Highlights
– A randomized, double‑blind phase 4 head‑to‑head trial (EVEREST) found dupilumab superior to omalizumab for reducing nasal polyp score and improving smell in severe CRSwNP with coexisting asthma at 24 weeks (both p<0.0001).
– A US real‑world cohort (ADVANTAGE) showed dupilumab was associated with 44% fewer severe asthma exacerbations and 28% fewer systemic corticosteroid prescriptions versus omalizumab over 12 months.
– A target‑trial emulation using electronic health records reported lower exacerbation incidence and numerically greater FEV1 gains with dupilumab versus omalizumab in patients selected by eosinophil and IgE thresholds.
Background and Clinical Context
Chronic rhinosinusitis with nasal polyps (CRSwNP) and asthma frequently coexist and are commonly driven by type‑2 (Th2) inflammation. Type‑2 inflammatory mediators—interleukin (IL)‑4, IL‑13, eosinophils, and IgE—contribute variably to individual patients’ airway disease. Targeted biologic therapies that interrupt these pathways have transformed management of severe disease. Omalizumab, an anti‑IgE monoclonal antibody, is licensed for allergic asthma and CRSwNP; dupilumab, an IL‑4Rα antagonist blocking IL‑4 and IL‑13 signaling, is approved for CRSwNP and type‑2 asthma phenotypes. Direct comparative evidence between these mechanisms of action has been limited, complicating biologic selection where multiple agents are appropriate.
Study Designs and Populations
1) EVEREST: Multicentre, randomised, double‑blind, head‑to‑head phase 4 trial
Design: 24‑week, international, double‑blind, randomized (1:1) comparison of dupilumab (300 mg q2w) versus omalizumab (weight‑ and IgE‑tiered dosing every 2–4 weeks), with background mometasone furoate nasal spray. Sites had multidisciplinary respiratory/allergy/ENT expertise and required nasal endoscopy capability.
Population: Adults (≥18 years) with severe uncontrolled CRSwNP (bilateral nasal polyp score ≥5 with ≥2 per nostril), ongoing nasal congestion and smell loss ≥8 weeks, and physician‑diagnosed asthma. 360 participants randomized (181 dupilumab; 179 omalizumab). Mean age ~52 years; 55% male.
Primary endpoints: Change from baseline at week 24 in endoscopic nasal polyp score and University of Pennsylvania Smell Identification Test (UPSIT).
2) ADVANTAGE: US retrospective real‑world comparative effectiveness study
Design: Observational cohort using TriNetX Dataworks electronic medical records; patients aged ≥12 initiating dupilumab or omalizumab between Nov 2018 and Sep 2020 with ≥12 months pre‑ and post‑index data. Inverse probability of treatment weighting and doubly robust negative binomial regression adjusted for confounding.
Population: 2,138 dupilumab and 1,313 omalizumab patients met criteria after data extraction; weighted analyses produced balanced covariates.
Primary outcomes: Asthma exacerbation rates and systemic corticosteroid (SCS) prescription counts over 12 months.
3) Target‑trial emulation: EHR-based comparative effectiveness
Design: Emulated randomized trial in a US academic health system (Mar 2016–Aug 2021), applying eligibility criteria to replicate a hypothetical trial. Inclusion required age ≥18, baseline IgE 30–700 IU/mL, and blood eosinophils ≥150 cells/μL. Outcomes measured over 12 months: asthma exacerbations and change in FEV1.
Population: 68 patients on dupilumab, 68 on omalizumab, and 65 on mepolizumab met inclusion criteria.
Key Results — Efficacy and Safety
Below is a synthesis and side‑by‑side comparison of the principal findings from the three studies.
EVEREST (Head‑to‑Head RCT, n=360)
– Nasal polyp score: Least squares mean difference (dupilumab − omalizumab) −1.60 (95% CI −1.96 to −1.25), p<0.0001, favoring dupilumab at week 24.
