Efficacy ans safety of mepolizumab in hypereosinophilic syndrome: a Phase III, randomized, placebo-controlled trial

Rationale: The anti-interleukin-5 monoclonal antibody, mepolizumab, reduces blood eosinophil counts (BEC) and oral corticosteroid (OCS) use in patients with hypereosinophilic syndrome (HES). We investigated the efficacy and safety of mepolizumab in patients with HES.

Methods: A randomized, placebo-controlled, double-blind, parallel-group, multicenter, Phase III trial. Eligible patients were ≥ 12 years old, diagnosed with HES ≥ 6 months and had ≥ 2 flares (worsening of HES-related clinical symptoms or BEC requiring therapy escalation) in the previous 12 months, with a BEC ≥ 1000 cells/µL and ≥ 4 weeks stable doses of HES therapy at screening. Patients were randomized (1 : 1) to receive s. c. mepolizumab (300 mg) or placebo, plus their baseline HES therapy every 4 weeks for 32 weeks. Investigators were blinded to patient BEC and rescue OCS therapy. Primary outcome was the proportion of patients who experienced a flare during the study. Flares defined as: (a) HES-related clinical manifestations requiring either increased maintenance OCS dose ≥ 10 mg/d for 5 days or increase in or addition of any cytotoxic and/or immunosuppressive therapies (b) ≥ 2 courses of blinded rescue OCS during the study. Withdrawal early from the study was counted as having a flare. Secondary outcomes included annual rates and time to first flare.

Results: The proportion of patients with ≥ 1 flare or who withdrew from the study was 50% lower for mepolizumab vs. placebo (15/54 [28%] and 30/54 [56%]; P = 0.002; odds ratio [95% CI] 0.28 [0.12, 0.64]). Time to first flare was increased with mepolizumab vs. placebo (P = 0.002). The annualized rate of flares and the risk of first flare over the treatment period were both 66% lower with mepolizumab vs. placebo (rate ratio [95% CI] 0.34 [0.19, 0.63], P ≤ 0.001; hazard ratio [95% CI] 0.34 [0.18, 0.67], P = 0.002). Proportions of patients with on-treatment adverse events (AEs) and serious AEs (SAEs) were similar with mepolizumab and placebo (AEs: 48/54 [89%] and 47/54 [87%]; SAEs: 10/54 [19%] and 8/54 [15%]). One fatality (not considered related to study treatment) was reported in the mepolizumab group.

Conclusion: Mepolizumab reduced the occurrence of flares compared with placebo, with no unexpected safety signals. This suggests that patients with relapsing HES may benefit from it.

Tab. 1 Summary of efficacy outcomes.

	Placebo (N = 54)	Mepolizumab 300 mg SC (N = 54)
Primary outcoume
Patients who experienced ≥ 1 flare during the 32-week study period or who withdrew from the study, n (%)	30 (56)	15 (28)
Patients who experienced ≥ 1 flare during the 32-week study period, n (%)	28 (52)	14 (26)
Patients with no HES flare whoe withdrew during the 32-week study period, n (%)	2 (4)	1 (2)
CMH p-value	p = 0.002
Odds ratio (95% CI	0.28 (0.12, 0.64)
Secondary outcome
Time fo first flare
Hazard ratio (95% CI); p value	0.34 (0.18, 0.67); p = 0.002
Rate of flares
Adjusted mean rate of flares per year	1.46	0.50
Rate ratio (95% CI); p value	0.34 (0.19, 0.63); p ≤ 0.001

Publication History

Article published online:
30 April 2021