control and minimising the future risk of exacerbations and disease progression (eg, decline of lung function and persistent airflow limitation). In many cases where patients have poor symptom control and/or exacerbations despite medium- or high-dose ICS and LABA therapy, their asthma may appear difficult-to-treat because of contributory factors, such as incorrect inhaler technique, poor adherence, smoking or comorbidities, or because of incorrect diagnosis.⁴ For these patients, GINA recommends assessment of these contributory factors and consideration of an add-on therapy, eg a long-acting muscarinic antagonist (LAMA).⁴ If problems persist, referral to a specialist centre for phenotypic assessment and consideration for add-on biologic targeted treatments are recommended.⁴ Even though there is guidance on when patients with asthma should be referred to a specialist, a large proportion of patients are not referred despite experiencing poor symptom control.⁵ Referral to specialist care is associated with a substantial impact on disease prognosis and patient health status.⁶ In the UK, 4% of patients who were eligible for specialist care and only 22% of patients in the US were referred.^5,6 While 41% of patients with severe asthma in Germany were referred to a pulmonologist, 89% of the population were receiving long-term oral corticosteroids (OCS), despite the side effects and recommendations against such therapy.⁷

Confirming the diagnosis of asthma, assessing contributory factors and optimising treatment strategy are the key steps for consideration in the diagnosis and management of severe asthma.⁴ Preventing exacerbations is important in the treatment of asthma and being able to identify and proactively treat at risk patients forms a central component of this strategy.⁸ Many tools can be used to assess the  risk of exacerbation e.g., Asthma Control Questionnaire (AIRQ), which is a composite measure of asthma control based on a series of yes/no questions answered by the patient, and ReferID+, a digital tool used to review patients with asthma which has led to improved clinical outcomes including fewer exacerbations.^9–11

To date, there has been great progress in the diagnosis and management of severe asthma,^12,13 with biologics representing a major advancement in the treatment landscape.¹⁴ However, many patients with severe asthma are still poorly controlled.¹⁵

Sub-optimal control of severe asthma 

A study found that approximately 60% of patients with severe asthma remained sub-optimally controlled despite treatment with standard-of-care medications.¹⁵ This significant finding was described following a retrospective and prospective analysis of the International Severe Asthma Registry – a data set of 4990 patients receiving GINA Step 5 treatment or with severe asthma remaining uncontrolled at GINA Step 4 (December 2014 to December 2017). Poorly controlled asthma was defined in this study according to Asthma Control Test (score 5–15; ‘very poorly controlled’) or Asthma Control Questionnaire (score >1.5; ‘poorly controlled’) categorisations.¹⁵

Healthcare resource utilisation and specifically OCS use is higher among patients with uncontrolled asthma.¹⁶ Sub-optimal management of patients can also influence the likelihood of hospital readmissions. 9.2% and 4.7% of patients in the US and UK, respectively, who had an asthma-related emergency department (ED) visit or hospitalisation, were re-admitted within 30 days.¹⁷ In Canada, nearly 20% of patients with asthma were readmitted into the ED within 30 days following an initial asthma-related ED visit.¹⁸ Readmissions were associated with increased disease severity, exacerbation frequency and a higher GINA step.¹⁷ Many patients are prescribed SCS when attending the ED with an exacerbation.¹⁹

Impact of poorly controlled severe asthma

Below is an example of a typical patient with severe asthma. Despite adherence to daily ICS-LABA treatment, he continues to experience symptoms that hinder his daily life and remains susceptible to severe exacerbations.

Sub-optimal asthma control can have a significant impact on patient outcomes:

• Exacerbations potentially leading to hospitalisation occur in 12–27% of patients with severe asthma in a year.^15,20,21
• Frequent exacerbations are associated with disease severity, increased asthma-related hospital re-admissions and increased systemic corticosteroid exposure.^17,19,22
• Increased risk of comorbidities and systemic side effects (eg, pneumonia, osteoporosis and type 2 diabetes) associated with frequent bursts of oral corticosteroids.^23,24
• Poor quality of life (eg, activity limitation, depression/anxiety).^25,26
• Increased risk of mortality.²⁷

Beyond the implications for patients, sub-optimal asthma control has wider implications:

• Healthcare costs associated with severe uncontrolled asthma are 3× higher than costs for patients with severe controlled disease.²⁸
• Absenteeism represented by an average of 13 working days lost following a hospital admission due to an asthma exacerbation, while 5.6 days are lost following an asthma exacerbation treated at home.²⁹
• The environmental impact of asthma treatment resulting from an overuse of inhalers and increased hospitalisations following asthma exacerbations.³⁰

Challenges associated with existing treatments for poorly controlled asthma

OCS are the primary therapy for resolution of acute exacerbations.³² However, patients with severe asthma are often exposed to multiple courses of OCS,³³ and cumulative and chronic exposure is associated with an increased risk of side effects.^6,34,35 In 93% of patients with severe asthma, morbidities related to potential corticosteroid use have been identified.³⁶ Many OCS-related morbidities (eg, osteoporosis, diabetes and hypertension) are associated with decreased lung function and reduced asthma control.³⁷ As little as 0.5–1 g (or up to four short courses) of OCS can cause serious adverse effects, including cataracts, pneumonia, type 2 diabetes, cardiovascular disease, renal impairment and osteoporosis.⁶ Increased OCS exposure was also associated with increased risk of mortality.³⁸

Globally, 20–60% of patients with severe or uncontrolled asthma have received long-term OCS.³⁴ The annual cost of OCS-related adverse events per person with severe asthma is estimated to be €1958, in Italy.³⁵ On a population level the cost of OCS-related adverse events to the Italian National Health System is €243 million annually.³⁵ Corticosteroid use was also associated with higher healthcare resource utilisation.³⁹ Updated GINA guidelines recommend minimising OCS use and only using short courses of OCS for patients with an acute asthma exacerbation.⁴

As such, there is a clear need to avoid maintenance OCS treatment where other options are available (in line with updated recommendations by GINA⁴) and to continue to develop and identify alternative steroid-sparing treatments for asthma exacerbations and for patients with severe asthma.⁶ To protect patients from the potential harm of SCS use, a structured and collaborative SCS stewardship approach is required.⁴⁰

Asthma is heterogeneous; patients often show activation of multiple innate and adaptive inflammatory pathways.^41–43 This contributes to a significant unmet need in the management of severe uncontrolled asthma.⁴ Targeting specific steps of the immune-inflammatory cascade through highly selective biologic therapies offers the potential of achieving optimal disease control in several severe asthma inflammatory phenotypes.¹

However, major unmet needs persist owing to lack of access and inadequate response to or ineligibility for currently available biologic treatments.¹

Indeed, 72% of patients with asthma in primary care in the UK, who are thought to have severe asthma, have never been referred to a specialist.⁴⁴ Globally, approximately 75% of patients with poorly controlled severe asthma (GINA Step 4/5) are not receiving biologics.¹⁵

For patients living with asthma, improved disease stability and consideration of remission as an attainable treatment goal remains a long-term aspiration to improve patient care.^45,46