Study: Asthma Patients on Benralizumab Can Reduce ICS Use Without Losing Asthma Control

In patients with severe eosinophilic asthma, treatment with the biologic benralizumab was associated with significant reductions in inhaled corticosteroid use in the phase IV, multicenter, open-label SHAMAL study.

Patients randomized to the ICS reduction arm of the study were exposed to less than a third of the total amount of cumulative ICS doses than patients in the usual ICS use group.

But reducing ICS use to as-needed was also associated with significant lung function declines, as measured by forced expiratory volume in 1 second (FEV₁), which was "weakly correlated" with a change in fractional exhaled nitric oxide (FeNO).

"The data further cement the central role of eosinophils in exacerbation pathogenesis and symptom control; however, the relationship between the decline in lung function and increase in FeNO concentration in those reducing regular ICS suggest this might be an eosinophil-independent, IL-13-driven process," wrote SHAMAL researcher David J. Jackson, PhD, of King’s College London, and colleagues. "Although we were unable to further delineate sub-phenotypes of severe eosinophilic asthma, these results favor the continuation of low-dose ICS in patients for whom combined assessments of changed in FEV₁ and FeNO concentration suggest an increased risk of lung function decline."

Benralizumab is an anti-IL-5 receptor α monoclonal antibody that "induces direct, rapid and nearly complete depletion of eosinophils through antibody-dependent cell-mediated toxicity." In randomized trials, treatment with benralizumab has been shown to reduce asthma exacerbations and oral corticosteroid use in patients with severe eosinophilic asthma.

"The fact that these patients appeared largely unresponsive to high-dose ICS suggests that lower-dose ICS might be sufficient in patients responding well to benralizumab therapy," the researchers wrote, adding that the high morbidity associated with high-dose, long-term ICS use makes the question particularly relevant.

The goal of the SHAMAL study, conducted at 22 treatment sites in France, Germany, Italy, and the United Kingdom, was to assess the potential for severe eosinophilic asthma patients who respond to treatment with benralizumab to reduce their ICS-formoterol maintenance regimen to the smallest dose necessary to maintain asthma control.

Eligible participants included adults (age ≥18 years) with severe eosinophilic asthma and a five-item Asthma Control Questionnaire score below 1.5 and who had been treated with at least three consecutive doses of benralizumab before screening. Patients were randomly assigned (3:1) to taper their high-dose ICS to a medium-dose, low-dose, and as-needed dose (reduction group) or continue (reference group) their ICS–formoterol therapy for 32 weeks, followed by a 16-week maintenance period.

The primary endpoint was the proportion of patients reducing their ICS–formoterol dose by week 32. The primary outcome was assessed in the reduction group, and safety analyses included all randomly assigned patients receiving study treatment.

Between late 2019 and early 2023, 208 patients were screened and 168 were randomized to the reduction (n=125, 74%) and reference (n=43, 26%) arms of the study. Among the main findings:

• A total of 110 (92%) patients in the reduction arm reduced their ICS–formoterol dose: 18 (15%) to medium-dose, 20 (17%) to low-dose, and 72 (61%) to as-needed only and reductions were maintained to week 48 in 113 (96%) patients.
• A total of 114 (91%) of patients in the reduction group had zero exacerbations during tapering.
• The least squares (LS) mean change from baseline in pre-bronchodilator FEV₁ at the end of the study was –88.9 mL (SE 27.2) in the reduction group and 5.9 mL (47.5) in the reference group. The mean change in FEV₁ between week 32 and week 48 was 9 mL (SD 232) in the reduction group and 4 mL (226) in the reference group.
• The LS mean changes in FeNO concentrations by the end of the study were 22.92 ppb (3.33) in the reduction group and 3.41 ppb (5.72) in the reference group.

In post hoc analysis involving a group stratified by ICS-formoterol dose at week 32, patients who reduced their ICS use to reliever only had the largest LS mean change from baseline in FEV₁ (–146.7 mL [34.6]) and FeNO concentrations (31.99 ppb [4.09]) by week 48. Changes in other groups were characterized by the researchers as modest.

Rates of adverse events were similar between groups, with 73% of patients experiencing adverse events in the reduction group, compared to 83% in the reference group. Twelve patients in the reduction group (10%) and five (12%) in the reference group experienced serious adverse events.

In an editorial published with the study, Jennifer Quint, MSc, PhD, and Pallav Shah, MD, of Imperial College London wrote that while the SHAMAL study had many strengths, the emphasis on symptom control as the key outcome complicated interpretation of the findings.

"Although this study concluded that people prescribed benralizumab might not need concomitant ICS to reduce exacerbations or maintain symptom control, in reducing the ICS dose FEV₁ declined and FeNO increased; what the trial does not address are possible long-term consequences of this," the editorial writers noted.

"Regular ICS use might control an interleukin-13 mediated process that leads to loss of lung function and the dose needed to do this might be different to the dose needed to control exacerbations and symptoms," Quint and Shah wrote. "As the authors acknowledge, using symptoms as was done in the trial might not be an appropriate way to guide ICS–formoterol dose reduction, and more objective markers could be more useful. Furthermore, the open-label design of the study is susceptible to bias."

Limiting the study population to patients who had responded well to benralizumab was cited by the researchers as a study limitation, limiting generalizability to other patients with severe eosinophilic asthma. The study was also conducted during the Covid-19 pandemic, and pandemic lock downs may have contributed to the low incidence of annualized exacerbations.

This research was funded by AstraZeneca.

Jackson reported receiving advisory board and speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, and Sanofi. Researcher Stephanie Korn reported receiving grants and personal fees for lectures and advisory boards from AstraZeneca, GSK, Novartis, Sanofi- Genzyme, and Teva.

Quint reported receiving grants from the Industrial Strategy Challenge Fund, the Medical Research Council, Health Data Research, GSK, Boehringer Ingelheim, Asthma + Lung UK, and AstraZeneca, and has received personal fees for advisory board participation, consultancy, or speaking fees from GlaxoSmithKline, Evidera, Chiesi, AstraZeneca, and Insmed, unrelated to the topic of this editorial.

Shah reported no disclosures.

Jackson DJ, et al "Reduction of daily maintenance inhaled corticosteroids in patients with severe eosinophilic asthma treated with benralizumab (SHAMAL): a randomized, multicenter, open-label, phase IV study" Lancet 2024; DOI: 10.1016/S0140-6736(23)002284-5.

Quint JK, Shah PI "What trials do and do not tell us about treatment for severe asthma" Lancet 2024; DOI: 10.1016/S0140-6736(23)02409-1.