Benralizumab reduces flare events in patients with hypereosinophilic syndrome

Treatment with benralizumab is associated with a significantly lower risk of flares in patients with hypereosinophilic syndrome (HES) than with placebo, according to the NATRON study presented at ASH 2025.

“HES can be life-threatening, and the approved therapeutic options are limited to imatinib and mepolizumab, but neither is effective in all cases,” said study author Dr Amy Klion from the National Institutes of Health in Bethesda, Maryland, US.

Hence, Klion and her team sought to assess the efficacy and safety of benralizumab, an anti-interleukin-5 receptor alpha monoclonal antibody, in patients with HES receiving background therapy.

This phase III, multicentre, double-blind, placebo-controlled trial involved 133 patients (median age 51 years, 61.7 percent female) with HES to receive either subcutaneous benralizumab 30 mg (n=67) or placebo (n=66) every 4 weeks for 24 weeks, in addition to background HES therapy.

By week 24, benralizumab treatment significantly reduced the risk of HES flares by 65 percent compared with placebo (hazard ratio [HR], 0.35; p=0.0024), with 13 vs 28 flare events, respectively. [ASH 2025, abstract 79]

“There was a statistically significant reduction in both the risk of and delay in time to first HES flare with benralizumab vs placebo,” said Klion.

As a result, significantly fewer patients on benralizumab experienced a flare or withdrew during the 24-week treatment period than those on placebo (22.4 percent vs 45.5 percent; odds ratio [OR], 0.31; p=0.0033).

Patients receiving benralizumab also had a significantly lower annualized flare rate (0.41 vs 1.23 flares per year; rate ratio [RR], 0.34; p=0.0008) and a reduced risk of haematologic relapse (5 vs 39 events; HR, 0.08; p<0.0001) compared with those receiving placebo.

Significant reductions in PROMIS Fatigue scores were observed with benralizumab as early as week 4, and these reductions persisted through week 24 (least squares mean difference, -4.72; p=0.0017) compared with placebo. “It is always fatigue that people complain most about, but only a few studies have been able to show, or none have been able to demonstrate a reduction in fatigue severity,” Klion noted.

Safety endpoints

Adverse events (AEs) occurred in 64.2 percent of patients in the benralizumab group vs 66.7 percent in the placebo group, with headache (16.4 percent vs 7.6 percent), upper respiratory tract infection (7.5 percent vs 7.6 percent), and COVID-19 (6 percent vs 6.1 percent) being the most frequently reported AEs.

The incidence of serious AEs was comparable between the benralizumab and placebo groups (7.5 percent vs 7.6 percent). Although one death occurred in the benralizumab group, Klion stated that it was due to sepsis and unrelated to the study drug.

Safety results were consistent with the known safety profile of benralizumab, noted Klion.

“Overall, the addition of benralizumab to background therapy led to significant reductions in the risk of HES flares, the proportion of patients with HES flares, annualized flare rate, and the risk of haematologic relapse compared with placebo,” Klion concluded.

"These results support targeting eosinophils as a therapeutic strategy and demonstrate the clinical benefit of benralizumab in patients with HES," she added.