MEX Trial: Asthma Exacerbations With Mepolizumab Have 2 Main Phenotypes

An investigation of exacerbations experienced by patients with severe refractory eosinophilic asthma treated with mepolizumab identified 2 main types of events: noneosinophilic, infection-driven events with low fractional exhaled nitric oxide (FeNO) and high C-reactive protein (CRP), and eosinophilic exacerbations with high FeNO. According to investigators, these findings challenge the routine use of oral corticosteroids (OCS) to treat all asthma exacerbations experienced by patients using mepolizumab. These were among the results of the MEX study (ClinicalTrials.gov Identifier: NCT03324230) that were recently published in The Lancet Respiratory Medicine.

The MEX study, a multicenter, prospective, observational cohort trial, was conducted at 4 UK specialist centers for patients with severe asthma between November 2017 and May 2019. The researchers sought to examine the inflammatory phenotype and physiologic characteristics of exacerbation events in patients with severe eosinophilic asthma who received mepolizumab therapy.

Study participants were treated with mepolizumab 100 mg subcutaneously every 4 weeks, had a scheduled study visit after 3 or months of treatment, completed symptom study diaries, measured their daily peak flow, and visited or contacted their study center for evaluation prior to taking rescue treatment in the event of an exacerbation.

The clinical endpoint was 100 clinical assessments at exacerbation completed across all sites for participants receiving mepolizumab prior to initiation of rescue therapy. Researchers compared characteristics of participants who experienced exacerbations vs those who did not. Further, participants’ peak flow and symptom diaries were compared with respect to evaluated vs missed exacerbations. Exacerbation phenotypes that were defined by sputum eosinophil counts were compared as well. The utility of CRP and FeNO in establishing exacerbation phenotype while on mepolizumab therapy was also assessed.

Among the 140 participants included in the analysis, there were 172 reported exacerbations, with 96 of these events evaluated prior to the initiation of rescue treatment. Notably, patients experiencing exacerbations reported more emergency department visits and higher exacerbation rates in the year prior to beginning mepolizumab therapy. 

Investigators determined that FeNO (≤20 or ≥50 ppb) was the most useful indicator for identifying inflammatory phenotype at exacerbation. Comparison of exacerbations with a high sputum eosinophil count (SE^HIGH; ≥2%) vs exacerbations with a low sputum eosinophil count (SE^LOW; <2%) revealed that SE^HIGH exacerbations were FeNO-high (P =.0004), with significantly lower forced expiratory volume in 1 second (FEV₁) percent predicted (P =.0075), significantly lower FEV₁ to forced vital capacity ratio (P =.0043), and significantly higher blood eosinophil counts (P =.0009). In contrast, SE^LOW exacerbations had significantly higher CRP concentrations (P <.0001), significantly higher sputum neutrophil counts (P <.0001), and were significantly more likely to undergo treatment with antibiotics (P =.031).

The change in peak expiratory flow at nadir in the evaluated exacerbation group vs the missed exacerbation group was mean –40.5 L/min vs mean –37.0 L/min, respectively; P =.84, with no difference observed in reported symptom burden. Hospital admission due to asthma exacerbation was the most frequently reported adverse event.

The investigators concluded that the findings from the MEX study “challenge the routine use of oral corticosteroids for asthma exacerbations on mepolizumab,” as well as the practice of switching biologics in response to treatment failure without profiling the inflammatory phenotype of the patient’s ongoing asthma exacerbations. Further studies are needed to evaluate whether differentiating inflammatory phenotype at assessment of exacerbation will help guide management… [and] to assess whether more eosinophil-depleting biological agents…predispose patients to infection-related neutrophilic events.”

Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

Reference

McDowell PJ, Diver S, Yang F, et al; Medical Research Council: Refractory Asthma Stratification Programme-UK Consortium . The inflammatory profile of exacerbations in patients with severe refractory eosinophilic asthma receiving mepolizumab (the MEX study): a prospective observational study. Lancet Respir Med. 2021;9(10):1174-1184. doi:10.1016/S2213-2600(21)00004-7