The efficacy advantage of dupilumab (Dupixent) over omalizumab (Xolair) in the phase 4 EVEREST trial stems from dupilumab's broader blockade of interleukin (IL)-4 and IL-13 signaling compared with omalizumab's narrower inhibition of immunoglobulin E (IgE), according to investigator Guy Brusselle, MD, PhD, of Ghent University Hospital, who discussed the mechanistic rationale with HCPLive. Brusselle presented the latest EVEREST data at the European Respiratory Society (ERS) 2026 Congress in Barcelona.1
EVEREST, a head-to-head phase 4 trial, showed significantly greater rates of composite asthma clinical remission with dupilumab than omalizumab at week 24 in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) and coexisting asthma. The study showed a 24% absolute difference favoring dupilumab.1,2 Both agents target type 2 inflammatory pathways, yet Brusselle attributed the gap to differences in cytokine targeting rather than to differences in the patient populations enrolled.
"Type 2 inflammation is, of course, heterogeneous, but IgE, immunoglobulin E, is only 1 part of the spectrum of type 2 diseases," Brusselle said.
IL-4 and IL-13 Blockade Versus IgE-Targeted Therapy
Dupilumab blocks the IL-4 receptor alpha subunit shared by IL-4 and IL-13, interrupting signaling from both cytokines simultaneously. One principal effect of IL-4 is inducing immunoglobulin class switching from IgG to IgE in B cells and plasma cells, a pathway already addressed indirectly by omalizumab's anti-IgE mechanism, Brusselle said.
Blocking the IL-4 receptor alpha subunit also interrupts IL-13 effects on airway epithelial cells, reducing mucus production, and on airway smooth muscle cells, limiting bronchoconstriction and helping preserve lung function, according to Brusselle. He said type 2 inflammation in both nasal polyposis and severe asthma extends well beyond IgE alone, and this broader mechanistic reach helps explain why dupilumab outperformed omalizumab across both upper and lower airway outcomes in patients with combined CRSwNP and asthma.
Continued Improvement in Patients Without Asthma Remission
Asthma clinical remission in EVEREST was defined as a composite, all-or-nothing outcome incorporating 4 stringent criteria assessed at week 24: absence of asthma-related exacerbations, no oral corticosteroid use, stable or improved FEV1, and an Asthma Control Questionnaire-5 score < 1.5.¹ Brusselle noted this dichotomous classification does not capture the full extent of treatment response.
Both patients who achieved remission and those who did not showed significant improvement in nasal polyp score and University of Pennsylvania Smell Identification Test (UPSIT) scores with dupilumab (P <.0001 for both). This reflects a continuous change from baseline rather than a binary outcome, Brusselle explained. A patient can fail just 1 of the 4 remission criteria and still be classified as a nonremitter despite considerable underlying improvement across other asthma and CRSwNP measures, he said.
"He or she has still improved considerably for their asthma, and this is also reflected in the benefits in the upper airways," Brusselle said.
References
De Corso E, Canonica GW, Heffler E, et al. Dupilumab versus omalizumab in patients with chronic rhinosinusitis with nasal polyps and coexisting asthma (EVEREST): a multicentre, randomised, double-blind, head-to-head phase 4 trial. Lancet Respir Med. 2025;13(12):1067-1077. doi:10.1016/S2213-2600(25)00287-5
Brusselle G, Heffler E, Busse WW, et al. Clinical asthma remission and nasal polyp outcomes over 24 weeks with dupilumab versus omalizumab in patients with severe chronic rhinosinusitis with nasal polyps and uncontrolled asthma: results from EVEREST. Presented at: European Respiratory Society (ERS) Congress 2026; September 5-9, 2026; Barcelona, Spain.
