For a long time, a lack of new treatment options has left respiratory physicians ‘plugging the holes’ in the leaky bucket that is severe asthma. But over the last few years a number of novel treatments, including monoclonal antibodies, have acquired Pharmaceutical Benefits Scheme (PBS) funding.¹ Importantly, additional, innovative small molecule inhibitors are under clinical trial investigation, and there is capacity to add oral medications as potential therapies in the future.² In the second part to our severe asthma series, the limbic spoke with Professor Philip Bardin, Professor/Director at Monash Lung and Sleep, Melbourne about the changing landscape of severe asthma management.

“We’ve known that asthma is a heterogeneous disease for a long time, but routine phenotyping of severe asthma patients wasn’t the norm because the options available to treat specific phenotypes were limited. Then physicians gained access to monoclonal antibody treatments and suddenly we were faced with new choices and the challenge of selecting the appropriate and correct treatment. That’s because most, but not every patient, managed by these therapies respond. Given monoclonal antibody treatments are so expensive, it comes with a lot of complexity and paperwork,” he explained and continued,^3,4 “we’re getting used to doing things differently, which for clinicians means navigating new workflows and keeping abreast of clinical trials. For patients, the hope is that we are moving to a future where fewer patients drift into acceptance of poorly controlled asthma.”⁵  

Adherence with inhaler preventer therapies is not always an avoidable issue in asthma

Prof. Bardin explained that issues around adherence with asthma therapies is not as simple as using a puffer daily – and correctly. “That’s a big part,” he expanded, “but many patients are reluctant to rely on oral corticosteroids (OCS) if high doses of inhaled therapies aren’t preventing exacerbations. Aversion to steroids and preventatives in general is something we see more and more in the younger generation. So options that align with patient preference have the potential to make an impact on this disease.” ^5,6

There is broad consensus that despite clear guidance from governing bodies on appropriate asthma management, many patients remain uncontrolled.⁷

Already, the availability of monoclonal antibodies has reinvigorated enthusiasm for referring uncontrolled patients through to specialists, he noted. “We’ve seen a notable increase in the volume of patients referred to us. Around 10-20% have difficult-to-control asthma, and have poor symptom control despite being on the highest dose of inhaled therapies. Of these, 5-10% may have true severe asthma where poor symptom control is not explained by poor adherence and/or inhaler technique.⁸ As a practical approach and to save time, we start phenotyping patients as soon as they are referred. Often they’ve had episodes of being in and out of hospital and getting them access to treatment is something that can be life-changing for them.”

The advent of biologic therapies has come with an added benefit of investment in understanding more about the underlying pathophysiology of the disease, and this research has unlocked potential new drug targets in its wake.⁴ The management of severe asthma appears to be moving rapidly towards a requirement for adequate biomarkers and targeted therapies that enable delivery of the right drug, to the right patient, at the right time.⁴ “This is going to mean clinicians need to be confident in phenotyping patients to facilitate treatment choices,” noted Prof. Bardin. In addition, an array of drugs targeting pathologic pathways that have shared functions, across multiple phenotypes will be of equal importance.⁴

Guidelines require Type 2 or non-Type 2 phenotype assessment to determine treatment options

Type 2 inflammation is characterised by eosinophils or increased FeNO while non-Type 2 inflammation may be typified by neutrophils. Patients with Type 2 inflammation generally respond to inhaled corticosteroids (ICS), but in severe asthma many patients show limited response and appear refractory to high doses of ICS.⁸ Type 2 inflammation is considered when the patient is taking high-dose ICS or daily OCS and any of the following are found:⁸

• Blood eosinophils ³150-300 cells/mL
• FeNO ³40 ppb
• Sputum eosinophils ³3%
• Allergy is a strong component of asthma.

Biomarkers of Type 2 inflammation are often suppressed by OCS, so tests should be performed before starting them, or at the lowest possible dose.⁸ The thresholds for blood eosinophils and FeNO have been derived from the lowest levels associated with response to biologics. “So, we expect the criteria to change as Type 2 targeted therapies become more widely available,” notes Prof. Bardin. He continued, “when it comes to non-Type 2 severe asthma, there are no monoclonal antibody or other therapies available right now, so there’s a real gap in the management options for the other approximately 50% of patients who don’t have Type 2 inflammation.” ⁸

Is there a treatment ‘niche’ for new agents in patients on optimised inhaled ICS therapy and monoclonal antibody treatments?

“The new classes of small molecule drug (SMD) treatments, including prostaglandin D2 receptor 2 (DP2) antagonists could find a therapeutic role flanked by inhaled therapies and monoclonal antibody treatments as used today.² As therapeutic agents they have potential to have broad applicability.⁹ If the Phase 3 clinical trial data are favourable, these oral, small molecule inhibitors could offer many patients a targeted therapy, often in cases that are  ineligible for biological treatments. A significant benefit is that these agents are taken by the oral route. Ongoing research should clarify whether this concept has merit and where they will fit into the therapeutic pathway.²

There might be other benefits, points out Prof. Bardin. “Less expensive oral therapies with minimal paperwork will be well-received. Right now the volume of patients with severe asthma requiring review by Respiratory specialists exceeds capacity. Simplifying processes could enable timelier access to treatment and provide time to step up to a monoclonal antibody therapy, if indicated. In reality we don’t know what will happen. It’s very much watch and wait for now,” he concluded.⁴

This article was sponsored by Novartis, 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 Novartis.

References:

1. Australian Government. Department of Health. 2019. The Pharmaceutical Benefits Scheme. Body System. Available from: http://www.pbs.gov.au/browse/body-system?depth=4&codes=r03dx#r03dx (Accessed 15 May 2019).
2. White C, et al. Expert Opin Investig Drugs 2018;27(2):199-207.
3. Nixon J, et al. Pharmacol Ther 2017;169:57-77.
4. Roth-Walter F, et al. Allergy 2019 Mar;74(3):432-448.
5. Katsaounou P, et al. ERJ Open Res 2018;4(4):00076-2018.
6. National Asthma Council Australia. 2019. Current practice and new approaches in asthma: Perspectives of asthma practitioners and patients. Available from: https://assets.nationalasthma.org.au/resources/Current-Practice-New-Approaches-in-Asthma.pdf (Accessed 15 May 2019).
7. Reddel HK, et al. Med J Aust 2015;202(9):492-496.
8. Global Initiative for Asthma (GINA). 2019. Difficult-to-treat & Severe Asthma in adolescent and adult patients: Diagnosis and Management. Available from: https://ginasthma.org/severeasthma/ (Accessed 15 May 2019).
9. Domingo C, et al. Respir Res 2018;19(1):189.