Background

Clinical trials have shown treatment benefits of dupilumab in patients with uncontrolled asthma for up to 1 year. This study aimed to evaluate the long-term safety and efficacy of dupilumab in patients with moderate-to-severe asthma, as data for extended treatment with dupilumab beyond 1 year are not available.

Methods

TRAVERSE was an open-label extension study in 362 hospitals and clinical centres across 27 countries that assessed the safety and efficacy of dupilumab 300 mg every 2 weeks up to 96 weeks in adults and adolescents (aged 12–84 years) with moderate-to-severe or oral-corticosteroid-dependent severe asthma who had completed a previous dupilumab asthma study (phase 2A EXPEDITION, phase 2B DRI [P2b], phase 3 QUEST, or VENTURE). The primary endpoint was the number and percentage of patients with any treatment-emergent adverse events. Secondary endpoints included annualised exacerbation rate (AER) over the treatment period and change from parent study baseline in pre-bronchodilator FEV₁, the five-item asthma control questionnaire (ACQ-5), the asthma quality of life questionnaire (AQLQ), type 2 biomarkers (blood eosinophils and serum total IgE), and anti-drug antibodies (ADAs). Statistical analyses were descriptive. We report safety in all enrolled patients, and efficacy in patients with non-oral-corticosteroid-dependent asthma and in subgroups, including patients with a type 2 inflammatory phenotype who received 148 weeks of treatment. This study is registered with ClinicalTrials.gov, NCT02134028.

Findings

Between Aug 5, 2014, and Oct 11, 2019, of 2302 patients assessed for eligibility, 2282 adults and adolescents were enrolled (median age 50 years, 62·1% female and 37·9% male). Safety during TRAVERSE was consistent with the known dupilumab safety profile. The proportion of patients reporting treatment-emergent adverse events throughout the study duration was similar to that observed in the parent studies and ranged from 76·3% to 94·7%. The most frequently reported treatment-emergent adverse events were nasopharyngitis (17·5–25·9%), injection-site erythema (2·2–23·4%), and bronchitis (9·3–19·0%). Serious asthma exacerbations (0·5–3·6%) and pneumonia (0·7–2·7%) were the most frequently reported serious adverse events. There were four treatment-emergent adverse events leading to death. Efficacy during TRAVERSE was also consistent with the results of parent studies. In patients who were non-oral-corticosteroid-dependent, AER remained low (0·277–0·327) across parent study and treatment groups, pre-bronchodilator FEV₁ improvements were sustained to the end of treatment at week 96 (mean changes from parent study baseline ranged from 0·22 L [SD 0·44] to 0·33 L [0·44] across parent study and treatment groups), and improvements in ACQ-5 and AQLQ scores were sustained to the last timepoint assessed at week 48. Rapid improvements were observed in pre-bronchodilator FEV₁ and sustained improvements were seen in all outcome measures for patients given dupilumab who previously received placebo in parent studies; further improvements in AER, asthma control, and health-related quality of life were observed in patients who continued receiving dupilumab. Blood eosinophils and serum total IgE decreased progressively. ADA status had no effect on safety or efficacy. In the subgroup of patients with a type 2 inflammatory phenotype followed-up for 148 weeks, AER decreased progressively, and initial lung function improvements were sustained over 148 weeks.

Interpretation

Data show that safety and efficacy of dupilumab in adult and adolescent patients with moderate-to-severe asthma are sustained when treatment is extended up to 148 weeks. These findings therefore support the long-term use of dupilumab in this patient population.

Funding

Sanofi and Regeneron Pharmaceuticals.

中文翻译：

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dupilumab 在中度至重度哮喘（TRAVERSE）患者中的长期安全性和有效性：一项开放标签扩展研究

背景

临床试验表明，dupilumab 对哮喘失控患者的治疗益处长达 1 年。本研究旨在评估 dupilumab 在中度至重度哮喘患者中的长期安全性和有效性，因为没有 dupilumab 延长治疗超过 1 年的数据。

方法

TRAVERSE 是一项在 27 个国家的 362 家医院和临床中心开展的开放标签扩展研究，评估了每 2 周至 96 周 dupilumab 300 mg 在成人和青少年（年龄 12-84 岁）中的安全性和有效性。已完成先前 dupilumab 哮喘研究（2A 期 EXPEDITION、2B 期 DRI [P2b]、3 期 QUEST 或 VENTURE）的重度或口服皮质类固醇依赖的重度哮喘。主要终点是出现任何治疗中出现的不良事件的患者数量和百分比。次要终点包括治疗期间的年化恶化率 (AER) 和支气管扩张剂前 FEV _{1从父研究基线的变化}、五项哮喘控制问卷（ACQ-5）、哮喘生活质量问卷（AQLQ）、2型生物标志物（血嗜酸性粒细胞和血清总IgE）和抗药物抗体（ADAs）。统计分析是描述性的。我们报告了所有入组患者的安全性，以及非口服皮质类固醇依赖性哮喘患者和亚组的疗效，包括接受 148 周治疗的 2 型炎症表型患者。该研究已在 ClinicalTrials.gov 注册，NCT02134028。

发现

在 2014 年 8 月 5 日至 2019 年 10 月 11 日期间，在 2302 名接受资格评估的患者中，有 2282 名成人和青少年入选（中位年龄 50 岁，62·1% 女性和 37·9% 男性）。TRAVERSE 期间的安全性与已知的 dupilumab 安全性概况一致。在整个研究期间报告治疗出现的不良事件的患者比例与在父母研究中观察到的相似，范围从 76·3% 到 94·7%。最常报告的治疗中出现的不良事件是鼻咽炎 (17·5–25·9%)、注射部位红斑 (2·2–23·4%) 和支气管炎 (9·3–19·0%)。严重哮喘发作 (0·5–3·6%) 和肺炎 (0·7–2·7%) 是最常报告的严重不良事件。有四起导致死亡的治疗中出现的不良事件。TRAVERSE 期间的疗效也与父母研究的结果一致。在非口服皮质类固醇依赖的患者中，AER 在父母研究和治疗组、支气管扩张剂前 FEV 中保持较低 (0·277–0·327)₁改善持续到第 96 周治疗结束（父母研究和治疗组与父母研究基线的平均变化范围从 0·22 L [SD 0·44] 到 0·33 L [0·44]），和ACQ-5 和 AQLQ 评分的改善持续到第 48 周评估的最后一个时间点。在支气管扩张剂前 FEV ₁中观察到快速改善对于之前在父母研究中接受安慰剂的给予 dupilumab 的患者，在所有结果测量中都看到了持续改善；在继续接受 dupilumab 治疗的患者中，观察到 AER、哮喘控制和健康相关生活质量的进一步改善。血嗜酸性粒细胞和血清总IgE逐渐下降。ADA 状态对安全性或有效性没有影响。在随访 148 周的 2 型炎症表型患者亚组中，AER 逐渐下降，初始肺功能改善持续超过 148 周。

解释

数据显示，当治疗延长至 148 周时，dupilumab 在成人和青少年中度至重度哮喘患者中的安全性和有效性得以维持。因此，这些发现支持在该患者群体中长期使用 dupilumab。

资金

赛诺菲和再生元制药。