– Smell function (UPSIT): LS mean difference +8.0 points (95% CI 6.3 to 9.7), p<0.0001, favoring dupilumab.
– Secondary endpoints: All prespecified secondary efficacy outcomes favored dupilumab (details in full manuscript).
– Safety: Treatment‑emergent adverse events (TEAEs) were similar in frequency: 64% dupilumab vs 67% omalizumab. Common TEAEs included nasopharyngitis, headache, accidental overdose, upper respiratory tract infection, and cough. No deaths reported.
ADVANTAGE (Real‑World US study)
– Exacerbations: Dupilumab associated with a 44% lower severe asthma exacerbation rate versus omalizumab (P < .0001) over 12 months after weighting and adjustment.
– Systemic corticosteroid prescriptions: Dupilumab linked with a 28% reduction in SCS prescriptions versus omalizumab (P < .05).
– These real‑world outcomes align with reduced clinical instability and steroid burden on dupilumab.
Target‑trial emulation (EHR‑based)
– Exacerbation incidence (per person‑year): dupilumab 0.46, omalizumab 0.93, mepolizumab 1.32.
– Adjusted incidence rate ratios (IRR): dupilumab vs mepolizumab IRR 0.28 (95% CI 0.09–0.84); dupilumab vs omalizumab IRR 0.36 (95% CI 0.12–1.09) — point estimates favor dupilumab, though the dupilumab vs omalizumab CI crosses 1.
– FEV1 change: numerical improvements favored dupilumab vs omalizumab (0.082 L; 95% CI −0.040 to 0.204 L) but CIs included the null.
Integrated Interpretation and Comparative Magnitude of Effect
All three sources converge in direction: dupilumab demonstrates greater clinical benefit than omalizumab across CRSwNP outcomes (EVEREST) and asthma control/exacerbation metrics (ADVANTAGE and target‑trial emulation). The randomized, double‑blind EVEREST provides highest internal validity for CRSwNP endpoints and smell function with robust statistical significance. Real‑world ADVANTAGE adds translational relevance—showing fewer exacerbations and lower steroid use over 12 months in routine practice. The target‑trial emulation strengthens the signal, particularly when restricting to patients with both elevated eosinophils and moderate IgE levels, a subgroup in which both agents could be considered.
Biological Plausibility
Dupilumab blocks IL‑4/IL‑13 signaling, upstream drivers of multiple type‑2 inflammatory effector pathways including eosinophilic recruitment, mucous production, and epithelial barrier dysfunction. Omalizumab specifically neutralizes circulating IgE, reducing FcεRI‑mediated allergic responses. In diseases where IL‑4/IL‑13 mediated mechanisms (eg, mucosal type‑2 inflammation and anosmia pathophysiology in CRSwNP) predominate or where eosinophilia is a major driver of exacerbations, IL‑4/IL‑13 blockade may offer broader downstream modulation than IgE neutralization alone—consistent with the observed clinical differentials.
Safety Considerations
Across studies adverse events were broadly consistent with known safety profiles. EVEREST reported similar overall TEAE frequencies with no deaths. Real‑world and EHR studies did not uncover new safety signals but may have limited power or follow‑up to detect rare events. Clinicians should continue to monitor for injection‑site reactions, conjunctivitis (noted previously with dupilumab in other indications), and hypersensitivity reactions with omalizumab, and individualize risk assessment.
Limitations and Caveats
– EVEREST evaluated a specific CRSwNP population with coexisting asthma and baseline severity criteria (polyp score ≥5), so generalizability to milder CRSwNP or patients without asthma may be limited.
– Omalizumab dosing in EVEREST was determined by weight/IgE tiers; enrollment exclusions related to omalizumab dosing led to many screen failures—this real‑world constraint reflects clinical practice but could affect applicability.
– The ADVANTAGE study, while large and adjusted, remains observational; residual confounding and channeling bias (treatment selection differences not captured in records) are possible despite inverse probability weighting.
