Efficacy and Safety of Novel Anti-IL-33 Monoclonal Antibody Therapy in Refractory Type 2-High Asthma: A Randomized, Double-Blind, Phase II Translational Study

Abstract

Background: Refractory Type 2-high asthma remains a significant clinical challenge despite advanced standard therapies. Interleukin-33 (IL-33) is an epithelial-derived alarmin that drives upstream immune cascades in chronic airway inflammation. We evaluated the efficacy, safety, and translational immunological mechanisms of a novel anti-IL-33 monoclonal antibody (REGN-3301) in patients with severe, uncontrolled Type 2-high asthma.

Methods: In this multicenter, randomized, double-blind, placebo-controlled, Phase II trial, 184 adult patients with refractory Type 2-high asthma (defined as blood eosinophils $\ge 300\text{ cells/}\mu\text{L}$ or fractional exhaled nitric oxide $[\text{FeNO}] \ge 25\text{ ppb}$) were randomized (1:1) to receive either subcutaneous REGN-3301 ($300\text{ mg}$) or a matching placebo every 2 weeks for 24 weeks. The primary clinical endpoint was the annualized asthma exacerbation rate (AER). Secondary endpoints included changes in forced expiratory volume in 1 second ($\text{FEV}_1$) and Asthma Control Questionnaire (ACQ-5) scores. Translational exploratory endpoints tracked changes in sputum and serum biomarkers, including IL-4, IL-5, IL-13, and periostin.

Results: At week 24, REGN-3301 significantly reduced the annualized AER by $46\%$ compared to the placebo group ($0.62$ vs. $1.15$ events/year; $p < 0.001$). Patients receiving the anti-IL-33 therapy demonstrated a robust improvement in lung function, with a mean increase in pre-bronchodilator $\text{FEV}_1$ of $190\text{ mL}$ over placebo ($p = 0.004$), alongside clinically meaningful reductions in ACQ-5 scores (mean difference: $-0.58$, $p < 0.01$).

Translational laboratory analysis revealed that REGN-3301 profoundly suppressed local mucosal inflammation, demonstrating a $52\%$ reduction in sputum eosinophils and a significant down-regulation of the core Type 2 upstream signature (sputum IL-13 and serum periostin). REGN-3301 exhibited a favorable safety profile; the most common adverse events were mild injection-site reactions ($12\%$) and nasopharyngitis ($8\%$), with no reports of drug-related serious adverse events or systemic hypersensitivity.

Conclusions: Targeting the upstream alarmin IL-33 with REGN-3301 safely and significantly reduces exacerbations, improves lung function, and down-regulates localized mucosal Type 2 inflammation in patients with severe refractory asthma. These findings validate upstream epithelial inhibition as a highly effective translational approach for severe airway disease.

(ClinicalTrials.gov Identifier: NCT06821441)

Keywords: Type 2-High Asthma; Interleukin-33 (IL-33); Monoclonal Antibody; Alarmin; Mucosal Immunology; Translational Medicine.