Eosinophilic asthma: From molecular signature to biologic treatment

Eosinophilic asthma, a common phenotype of severe asthma, is characterized by elevated blood eosinophil count (BEC) and is often associated with poor outcomes. At the Annual Scientific Meeting 2023 of the Hong Kong Thoracic Society and CHEST Delegation Hong Kong and Macau, Professor Ratko Djukanović of University of Southampton, UK, and Professor Kian-Fan Chung of Imperial College London, UK, shared insights into the molecular signature of eosinophilic asthma and discussed clinical evidence supporting the efficacy of add-on biologic treatments, such as mepolizumab, for severe eosinophilic asthma (SEA) and other airway disorders.

Significance of BEC in eosinophilic asthma
Eosinophilic asthma, characterized by increased BEC, is a common phenotype of severe asthma and is driven by type 2 (T2) inflammation. The C-BIOPRED cohort study in China (n=645) revealed that 38.4 percent of severe asthma patients had an eosinophilic phenotype, as defined by BEC ≥300 cells/μL. [Chest 2021;160:814-830; Clin Transl Med 2022;12:e710]

Increased BEC is associated with poor asthma outcomes. In a UK cohort study, asthma patients with BEC >400 cells/μL (n=20,929) were more likely to experience severe exacerbations (adjusted rate ratio [RR], 1.42; 95 percent confidence interval [CI], 1.36–1.47; p<0.0001) and less likely to achieve asthma control (adjusted odds ratio [OR], 0.74; 95 percent CI, 0.72–0.77; p<0.0001) than patients with BEC ≤400 cells/μL (n=109,319). When stratified according to baseline BEC, patients in ascending categories of BEC showed higher severe exacerbation risks and worse overall asthma control vs the reference BEC of ≤200 cells/μL. (Figure 1) [Lancet Respir Med 2015;3:849-858]

Targeting eosinophilia can be an effective strategy for managing SEA. A clinical study showed significantly reduced severe asthma exacerbations with management based on sputum eosinophil count vs symptom assessment (35 events vs 109 events; p=0.01) in patients with moderate-to-severe asthma treated with bronchodilators ± corticosteroids. [Lancet 2002;360:1715-1721]

“While patients with eosinophilic asthma often respond well to oral corticosteroids [OCS], some may experience persistent symptoms despite OCS,” pointed out Djukanović. [ERJ Open Res 2016;2:00100-2015; Respir Med 2014;108:1723-1732]

Molecular signatures of asthma with eosinophilic endotype
“The relationship between molecular mechanism of asthma and treatment responses [including asthma exacerbations] remains unclear. To gain better understanding of asthma endotypes, we analyzed and compared transcriptome profiles of sputum cells from moderate-to-severe asthma patients and healthy individuals,” Chung said.

Using unbiased hierarchical clustering, Chung and colleagues defined three transcriptome-associated clusters with distinct signatures. The TAC1 cluster was characterized by upregulation of eosinophil-related genes, including IL-33R, TSLPR and CCR3, with specific SEA and T2-high features, namely, severe airflow obstruction, nasal polyps, frequent asthma exacerbations, and high OCS dependency. [Eur Respir J 2017;49:1602135]

“Given the T2-high features, patients with the SEA endotype can be treated with anti–interleukin 5 [anti–IL-5] agents,” suggested Chung. [Curr Opinion Pulm Med 2018;24:4-10]

Role of mepolizumab in SEA treatment
According to guidelines of the European Respiratory Society (ERS)/American Thoracic Society (ATS), add-on anti–IL-5 treatment (eg, mepolizumab) is recommended for adults with severe uncontrolled asthma and eosinophilia, and for those with severe corticosteroid-dependent asthma (conditional recommendation). [Eur Respir J 2020;55:19]

Asthma exacerbations
In the meta-analysis featured in ERS/ATS guidelines, mepolizumab demonstrated a 50 percent reduction in the annualized rate of any exacerbations vs placebo (0.92 vs 1.69 events/patient/year; RR, 0.50; 95 percent CI, 0.39–0.65). [Eur Respir J 2020;55:19]

Mepolizumab also demonstrated greater reductions in annualized rate of exacerbations (ARE) in patients with higher baseline BEC. In the previously mentioned meta-analysis, ARE reduction with mepolizumab vs placebo was 53 percent at baseline BEC ≥150 cells/μL, and 73 percent at baseline BEC ≥500 cells/μL. On the other hand, anti–IL-5 receptor alpha treatment with benralizumab reduced ARE vs placebo by 29 percent at baseline BEC <300 cells/μL and by 41 percent at baseline BEC ≥300 cells/μL. (Figure 2)

