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.

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.

靶向2型炎症驱动因素和介质的生物制剂dupilumab和omalizumab（分别靶向白细胞介素[IL]-4/IL-13信号传导和免疫球蛋白E[IgE]）在治疗CRSwNP方面是有效的，但直接比较很少。

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.

在EVEREST（EValuating trEatment RESponses of dupilumab versus omalizumab，即“评价 dupilumab 与 omalizumab 治疗反应”）中，这是首个针对呼吸生物制剂的头对头试验，我们的目标是比较在患有轻度、中度或重度哮喘的严重CRSwNP患者中，dupilumab和omalizumab的疗效和安全性。

Methods

EVEREST was an international, randomised, double-blind, phase 4 trial, conducted at 100 hospitals or clinical centres in 17 countries.

EVEREST是一项国际性的、随机的、双盲的、第四阶段试验，在17个国家的100家医院或临床中心进行。

Sites were selected with otolaryngology, pneumologist, allergist, and immunologist practices; needed to have previously conducted double-blindstudies; and were required have nasal endoscopy and electrocardiogram machines.

选定的地点包括耳鼻喉科、肺科、过敏科和免疫科诊所；必须之前进行过双盲研究；并且要求具备鼻内窥镜和心电图机。

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.

符合条件的患者年龄在18岁或以上，患有严重的、未得到控制的CRSwNP（鼻息肉评分5分或以上[每个鼻孔至少2分]），在筛选前至少8周出现鼻塞和嗅觉丧失的症状，并且被医生诊断为哮喘。

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.

患者被随机分配（1:1）至每两周皮下注射300毫克度普利尤单抗或每两周或每四周根据体重和IgE水平调整剂量的奥马珠单抗，持续24周，同时使用莫米松糠酸酯鼻喷剂作为背景治疗。

Patients and investigators were masked to the study drugs.

患者和研究人员对研究药物进行了盲法处理。

Primary endpoints were change from baseline in endoscopic nasal polyp score and University of Pennsylvania Smell Identification Test (UPSIT) at 24 weeks.

主要终点是24周时鼻息肉内镜评分和宾夕法尼亚大学嗅觉识别测试（UPSIT）从基线的变化。

Efficacy was assessed in the intention-to-treatpopulation and safety was assessed in patients who received at least one dose of study medication.

疗效在意向治疗人群中评估，安全性在至少接受一次研究药物剂量的患者中评估。

The trial was registered at ClinicalTrials.gov, NCT04998604.

该试验已在ClinicalTrials.gov注册，注册号为NCT04998604。

Results

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).

在2021年9月27日至2024年12月27日期间，共有819名个体接受了研究纳入筛查，其中459人被排除在外（最常见的筛查失败原因包括：167人鼻息肉评分未达到≥5分或没有持续的鼻塞和嗅觉丧失症状，114人未达到吸入支气管扩张剂前FEV1 ≤85%的预测正常值，以及99人不符合奥马珠单抗药物剂量的纳入标准），最终有360名参与者被随机分配（181人分配至dupilumab组，179人分配至omalizumab组）。

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).

在360名参与者中，198名（55%）为男性，162名（45%）为女性，总体人群样本的平均年龄为52岁（标准差13.1）。

Improvements were significantly greater with dupilumab than omalizumab for all primary and secondary efficacy endpoints at week 24.

在第24周，与奥马珠单抗相比，达普利单抗在所有主要和次要疗效终点的改善显著更大。

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.

从基线开始，与奥马珠单抗相比，度普利尤单抗的最小二乘均值差异为：鼻息肉评分-1.60（95%置信区间-1.96至-1.25；p<0.0001）和UPSIT 8.0（6.3至9.7；p<0.0001）。在度普利尤单抗组的179名参与者中有115名（64%），在奥马珠单抗组的173名参与者中有116名（67%）报告了治疗后出现的不良事件，其中最常见的不良事件是鼻咽炎、意外过量、头痛、上呼吸道感染和咳嗽。

There were no deaths in the study.

研究中没有死亡事件。

interpretation

Dupilumab was superior to omalizumab in patients with severe CRSwNP and coexisting asthma.

在患有严重CRSwNP和共存哮喘的患者中，Dupilumab比omalizumab更有效。

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.

这些发现支持在2型呼吸系统疾病患者中，与活性生物制剂比较物omalizumab相比，dupilumab的疗效，以及dupilumab和omalizumab已知的安全性档案，这可能有助于在临床实践中为CRSwNP和哮喘患者提供更好的治疗定位。

funding

Sanofi and Regeneron Pharmaceuticals.

赛诺菲和再生元制药公司。