Target the ‘bomb’ or the ‘magnet’: a new therapeutic framework for biologics in asthma?

Sub-stratification of type 2 inflammatory airway disease according to whether blood eosinophil level or FeNO is the primary driving factor could underpin a new, more targeted approach to the treatment of asthma with biologics, UK experts say.

A new therapeutic framework in which treatment decisions are based on the dominant driver of inflammation could theoretically help to ensure the “right biologic for the right patient” and thus improve outcomes, write Professor Ian Pavord, Dr Simon Couillard and colleagues in a comment piece published in Respirology.

The concept, they said, “is based on the demonstration that the two clinically accessible biomarkers of type-2 inflammation, fractional exhaled nitric oxide (FeNO) and the blood eosinophil count, provide independent prognostic (of exacerbations) and predictive (of  corticosteroid response) information because they identify different aspects of type-2 inflammation”.

It stems from a recent sectional analysis of sputum and serum markers of type-2 inflammation in patients with severe asthma taking high-dose ICS, which showed that FeNO correlated with nearly all assessed aspects of the airway type-2 immune response in sputum, while blood eosinophil count was associated with serum IL-5 but no measure of air-way inflammation.

“FeNO and blood eosinophils therefore relate to different components and compartments of type-2 inflammation: FeNO reflects airway type-2 activity and the chemotactic pull to the airways (the magnet), whereas blood eosinophils reflect the systemic pool of available effector cells and circulating IL-5 (the bomb),” they said.

Furthermore, randomised clinical trials have shown that while elevated levels of baseline FeNO and blood eosinophils “act synergistically to predict asthma attacks in the placebo arm”, the greater risk of attack was “entirely removed by appropriate type-2 targeting anti-inflammatory therapy”.

Choosing a biologic

According to the authors, these findings “imply that we might be in a position to choose the most appropriate biologic for an individual patient based on their biomarker profile and the primary target of the biologic”.

As such, patients presenting with a ‘magnet’ FeNO-predominant biomarker profile with ICS-resistant inflammation might have the best treatment response to biologics targeting relevant airway mucosal processes such as anti-TSLP (tezepelumab) or anti-IL-4 receptor alpha (dupilumab), while those with a ‘bomb’ blood eosinophil-predominant biomarker profile would best respond to biologics targeting IL-5, they suggest.

There is already some clinical evidence in support of such an approach: posthoc analysis of the Phase 3 QUEST and Phase 2b DREAM studies showed that patients with FeNO >25 ppb but blood eosinophil count of <150 cells/μl (consistent with the proposed ‘magnet’-driven profile) responded to treatment with dupilumab but not to mepolizumab.

Also, patients with a blood eosinophil count >500 cells/μl (consistent with a ‘bomb’-driven profile) have “a very large and complete response to biologics targeting IL-5,” independent of FeNO.

The authors acknowledged that the bomb-meets-magnet therapeutic framework is “largely speculative”, that the two inflammation processes can overlap, and that elevated FeNO “translates to more than just a ‘magnetic ’pull for eosinophils in so far as it relates to accelerated lung function decline”.

However, validity of this proposed approach could be further explored by post hoc analyses of other trials in involving asthma biologics, examining the treatment effect on asthma attack in patients using either a composite stratification score combining blood eosinophils and FeNO or by determining the strength of signal for each inflammation biomarker.

“The expectation would be that tezepelumab and dupilumab would be more effective than biologics targeting IL-5 in ‘magnet’-predominant patients, whereas the opposite would be seen in ‘bomb’-predominant patients,” they said.

“We suggest that these post hoc studies and new comparative studies are urgently needed to test whether sub-stratification of type-2 high airway disease is a valid means to better match patients and biologics and determine whether this stratification allows us to make other clinically useful predictions,” they added.

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