Background
Phase 3 NATRON, randomized, double-blind, placebo-controlled. N=133 FIP1L1::PDGFRA-negative hypereosinophilic syndrome (median age 51, 62% female) on stable background therapy. Benralizumab = eosinophil-depleting anti-IL-5Rα mAb (ADCC-mediated), established in eosinophilic asthma and EGPA.
Results
Interventions and follow up: Arm A: benralizumab 30 mg SC q4w, add-on to background therapy
Arm B: placebo SC q4w, add-on
Primary endpoint: time to first HES flare
mFollow up: 24-week randomized treatment period
Results: Time to first flare: HR 0.35 (95% CI 0.18–0.69), P=.0024 — 65% reduction in flare risk
OS: NR (not a survival trial)
Arm B: placebo SC q4w, add-on
Primary endpoint: time to first HES flare
mFollow up: 24-week randomized treatment period
Results: Time to first flare: HR 0.35 (95% CI 0.18–0.69), P=.0024 — 65% reduction in flare risk
OS: NR (not a survival trial)
Adverse events
Any AE: 64.2% vs 66.7%
Safety profile: consistent with known benralizumab profile; no new signals
Safety profile: consistent with known benralizumab profile; no new signals
Conclusions
Add-on benralizumab significantly reduced HES flares vs placebo with placebo-like tolerability. Establishes IL-5Rα blockade as an effective steroid-sparing strategy in PDGFRA-negative HES.
Key Limitations
Short 24-week blinded period; flare endpoint partly driven by protocolized steroid tapering. FIP1L1::PDGFRA-positive (imatinib-responsive) disease excluded. No head-to-head vs mepolizumab; long-term durability and steroid-sparing magnitude need extension data.
Clinical Context
FDA approved benralizumab (Fasenra) for HES age ≥12 in May 2026 on NATRON — joining mepolizumab (anti-IL-5, approved 2020) as biologic options for PDGFRA-negative HES. Imatinib remains standard for PDGFRA-rearranged disease; steroids remain first-line for most others.