Therapeutic blockade of IL-4 and 13 signaling with dupilumab (SAR231893/REGN668) inhibits key biomarkers in asthma

Dupilumab is a potent inhibitor of interleukin (IL) 4 and 13 cytokines implicated in asthma. Moderate-to-severe, persistent asthma patients treated with medium-to-high dose inhaled corticosteroids (ICS) and long-acting beta-agonists (LABA) and with blood eosinophils >300 cells/µL (101 patients) or sputum eosinophils >3% (3 patients) were administered dupilumab or placebo for 12 weeks or until asthma exacerbation. At Week 4, LABA was withdrawn. Fluticasone was then withdrawn over 3-4 weeks. Fractional exhaled nitric oxide (FeNO), serum thymus and activation regulated chemokine (TARC), immunoglobulin E (IgE), eotaxin-3 and blood eosinophils were measured. Mixed model analysis with least square mean values are reported. FeNO markedly decreased despite ICS withdrawal (dupilumab vs placebo mean % change at Week 12: -28.7% vs +35.0%; p 1 ) improved on dupilumab and this correlated with reduction in FeNO (r=-0.408, p=0.009) at Week 12. Dupilumab reduced bronchial and systemic biomarkers associated with T-helper 2 inflammation (FeNO, TARC, eotaxin-3, IgE) in moderate-to-severe persistent asthma patients. The correlation between reduced FeNO and improved FEV 1 suggests that effects on Th2 inflammation lead to improved pulmonary function.