Dupilumab
The Th2-like cytokines IL-4 and IL-13 and the heterodimeric IL-4 receptor (IL-4R) complexes that they activate play a key pathogenic role in asthma 169. Dupilumab is a human IgG4 mAb that targets the IL-4 receptor α chain (IL-4Rα), common to both IL-4R complexes: type 1 (IL-4Rα/γc; IL-4 specific) and type 2 (IL-4Rα/IL-13Rα1: IL-4 and IL-13 specific)170.
In several RCTs, dupilumab reduced the annualized rate of asthma exacerbations in patients with moderate-to-severe uncontrolled asthma compared to placebo171-173. Dupilumab in patients with severe asthma caused rapid (2 weeks) and long-lasting improvement in FEV1 versusplacebo172, 173. Furthermore, the trend curves of FEV1 post bronchodilation showed a loss of function in the placebo group and no decrease in FEV1 over time in the dupilumab group. The latter findings suggest that dupilumab might exert a positive effect on structural airway remodeling. Moreover, in a mouse model of asthma, dual IL-4/IL-13 blockade with dupilumab prevented eosinophil infiltration into lung tissue without affecting circulating eosinophils 174. A real-life retrospective study demonstrated that 4 weeks of treatment were necessary to achieve a significant improvement in FEV1 compared to baseline175.
It should be noted that blood eosinophilia was reported in 4 to 25% of patients in the dupilumab group compared to 0.6% in the placebo group173, 176. This paradoxical effect has also been reported in patients treated with dupilumab for moderate-to-severe atopic dermatitis 177.
The VESTIGE study (NCT04400318), evaluating dupilumab effects on lung function and structural airway changes using functional respiratory imaging (FRI), is ongoing.
Additionally, indirect evidence of a combined anti-inflammatory effect as well as on tissue and structural cells can be derived from the observation that all of the above mentioned anti-Th2 cytokine or receptor antibodies have been shown to reduce nasal polyposis in patients with chronic rhinosinusitis178-181.