Maintenance OCS dose reduction
The OCS-sparing effect of mepolizumab was shown in a post hoc analysis of REALITI-A, a single-arm, international, real-world study of 320 patients receiving maintenance OCS (mOCS; median dose, 10 mg/day) at baseline. After 1 year of mepolizumab treatment, median daily dose of mOCS was reduced by 75 percent, and the reduction went further down to 100 percent in weeks 81–104. At 2 years, 57 percent of patients (n=95/168) discontinued mOCS entirely. [Pollard S, et al, ACAAI ASM 2022, poster P103]

“Mepolizumab treatment may take some time to reach its full effect, and median doses of mOCS may continue to reduce after mepolizumab initiation. Therefore, instead of hastily switching to other biologics in intermediate responders, we should discuss with the patients the option of continuing treatment for a year [before assessing treatment response],” Djukanović advised. [Pollard S, et al, ACAAI ASM 2022, poster P103; Eur Respir J 2017;49]

Clinical remission
“Mepolizumab treatment may lead to clinical remission in SEA patients, as demonstrated by [a post hoc analysis of] the single-arm, multicentre, real-world REDES study [n=318],” remarked Chung. “In the analysis, data for 4-component remission [ie, free of exacerbation or OCS, an Asthma Control Test (ACT) score of ≥20 and a forced expiratory volume in 1 second (FEV₁) of ≥80 percent] was available in 45 percent of SEA patients. After 1 year of mepolizumab, 30 percent of these patients achieved 4-component clinical remission, 38 percent were exacerbation-free and OCS-free with an ACT score ≥20, while 45 percent were exacerbation-free and OCS-free.” (Figure 3) [Front Immunol 2023;14:1150162]

Effect on residual eosinophils
“Mepolizumab has minimal effects on the transcriptome profile of residual eosinophils in SEA patients,” Djukanović highlighted. [Eur Respir J 2022;59:2100935]

A study evaluated the effect of mepolizumab on residual eosinophils by comparing blood eosinophils from SEA patients receiving mepolizumab or anti–immunoglobulin E therapy (ie, omalizumab) for ≥6 months and healthy individuals. Results revealed comparable transcriptome profiles of eosinophils in the three groups of participants and did not identify gene clustering or differentially expressed genes. Upon activation with IL-33, only 14 genes were differentially regulated in eosinophils from patients on mepolizumab or omalizumab. These findings suggest that mepolizumab treatment may spare residual eosinophils and allow gene expression that is generally similar to that of healthy individuals.

Safety
In REDES, mepolizumab showed a low rate of treatment-related adverse events (TRAEs). During the 1-year study, TRAE rate was 2.8 percent, while severe adverse events (SAEs) were not reported. [Drugs 2021;81:1763-1774] In REALITI-A, the 2-year rates of TRAEs and SAEs were 11 percent and <1 percent, respectively. No unexpected safety signals were identified. [Pollard S, et al, ACAAI ASM 2022, poster P103]

Mepolizumab in CRSwNP and EGPA
In addition to SEA, mepolizumab is indicated for treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) and eosinophilic granulomatosis with polyangiitis (EGPA). [Nucala Hong Kong Prescribing Information]

In the phase III SYNAPSE study involving 407 CRSwNP patients, mepolizumab significantly improved endoscopic nasal polyp score at week 52 (adjusted difference in medians, -0.73; 95 percent CI, -1.11 to -0.34; p<0.0001) as well as nasal obstruction (adjusted difference in medians, -3.14; 95 percent CI, -4.09 to -2.18; p<0.0001), and significantly reduced the need for nasal surgery (hazard ratio, 0.43; 95 percent CI, 0.25–0.76; p=0.0032) vs placebo. [Lancet Respir Med 2021;9:1141-1153]

In the 1-year phase III MIRRA study (n=136), a significantly greater proportion of EGPA patients on mepolizumab vs placebo achieved ≥24 weeks of accrued remission (OR, 5.91; 95 percent CI, 2.68–13.03; p<0.001) as well as remission at both 36 and 48 weeks (OR, 16.74; 95 percent CI, 3.61–77.56; p<0.001). The annualized rate of relapse was significantly reduced with mepolizumab vs placebo (OR, 0.50; 95 percent CI, 0.36–0.70; p<0.001). [N Engl J Med 2017;376:1921-1932]