– The target‑trial emulation cohort was small, limiting precision—CIs for dupilumab vs omalizumab included the null for some outcomes.
– None of the studies provide long‑term comparative outcomes beyond 12–24 weeks (EVEREST 24 weeks; ADVANTAGE and emulation 12 months) for all endpoints; durability over multiple years requires further study.
Clinical Implications and Practical Recommendations
– For patients with severe CRSwNP and coexisting asthma, EVEREST supports using dupilumab when both polyp burden and smell loss are priority targets, particularly where IL‑4/IL‑13–driven disease is suspected.
– In asthma management where exacerbation reduction and steroid‑sparing are goals, real‑world data favor dupilumab over omalizumab in broadly defined treated cohorts; however, individual biologic selection should integrate phenotype (allergic vs eosinophilic), comorbidities, biomarker profiles (FeNO, blood eosinophils, total IgE), prior response to treatments, and patient preferences.
– When both agents are indicated, consider dupilumab for patients with prominent nasal polyps, marked anosmia, or high eosinophil counts; omalizumab remains an important option for IgE‑mediated allergic asthma especially where IgE is a clear dominant driver or in pediatric allergic disease depending on label.
Research Gaps and Future Directions
– Longer‑term head‑to‑head outcomes (clinical control, revision surgery rates for CRSwNP, sustained steroid sparing, safety) are needed.
– Biomarker‑driven stratification trials could clarify which subgroups derive the largest incremental benefit from IL‑4/IL‑13 versus IgE blockade.
– Cost‑effectiveness analyses incorporating real‑world effectiveness, quality‑of‑life gains, and health‑care utilization will inform formulary and policy decisions.
Expert Commentary
These three complementary studies—randomized, real‑world, and emulated trial—create a convergent evidentiary picture favoring dupilumab over omalizumab for several clinically meaningful outcomes in type‑2 respiratory disease. While head‑to‑head RCT evidence is the gold standard and supports superiority in CRSwNP, real‑world effectiveness and target‑trial findings extend that benefit to asthma control and steroid reduction. Clinicians should interpret results in the context of individual patient biomarkers, comorbidity profiles, approvals, and access constraints.
Conclusion
Across a randomized head‑to‑head trial, a large real‑world cohort, and an EHR‑based emulation, dupilumab shows consistent advantages over omalizumab in reducing nasal polyp burden and smell loss, decreasing asthma exacerbations, and limiting systemic corticosteroid exposure. These data support prioritizing IL‑4/IL‑13 blockade when clinical features and biomarkers indicate a type‑2 inflammatory phenotype driven beyond IgE‑mediated mechanisms, while still recognizing an ongoing role for omalizumab in appropriately selected allergic patients.
Funding and ClinicalTrials.gov
EVEREST was funded by Sanofi and Regeneron Pharmaceuticals and registered at ClinicalTrials.gov (NCT04998604). ADVANTAGE and the target‑trial emulation were investigator‑led analyses supported by their respective study sponsors as listed in the source publications.
References
1. 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 Dec;13(12):1067‑1077. doi:10.1016/S2213‑2600(25)00287‑5. PMID: 41033334.
2. Bleecker E, Blaiss M, Jacob‑Nara J, et al. Comparative effectiveness of dupilumab and omalizumab on asthma exacerbations and systemic corticosteroid prescriptions: Real‑world US ADVANTAGE study. J Allergy Clin Immunol. 2024 Dec;154(6):1500‑1510. doi:10.1016/j.jaci.2024.07.029. PMID: 39186985.
3. Akenroye AT, Segal JB, Zhou G, et al. Comparative effectiveness of omalizumab, mepolizumab, and dupilumab in asthma: A target trial emulation. J Allergy Clin Immunol. 2023 May;151(5):1269‑1276. doi:10.1016/j.jaci.2023.01.020. PMID: 36740144; PMCID: PMC10164684.
