Biologics are redefining expectations in severe asthma

While around one in nine Australians have asthma, between three to ten percent have severe, or treatment resistant asthma.¹ Severe asthma is associated with more asthma flare-ups, healthcare visits and hospitalisations and as well as lost productivity and quality of life.¹

Until recently, there were limited advanced treatment options for patients with severe asthma.^2-4 Finally, as a pipeline of biologics emerge onto to market clinicians are faced with choices not faced before.^3,4 To discuss the positives and the challenges, the limbic spoke with Professor Tim Harrison, Honorary Consultant at the Faculty of Medicine & Health Sciences at the University of Nottingham during his recent tour of Australia.

What is living with severe asthma like for patients?

Although severe asthma can occur in patients of any age, many adults who present in my clinic are between 30 and 60 years of age, explains Professor Harrison. Their experiences are quite different, with “The degree of severity varying from patient to patient. The best case is a patient who is very dependent on high dose inhaled medication twice daily, but otherwise can live a pretty normal life most of the time. That is except for intermittent exacerbations, which are often precipitated by a respiratory viral infection, and leave them more breathless, and often unable to continue daily activities and which require a marked increase in their medication – including oral corticosteroids – to get them back to a period of stability. On the other end of the spectrum are people who, despite considerable medication (inhaled, oral steroids and/or new biological treatments) live a life where everything they do is impacted by their breathlessness.”

As Professor Harrison explains, there are now a number of biological agents available and the process in assigning a biologic to an appropriate patient requires more steps.⁵ Therefore, overall it is now a more satisfying disease to treat, “largely because dependence on oral corticosteroids is reducing. It’s getting easier to improve the quality of life of more patients because we now have a better understanding of the disease process and a number of treatments that target specific severe asthma phenotypes. For a long time we only had omalizumab which was helpful for patients with high confirmed allergic asthma and elevated IgE levels but even amongst suitable patients not everyone achieves a good clinical response. With more biological agents, targeting different parts of the inflammatory pathway, there is the potential to help more patients in a personalised approach.”^2-4

Can we see an oral corticosteroid-free future?

“Managing severe asthma without oral corticosteroids should be our primary focus because of the unpleasant and serious adverse effects associated with their use such as, weight gain, diabetes, osteoporosis and increased risk of infections.⁶ Unfortunately, when it comes to acute exacerbations of severe asthma, we really don’t have any choice and even patients on new biological therapies continue to experience exacerbations. Where I think we will see a change is with maintenance corticosteroids. Biological therapies have been shown to reduce the dose of maintenance corticosteroids and some patients have been able to stop them altogether.⁷ For those who continue to need maintenance corticosteroids clinical management is all about the balance for each individual in terms of how well their asthma is controlled v the long term risk of adverse effects; there is no ideal dose,” explains Professor Harrison. “However, with the introduction of a wider range of biological therapies we should expect to see a reduction in patients with the classic steroid-induced profile.”⁶

Making way for biologic maintenance therapies

In Australia, there are three biologic treatments available for severe asthma. Omalizumab is a two- or four-weekly subcutaneous injection indicated for adults and adolescents aged 12 years and over with moderate to severe allergic asthma despite inhaled corticosteroid treatment and raised IgE levels. In children aged 6 to <12 years, Xolair is indicated as add-on therapy to improve asthma control in patients with severe allergic asthma who have documented exacerbations despite daily high dose inhaled corticosteroids, and who have immunoglobulin E levels corresponding to the recommended dose range.²

There are also two IL-5 inhibitors, that inhibit IL-5 in different ways.^3,4 Mepolizumab, a four-weekly subcutaneous injection used as an add-on treatment for patients aged 12 years and over with severe refractory eosinophilic asthma.³ It binds to IL-5 preventing it binding to the IL-5 receptor on the eosinophil cell surface.³

Benralizumab, an eight-weekly subcutaneous injection after three four-weekly injections that is indicated as add-on therapy in patients aged 12 years and over with severe eosinophilic asthma (blood eosinophil count ≥300 cells/μL or ≥150 cells/μL if on oral corticosteroid treatment).⁴ It binds to the IL-5 receptor, blocking the binding of IL-5 but also increasing the affinity for the Fc receptor on natural killer (NK) cells, leading to antibody-dependent cell-mediated cytotoxicity (ADCC) of eosinophils.⁴ For access to each of these treatments, patients must be under the care of a respiratory physician for at least 12 months and demonstrate their asthma is not well controlled despite optimal inhaled therapy.⁵ As Professor Harrison explains, this involves considerable work-up to ensure the asthma is indeed severe and uncontrolled. While in the past there was little that could be offered beyond oral steroids for many patients, Professor Harrison is “hopeful that the biologic era, while complex may mean fewer patients are reliant on oral corticosteroids throughout the majority of the year.”⁷

Triaging patients for biologic maintenance therapies

As more and more biologics enter the market, it becomes more challenging to determine which biologics are best suited for specific patients, particularly as it is unlikely there will be many head-to-head trials. “In the early days,” Professor Harrison explains, “when omalizumab was first available, all we had to determine was whether the patient was allergic to a perennial aeroallergen and had elevated IgE level.² We now have IL-5 antagonists, which are suitable for patients with raised blood eosinophil counts of >300 cells/uL depending on the biologic in question.^3,4 So, if the patient presents with this, and no evidence of allergy or raised IgE, the choice is simple – an IL-5 antagonist. For those patients who present with features that meet both criteria then the choice becomes tricky.” In this instance, features like the overall safety profile and convenience of the therapy may play a bigger role in treatment decisions rather than efficacy due to a lack of head-to-head data, suggests Professor Harrison. Further work to help personalise these therapies is also high on his priority list.

