Benralizumab Led to Histologic Responses in Eosinophilic Esophagitis

More patients with eosinophilic esophagitis experienced a histologic response with benralizumab (Fasenra) compared with placebo, despite similar levels of continuing symptoms in the two groups at 24 weeks, the phase III randomized MESSINA trial showed.

Among 211 patients ages 12 to 65 years, 87.4% of those receiving benralizumab had a histologic response — defined as at least six eosinophils per high-power field — compared with 6.5% of patients receiving placebo (P<0.001), reported Marc E. Rothenberg, MD, PhD, of Cincinnati Children’s Hospital Medical Center, and colleagues.

However, there was no significant difference between the two groups in change from baseline scores on the Dysphagia Symptom Questionnaire at week 24 (P=0.18), they wrote in the New England Journal of Medicine.

Treatment with benralizumab also did not improve endoscopic findings. “Whereas benralizumab depleted both tissue and blood eosinophils, as expected, and heterogeneity may exist among patients with eosinophilic esophagitis, we were unable to identify a subgroup of patients who appeared to benefit symptomatically,” the researchers noted. Even at week 52, symptoms had not significantly decreased in those receiving benralizumab.

“This trial calls into question the clinical relevance of monitoring eosinophilic esophagitis for treatment effect solely on the basis of the degree of eosinophilic inflammation,” Rothenberg and colleagues concluded. “Future therapeutic strategies may involve broader targets or those higher upstream in pathogenic pathways.”

Incidence of eosinophilic esophagitis has rapidly increased in recent years, but only two treatments — budesonide oral suspension (Eohilia) and the monoclonal antibody dupilumab (Dupixent) — have been approved by the FDA.

A phase III trial on dupilumab in kids ages 1 to 11 years, presented at last year’s American College of Gastroenterology annual meeting and also published in the New England Journal of Medicine, showed improvements not only in histology, but also in symptoms, endoscopic findings, gene expression, and other secondary endpoints.

Even though the disease is defined by a presence of eosinophils in the esophagus (a peak of at least 15 eosinophils per high-power field), previous clinical trials have suggested that strategies targeting eosinophils do not reduce symptoms, noted Benjamin L. Wright, MD, of the Mayo Clinic Arizona in Scottsdale and Phoenix Children’s Hospital, in an accompanying editorial.

“The discordance between symptoms and eosinophil counts has driven efforts to identify additional biomarkers of disease activity,” he wrote. The success of the dupilumab trial confirmed “the importance of interleukin-13, and possibly interleukin-4, signaling in eosinophilic esophagitis,” but it left several crucial questions remaining, including why a third of patients did not respond to the drug.

Nevertheless, “together, these trials provide exciting advances in our understanding of, and treatment options for, this increasingly common and perplexing disease,” he concluded.

MESSINA enrolled 211 patients from 78 sites across 12 countries and included a 2- to 8-week run-in period followed by a 24-week double-blind treatment period and then a 28-week open-label treatment period, plus an optional extension.

The patients all had symptomatic and histologically active eosinophilic esophagitis, with at least 15 eosinophils per high-power field. Median age was 33.7, 13.3% were younger than 18, 74.8% were male, and 93.2% were white.

Patients could take other medications for eosinophilic esophagitis as long as they had been receiving a stable dose for at least 4 weeks before the run-in period and met other trial criteria.

Of the patients, 104 received 30 mg of subcutaneous benralizumab every 4 weeks and 107 received a placebo. Two people in each arm discontinued the trial before 24 weeks, and all but one entered the open-label period that extended to 52 weeks.

None of the secondary endpoints, including change in abdominal pain and nausea, and change from baseline in tissue eosinophil count and in the Eosinophilic Esophagitis Histology Scoring System and the Eosinophilic Esophagitis Endoscopic Reference Score, significantly differed between the benralizumab and placebo groups at 24 or 52 weeks.

Reporting of adverse events was similar in both groups, occurring in 64.1% of patients receiving benralizumab and 61.7% of patients receiving placebo. No patients discontinued participation due to adverse events.

Common adverse events among the benralizumab and placebo groups included COVID-19 (12.6% and 12.1%), headache (8.7% and 10.3%), nasopharyngitis (7.8% and 5.6%), and asthma (3.9% and 3.7%), among others. Serious adverse events, including asthma, bronchospasm, and pneumonia, occurred in 1.9% and 0.9% of the two groups, respectively.

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