Investigational approaches for unmet need in severe asthma

ABSTRACT

Introduction

Molecular antibodies (mAb) targeting inflammatory mediators are effective in T2-high asthma. The recent approval of Tezepelumab presents a novel mAb therapeutic option for those with T2-low asthma.

Areas covered

We discuss a number of clinical problems pertinent to severe asthma that are less responsive to current therapies, such as persistent airflow obstruction and airway hyperresponsiveness. We discuss selected investigational approaches, including a number of candidate therapies under investigation in two adaptive platform trials currently in progress, with particular reference to this unmet need, as well as their potential in phenotypes such as neutrophilic asthma and obese asthma, which may or may not overlap with a T2-high phenotype.

Expert opinion

The application of discrete targeting approaches to T2-low molecular phenotypes, including those phenotypes in which inflammation may not arise within the airway, has yielded variable results to date. Endotypes associated with T2-low asthma are likely to be diverse but await validation. Investigational therapeutic approaches must, likewise, be diverse if the goal of remission is to become attainable for all those living with asthma.

KEYWORDS:

• Airway hyper-responsiveness
• astegolimab
• Charcot-Leyden crystals
• dexpramiprexole
• galectin-10
• glucagon-like peptide 1
• mucus plugging
• neutrophilic asthma
• obese asthma
• OM-85 BV

Article highlights

• Most cases of severe asthma are ‘Type 2 high,’ characterized by the presence of T_H2-type inflammation.

• Asthma is characterized as ‘Type 2 high’ according to relevant biomarkers (e.g. blood eosinophil count and exhaled nitric oxide). Type 2 high asthma is typically responsive to glucocorticoid therapy.

• The anti-inflammatory action of glucocorticoid therapy is broad, and this therapy is associated with adverse effects such as hyperglycemia and reduced bone density.

• More targeted anti-inflammatory action may be achieved with monoclonal antibody (mAb) therapy, also referred to as biologic therapy.

• Biologic therapy is generally recommended at GINA Step 5 to reduce or prevent requirement for oral glucocorticoids (whether as maintenance or as high dose ‘bursts’ to management exacerbations) and to be used in addition to controller therapy (including inhaled corticosteroid and long-acting beta-agonist therapy)

• Six biologic agents have been licensed for severe asthma: omalizumab, mepolizumab, reslizumab, benralizumab, dupilumab, and most recently tezepelumab.

• Only tezepelumab has shown efficacy irrespective of biomarker status and oral steroid dependence, with other agents targeting Type 2 inflammation only.

• An individual with severe asthma may be eligible for more than one biologic agent, and several considerations (e.g. local payer criteria, comorbidities, and previous lack of other responses to other biologic agents) may determine treatment selection.

• Prior to 2015, only one biologic therapy, omalizumab, was licensed for severe asthma. Long-term data on newer agents remain limited.

• Even with the licensing of five new biologic agents since 2015, significant unmet need may be anticipated, particularly among those patients with severe asthma and without evidence of Type 2 inflammation.

• So-called ‘Type 2 low’ asthma remains poorly understood. Treatment strategies involving the discrete targeting of inflammatory mediators, effective in Type 2 high asthma, may be ineffective when applied to Type 2 low asthma where inflammatory response may be adaptive.

• A diversity of research approaches is therefore needed, for example antimicrobial strategies targeting Proteobacteria dysbiosis in neutrophilic asthma. We discuss investigative therapies with particular reference to platform studies currently in progress with a focus on unmet need in severe asthma.

Declaration of interest

A Menzies-Gow has attended advisory boards for AstraZeneca, GlaxoSmithKline, Novartis, Sanofi and Teva; has received speaker fees from AstraZeneca, Novartis, Roche and Teva; has participated in research with AstraZeneca, for which his institution has been remunerated; has attended international conferences with Teva; and has consultancy agreements with AstraZeneca and Sanofi.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.