Is there a future for biologics in COPD and asthma?

Biologics can achieve clinically important risk reductions in eosinophilic airway disease – as long as you give them to the right patients with the right pathology and look at the right outcome measures, an international expert says.

Speaking at a respiratory forum in Melbourne Professor Ian Pavord, a consultant respiratory physician at the University of Oxford Hospitals in the UK, said studies had shown biologics could reduce asthma exacerbations and oral corticosteroid use and achieve significant improvement in quality of life in patients with eosinophilic inflammation.

Blocking the IL-5 pathway

When the IL-5 blocker mepolizumab was first investigated in the 1990s the clinical effects were disappointing in terms of airway responsiveness to histamine, lung function, FEV1 or symptom scores, though it did reduce the eosinophil count in sputum, Professor Pavord told delegates attending the respiratory insights forum in Melbourne.

Since then, there has been new information that severe asthma is highly heterogeneous, with a marked discordance between symptoms and lung function and airway pathology.

For instance, patients with inflammation might have fewer symptoms but are more prone to exacerbations, while those with symptom-predominant disease have airway dysfunction but no eosinophilic airway inflammation, Professor Pavord explained.

Last year the FDA approved mepolizumab for add-on maintenance treatment of patients with severe asthma.

According to Professor Pavord it was likely that IL-5 would also play a role in eosinophilic COPD and pneumonia.

“We are really treating eosinophilic airways disease rather than asthma or COPD,” he told delegates.

Recent studies of mepolizumab in patients with raised eosinophil counts who were having recurrent exacerbations have been strikingly successful, with the number of asthma exacerbations halved, he said.

The DREAM study found a dose of mepolizumab 75 mg had a pronounced effect on blood eosinophils, and the MENSA study showed clinically important benefits including halving the rate of exacerbations, emergency department attendance and hospitalisation.

Biologic treatment depends on clinical pathology

When biologics are stopped, the first thing to increase is blood eosinophil count, closely followed by sputum eosinophil count and increased asthma exacerbations, indicating that there is no evidence biologic treatment is disease modifying, Professor Pavord said.

“If you are going to give mepolizumab to symptomatic patients, you will treat the group who don’t have the pathology that the drug treats. We need to look at mepolizumab on the basis of clinical pathology and understand the likely outcome would be a reduced risk of exacerbations,” he said.

Other biologics under investigation include IL-5 blockers such as reslizumab and tenralizumab, which both have broadly similar effects to mepolizumab, Professor Pavord said.

Benralizamab achieved much greater reductions in circulating blood eosinophil count, the clinical relevance of which was unclear, but may offer an alternative to prednisolone in the future, he added.

Studies into blocking IL-13 with lebrikizumab and tralokinumab in severe asthma have been disappointing, but a combined blockade of IL-4 and IL-13 with the IL-4Rα blocker dupilumab looked more promising, with clinically important beneficial effects in atopic dermatitis and nasal polyposis.

Unfamiliar biomarkers

Professor Pavord said the optimal use of biological agents would mean respiratory physicians would have to get used to measuring some unfamiliar biomarkers.

For example, FeNO (fraction of exhaled nitric oxide) is an excellent predictor of IL-4 and IL-13 activity, while blood eosinophil count is a biomarker of IL-5 response. However, IgE is a poor biomarker of clinical response to biologic agents.

While there was not enough information of the optimum duration of treatment or the long-term effects, it appeared that biologics could potentially be useful in both asthma and COPD, he said.

“We have got to think differently – it’s like lowering cholesterol and blood pressure, there shouldn’t be an expectation that reduced eosinophil airway inflammation will reduce symptoms, but there will still be clinically important risk reductions.”

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