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.

Abstract

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is predominantly driven by type 2 inflammation. The biologics dupilumab and omalizumab, which target drivers and mediators of type 2 inflammation (interleukin [IL]-4/IL-13 signaling and immunoglobulin E [IgE], respectively), are efficacious in treating CRSwNP but direct comparisons are few. In EVEREST (EValuating trEatment RESponses of dupilumab versus omalizumab), the first head-to-head trial in respiratory biologics, we aimed to compare the efficacy and safety of dupilumab and omalizumab in patients with severe CRSwNP who had mild, moderate, or severe asthma.

METHODS: EVEREST was an international, randomised, double-blind, phase 4 trial, conducted at 100 hospitals or clinical centres in 17 countries. Sites were selected with otolaryngology, pneumologist, allergist, and immunologist practices; needed to have previously conducted double-blind studies; and were required have nasal endoscopy and electrocardiogram machines. Eligible patients aged 18 years or older with severe uncontrolled CRSwNP (with a nasal polyp score of 5 or more [and =2 for each nostril]), symptoms of nasal congestion and loss of smell for at least 8 weeks before screening, and physician-diagnosed asthma. Patients were randomly assigned (1:1) to subcutaneous dupilumab 300 mg every 2 weeks or omalizumab weight-tiered and IgE-tiered dosing every 2 weeks or 4 weeks for 24 weeks, with background mometasone furoate nasal spray. Patients and investigators were masked to the study drugs. Primary endpoints were change from baseline in endoscopic nasal polyp score and University of Pennsylvania Smell Identification Test (UPSIT) at 24 weeks. Efficacy was assessed in the intention-to-treat population and safety was assessed in patients who received at least one dose of study medication. The trial was registered at ClinicalTrials.gov, NCT04998604.

FINDINGS: Between Sept 27, 2021, and Dec 27, 2024, 819 individuals were screened for study inclusion, 459 were excluded (most common screen failures were: 167 did not meet nasal polyp score =5 or did not have ongoing symptoms of nasal congestion and loss of smell, 114 did not meet pre-bronchodilator FEV1 =85% predicted normal, and 99 did not meet eligibility as per omalizumab drug-dosing), and 360 participants were randomly assigned (181 assigned to the dupilumab group and 179 assigned to the omalizumab group). Of the 360 participants, 198 (55%) participants were male, 162 (45%) were female, and the mean age of the total population sample was 52 years (SD 13·1). Improvements were significantly greater with dupilumab than omalizumab for all primary and secondary efficacy endpoints at week 24. Least squares mean differences in change from baseline dupilumab over omalizumab were: nasal polyp score -1·60 (95% CI -1·96 to -1·25; p<0·0001) and UPSIT 8·0 (6·3 to 9·7; p<0·0001). 115 (64%) of 179 participants in the dupilumab group and 116 (67%) of 173 participants in the omalizumab group reported treatment-emergent adverse events, the most common of which were nasopharyngitis, accidental overdose, headache, upper respiratory tract infection, and cough. There were no deaths in the study.

INTERPRETATION: Dupilumab was superior to omalizumab in patients with severe CRSwNP and coexisting asthma. These findings support the efficacy of dupilumab in patients with type 2 respiratory diseases versus an active biologic comparator, the known safety profiles of dupilumab and omalizumab, and could enable better treatment targeting for patients with CRSwNP and asthma in clinical practice.

FUNDING: Sanofi and Regeneron Pharmaceuticals.