Benralizumab Decreases Eosinophils, But Not Symptoms, in EoE

Benralizumab, an anti–interleukin-5 receptor alpha monoclonal antibody, was significantly better than placebo at producing a histologic response of up to six eosinophils per high-power field (eos/hpf) in patients with eosinophilic esophagitis (EoE), according to a new randomized study.

At 24 weeks, 80.8% more patients in the benralizumab group had a histologic response than those in the placebo group. However, changes from baseline in dysphagia symptoms and endoscopic abnormalities didn’t differ significantly between the two groups.

“This trial calls into question the clinical relevance of monitoring for treatment effect solely on the basis of the degree of eosinophilic inflammation,” wrote principal investigator Marc Rothenberg, MD, director of allergy and immunology and director of the Cincinnati Center for Eosinophilic Disorders at Cincinnati Children’s Hospital Medical Center in Cincinnati and colleagues from the MESSINA trial.

“These findings support the need for biomarkers other than peak esophageal eosinophil count as an objective end point for therapy for [EoE],” they wrote. 

The study was published online in The New England Journal of Medicine.

Analyzing the MESSINA Trial

Rothenberg and colleagues analyzed benralizumab in a phase 3, double-blind, randomized, placebo-controlled trial of patients aged 12-65 years with symptomatic and histologically active EoE. It was conducted across 78 sites in 12 countries between September 2020 and October 2022. The trial had four periods: A 2-8–week run-in period, a 24-week double-blind treatment period, a 28-week open-label benralizumab treatment period, and an optional open-label extension treatment.

At the initial screening endoscopy, patients had ≥ 15 eos/hpf in centrally read biopsy samples obtained at two or more esophageal levels. Most patients had previously received glucocorticoids and proton pump inhibitors, with > 40% reporting no response in symptoms or histologic features. During the trial, other medications for EoE were allowed as long as the patient received a stable dose for ≥ 4 weeks before the run-in period and met histologic and symptomatic inclusion criteria.

Among 211 patients, 104 received 30 mg of subcutaneous benralizumab every 4 weeks, and 107 received a placebo. The research team looked at two primary endpoints — a histologic response of up to six eos/hpf and changes in dysphagia symptoms based on the Dysphagia Symptom Questionnaire (DSQ).

At week 24, more patients had a histologic response with benralizumab than with the placebo: 87.4% vs 6.5% (P

However, the change from baseline in the DSQ score didn’t differ significantly between the two groups (difference in least-squares means, 3.0 points; P = .18). No prespecified subgroups appeared to show symptomatic benefits.

At week 52, findings were similar to those of week 24 for histologic response, at 83% for benralizumab and 89% for those initially on placebo who switched to benralizumab. DSQ score differences remained nonsignificant at this time point.

In addition, there were no substantial between-group differences in the change from baseline in the EoE Endoscopic Reference Score, which indicates endoscopic abnormalities. There were also no apparent differences in abdominal pain, nausea severity, and health-related quality of life on other questionnaires.

Adverse events were similar between the two groups and reported in 64.1% of patients in the benralizumab group and 61.7% of those in the placebo group. The most common adverse events included COVID-19, headache, and nasopharyngitis. No patients discontinued the trial due to adverse events.

In the end, the open-label period was discontinued early because the between-group difference for dysphagia symptoms wasn’t significant.

“This trial is not the first to suggest a discordance between histologic and symptom response in patients with [EoE],” the authors wrote. “Future therapeutic strategies may involve broader targets or those higher upstream in pathogenic pathways.”

Considering Next Steps

The MESSINA trial raises several questions around the mechanisms behind the symptoms and inflammation seen in EoE, as well as targets for treatment.

“This landmark study confirms that EoE is a disease with a complex pathogenesis that is not simply summarized by eosinophil-driven inflammation alone as it shows that getting rid of eosinophils does not resolve symptoms for everyone,” Fei Li Kuang, MD, assistant professor of medicine in allergy and immunology at the Feinberg School of Medicine, Northwestern University, Chicago, told Medscape Medical News. 

“Indeed, multiple cell types are involved in this disease, which was previously well-appreciated,” she said. “Treatment response varies from person to person, as is true for proton pump inhibitors, topical steroids, dietary elimination therapy, and even the recently US Food and Drug Administration–approved biologic, dupilumab, that targets T cells.”

Even so, Kuang noted the utility of tracking histologic response and eosinophil data as research continued.

“Though eosinophil depletion did not, on average, resolve all symptoms for the patients in this study, the eosinophil cell itself may still play an important role in the disease,” she said. “In other words, don’t throw the baby out with the bath water.” 

The trial was sponsored by AstraZeneca. Several authors reported grants, consultancy fees, and advisory roles for numerous pharmaceutical companies, including AstraZeneca and others that produce anti-eosinophil products. Kuang reported no relevant disclosures. 

Carolyn Crist is a health and medical journalist who reports on the latest studies for Medscape Medical News, MDedge, and WebMD.