Gene panel predicts response to mepolizumab among children with asthma
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Key takeaways:
- High SWAP70 expression predicted the best response.
- High ACER2, low SWAP70 and low TCIRG1 expression indicated a negative response.
- High TCIRG1 and low SWAP70 expression predicted modest to no response.
SAN DIEGO — The relative expressions of three genes associated with the airway predicted mepolizumab response among urban children with asthma, according to a study presented at the American Thoracic Society International Conference.
These biomarkers may enable clinicians to select patients more accurately for biologic therapy that targets eosinophils, Matthew C. Altman, MD, MPhil, MA, head of the allergy section, division of allergy and infectious diseases, University of Washington, and colleagues wrote.
“We basically are in this brave new world where we have these wonderful biologics,” Altman said during his presentation.
Although biomarkers such as blood eosinophils, FeNO and allergic sensitization are useful in identifying patients who may respond to a given biologic, he continued, they do not do a very good job in predicting the patient’s response.
“Our question was whether we can use these rationally designed biologics to better understand and predict mechanisms of treatment response or failure towards the goal of better biomarkers and more precise treatment selection and ultimately to identify new treatment approaches for those who don’t respond,” Altman said.
The MUPPITS-2 study included 290 urban and disadvantaged children aged 6 to 17 years with relatively severe disease, including exacerbation-prone asthma and eosinophil counts of 150 or higher per microliter.
“They all have two or more exacerbations in the prior year and elevated blood eosinophils,” Altman said. “By our current biomarkers, they should all be responsive to mepolizumab.”
Patients received guideline-based asthma care in addition to placebo or mepolizumab (Nucala, GSK) for 52 weeks.
“The clinical question was, does the drug work? Does it reduce exacerbations?” Altman said.
Annualized rates of asthma exacerbations treated with systemic corticosteroids included 0.96 (95% CI, 0.78-1.17) for the mepolizumab group and 1.3 (95% CI, 1.08-1.57) for the placebo group for a rate ratio of 0.73 (95% CI, 0.56-0.96; P = .027).
Although Altman said mepolizumab significantly reduced exacerbation rates in the treatment group, he added that it was less effective compared with its use in adult populations.
“Then the mechanistic question was, what are the reasons why some people respond and others don’t, and can we actually use that towards prediction?” he continued.
The researchers also collected nasal lavage samples from 249 patients for RNA sequencing and for modular and gene level analysis of baseline airway inflammation patterns.
“We’re using a lavage to get a cell infiltrate of epithelium and immune cells and to get cell differential information,” Altman said. “Of course, we have the conventional markers of FeNO and blood eosinophils with which we can compare these omics level data.”
Least absolute shrinkage and selection operator analysis found 20 genes in the patients who provided nasal lavage samples that predicted exacerbation rates. Three of these genes enabled classification of patients by positive, negative or no response to mepolizumab.
These genes included SWAP70, which is associated with eosinophils; TCIRG1, which is associated with neutrophils; and ACER2, with is associated with the epithelium.
A subgroup of 30 patients with the highest levels of SWAP70 expression had the best response to mepolizumab treatment (rate ratio = 0.18; 95% CI, 0.08-0.41).
“Those individuals are really the ones most in need of this therapeutic,” Altman said. “They have a very high rate of exacerbations in the absence of treatment.”
Another subgroup of 33 patients with relatively high ACER2 expression and low SWAP70 and TCIRG1 expressions had increased exacerbations despite treatment with mepolizumab (rate ratio = 1.88; 95% CI, 1.05-1.88).
A third subgroup of patients with relatively high TCIRG1 expression and low SWAP70 expression had low exacerbation rates and modest to no mepolizumab response, the researchers said.
Cross-validation and bootstrapping indicated that the predictive accuracy of these results not only was robust, the researchers said, but also exceeded the predictive accuracies of demographic variables, pulmonary functions and blood cell counts, which were not significant.
“It gives us a robust way to partition this population into responders and non-responders,” Altman said.
Based on these findings, the researchers said that this small panel of genes associated with the airway can accurately predict whether urban children with eosinophilic asthma prone to exacerbations will respond to mepolizumab.
“We can accurately predict beneficial and deleterious responses,” Altman said.
Further, the researchers said that validation of these results could provide biomarkers that could be used to more accurately select patients who would respond to biologic therapy that targets eosinophils.