Spotlight on benralizumab through the clinical trials

Benralizumab has been evaluated in 3 randomised, double-blind, parallel-group, placebo-controlled clinical trials.^7-9 Two (SIROCCO and CALIMA) were long-term exacerbation trials in adults and adolescents aged 12 years and older and one (ZONDA) oral corticosteroid reduction trial in adults.^7-9

Patients enrolled into SIROCCO and CALIMA were required to have a history of ≥2 asthma exacerbations requiring oral or systemic corticosteroid treatment in the past 12 months, a documented post-bronchodilator reversibility of at least 12% and at least 200 mL in FEV₁ in the last 12 months, an Asthma Control Questionnaire-6 (ACQ-6) score of ≥1.5 at screening and reduced lung function at baseline [pre-bronchodilator forced expiratory volume in 1 second (FEV₁) <80% in adults and <90% in adolescents] despite treatment with high-dose inhaled corticosteroids (SIROCCO) or with medium- or high-dose inhaled corticosteroids (CALIMA) and their current standard of care.^8,9 Medium and high-dose inhaled corticosteroids were defined as ≥250 μg and ≥500 μg/day fluticasone propionate dry powder formulation or equivalent respectively.^8,9

“In SIROCCO and CALIMA, both trials were very effective in reducing exacerbations and improved lung function,”^8,9 says Professor Harrison. The primary endpoint for both SIROCCO and CALIMA was the annual asthma exacerbation rate ratio versus placebo.^8,9 Treatment with benralizumab significantly reduced the annual rate of exacerbations by 51% (SIROCCO) and 28% (CALIMA) compared to placebo in the 8=weekly arm.^8,9 “However, when it came to the Asthma Control Questionnaire, we didn’t see clinically important effects.^8,9 This is something that seems to crop up in severe asthma trials again and again. We are now highly suspicious that the Asthma Control Questionnaires are not really suitable for patients with severe asthma as they have been developed and validated for patients with milder disease.”

“For those patients already on maintenance oral corticosteroids, the ZONDA study was very important in identifying how much we could reduce their dose without exacerbations,” says Professor Harrison. Indeed, the ZONDA trial included patients who were treated with daily oral corticosteroids (7.5 to 40 mg/day) in addition to regular use of high-dose inhaled corticosteroid/long-acting beta antagonist with or without additional controller(s) to maintain asthma control.⁷ Patients were also required to have blood eosinophil counts ≥150 cells/μL and a history of at least one exacerbation in the past 12 months.⁷

For ZONDA, the primary endpoint was the reduction from baseline of the final oral corticosteroid dose, while maintaining asthma control.⁷ There was a 75% reduction in the median OCS dose from baseline with benralizumab compared to 25% with placebo.⁷ Reductions of ≥50% in the oral corticosteroid dose were observed in 66% of patients receiving benralizumab compared to 37% for placebo.⁷ The proportion of patients with a mean final OCS dose ≤5 mg at weeks 24 to 28 were 59% for benralizumab and 33% for placebo.⁷ A significant difference was observed in the percentage of eligible patients who achieved 100% reduction with benralizumab compared to placebo (52.4% vs 19.0%).⁷ Patients were eligible for 100% reduction of their OCS if their baseline dose was less than 12.5 mg/day.⁷

“I think the future is definitely positive when it comes to severe asthma. With every new therapy there comes another patient population who can potentially help stay off oral corticosteroids and at the end of the day keeping patients well is what really matters,” remarks Professor Harrison.

This article was sponsored by AstraZeneca, which has no control over editorial content. The content is entirely independent and based on published studies and experts’ opinions, the views expressed are not necessarily those of AstraZeneca.

References:

1. Asthma Australia. Severe Asthma, it’s not just asthma. Available at: https://www.asthmaaustralia.org.au/act/about-asthma/severe-asthma (accessed 23 April 2018).
2. Xolair (omalizumab) Approved Product Information, 30 March 2017.
3. Nucala (mepolizumab) Approved Product Information, 11 May 2017.
4. Fasenra (benralizumab) Approved Product Information, 2 April 2018.
5. Australian Asthma Handbook. Managing severe, high-risk and difficult-to-control asthma in adults. Available at: http://www.asthmahandbook.org.au/management/adults/difficult-asthma (accessed 23 April 2018).
6. Australian Asthma Handbook. Guide to systemic corticosteroids. Available at: http://www.asthmahandbook.org.au/resources/medicines-guide/systemic-corticosteroids (accessed 23 April 2018).
7. Nair P et al. N Engl J Med 2017;376:2448-58.
8. FitzGerald JM et al. Lancet 2016;388:2128-41.
9. Bleecker ER et al. Lancet 2016;388:2115-27.