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.