Efficacy and safety of benralizumab in patients with hypereosinophilic syndrome: Results from the Phase 3 natron study

Abstract

Abstract Background: Hypereosinophilic syndrome (HES) is a group of rare, heterogeneous disorders characterized by persistent hypereosinophilia and eosinophil-mediated end-organ damage. Benralizumab, an anti-IL-5 receptor α antibody, causes rapid, near-complete depletion of eosinophils and has demonstrated efficacy in severe asthma and eosinophilic granulomatosis with polyangiitis and promising results in a phase 2 trial in patients (pts) with HES. Methods: NATRON (NCT04191304) is a phase 3, multicenter, randomized, double-blind, placebo (PBO)-controlled study evaluating the efficacy and safety of benralizumab in pts with HES. Eligibility criteria included age ≥12 years, FIP1L1::PDGFRA-negative, absolute eosinophil count [AEC] ≥1x109/L at screening, signs/symptoms of HES flares at Visit 1 or history of ≥2 HES flares within 12 months before enrollment, and a stable treatment regimen ≥4 weeks before randomization. After confirmation of corticosteroid responsiveness (AEC <1x109/L after 2 days of oral corticosteroid [OCS; prednisone/prednisolone] 1 mg/kg/day in addition to background therapy), pts were randomized (1:1) to benralizumab (30 mg) or PBO every 4 weeks for 24 weeks, in addition to background HES therapy. The primary endpoint was time to first HES flare. Key secondary endpoints included the proportion of pts with HES flares, annualized rate of HES flares, time to first hematological relapse (AEC ≥1x109/L), and change from baseline to Week 24 in PROMIS Fatigue scores. Other secondary endpoints included the proportion with hematologic relapse, proportion with sustained AEC <0.5x109/L for 24 weeks, proportion requiring an increase in OCS dose, as well as safety. Results: A total of 133 pts (median [range] age 51 [14–87] years; 61.7% female) were randomized to benralizumab (n=67) or PBO (n=66). Most (100; 75.2%) had idiopathic HES (n=49 [benralizumab] and n=51 [PBO]). Five pts in the benralizumab arm and 11 in the PBO arm had lymphocytic HES. The median number of HES flares in the prior 12 months was 2 in both arms. At baseline, fatigue was the most commonly reported bothersome symptom (52 [39.1%] pts). Most pts (102; 76.7%) were receiving background systemic OCS, and 11 (8.3%) were receiving background cytotoxic/immunosuppressive therapy. Median (range) background OCS dose at baseline was 5.0 (0.0–30.0) mg/day. There was a statistically significant reduction in risk of and delay in time to first HES flare with benralizumab vs PBO (HR: 0.35; 95% CI: 0.18, 0.69; P=0.0024). The proportion of pts who experienced a HES flare or withdrew from the study was 22.4% in the benralizumab arm and 45.5% in the PBO arm (OR: 0.31; 95% CI: 0.14, 0.69; P=0.0033). Treatment with benralizumab resulted in a lower annualized rate of HES flares vs PBO: 0.41 vs 1.23 flares per year, respectively (RR: 0.34; 95% CI: 0.18, 0.63; P=0.0008). Time to first hematologic relapse was delayed for pts on benralizumab vs PBO (HR: 0.08; 95% CI: 0.03, 0.20; P<0.0001). Significant improvements in fatigue severity with benralizumab vs PBO were observed by Week 4 and persisted to Week 24 (Week 24 least squares mean difference: –4.72; 95% CI: –7.64, –1.80; P=0.0017). Fewer pts experienced hematologic relapse or withdrew from the study with benralizumab compared with PBO: 6 (9.0%) vs 42 (63.6%), respectively (OR: 0.05; 95% CI: 0.02, 0.13; P<0.0001). The proportion with AEC <0.5x109/L for 24 weeks was 61 (91.0%) in the benralizumab arm and 8 (12.1%) in the PBO arm (OR: 87.87; 95% CI: 26.09, 295.97; P<0.0001). Overall, 17 (25.4%) pts in the benralizumab arm and 32 (48.5%) in the PBO arm required an increase in OCS dose (OR: 0.35; 95% CI: 0.16, 0.73; P=0.005). Adverse events (AE) were experienced by 43 (64.2%) and 44 (66.7%) pts in the benralizumab and PBO arms respectively; most commonly headache (11 [16.4%] and 5 [7.6%]) and upper respiratory tract infection (5 [7.5%] and 5 [7.6%]). Five (7.5%) benralizumab and 5 (7.6%) PBO pts experienced a serious AE, with one death in the benralizumab arm due to sepsis, considered unrelated to treatment by the investigator. Conclusion: The addition of benralizumab to background therapy significantly reduced the risk of flares and of hematologic relapse, and improved fatigue compared to PBO. Benralizumab tolerability was consistent with its known safety profile, including in adolescents. These results demonstrate the clinical and biological efficacy of benralizumab in pts with HES.