比利时根特大学Claus Bachert研究小组的一项最新研究探讨了Dupilumab（一种全人源单克隆抗体）治疗重度慢性鼻窦炎伴鼻息肉（CRSwNP）患者的疗效和安全性。该研究2019年9月19日在线发表于《柳叶刀》杂志。

LIBERTY NP SINUS-24和LIBERTY NP SINUS-52是两个多国、多中心、随机、双盲、安慰剂对照的平行组研究，其中SINUS-24在13个国家的67个中心进行，SINUS-52在14个国家的117个中心完成。参与者年龄均在18岁及以上，尽管使用鼻内皮质类固醇治疗但仍有双侧CRSwNP，在过去2年内接受过全身性皮质类固醇治疗或施行过鼻窦手术。

2016年12月5日至2017年8月3日，SINUS-24共招募了276名患者，143名接受dupilumab（300 mg）治疗，133名接受安慰剂治疗。2016年11月28日至2017年8月28日，SINUS-52共招募了448名患者，150名每2周至少一剂dupilumab，145名前24周每2周至少1剂dupilumab，之后每4周至少1剂，持续至52周，153名接受安慰剂治疗。

在这两项研究中，Dupilumab组的鼻息肉评分、鼻腔充血或鼻梗阻、鼻窦CT影像等指标均显著优于安慰剂组。安慰剂组中不良反应更常见，主要包括鼻咽炎、鼻息肉和哮喘恶化、头痛、鼻出血和注射部位红斑等。

总之，对于重度CRSwNP成年患者，Dupilumab可有效减少息肉大小，改善鼻窦浑浊等症状，且患者的耐受性良好。该结果支持在其他疗法无效的重度CRSwNP患者的标准治疗中加用Dupilumab。

据介绍，CRSwNP患者通常症状负担较高，健康相关的生活质量较差，常需要反复进行全身皮质类固醇治疗，或反复行鼻窦手术。Dupilumab是一种全人源单克隆抗体，可抑制白介素(IL) 4和13的信号传导，而IL-13是2型炎症的主要驱动因子。

附：英文原文

Title: Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials

Author: Claus Bachert, Joseph K Han, Martin Desrosiers, Peter W Hellings, Nikhil Amin, Stella E Lee, Joaquim Mullol, Leon S Greos, John V Bosso, Tanya M Laidlaw, Anders U Cervin, Jorge F Maspero, Claire Hopkins, Heidi Olze, G Walter Canonica, Pierluigi Paggiaro, Seong H Cho, Wytske J Fokkens, Shigeharu Fujieda, Mei Zhang, Xin Lu, Chunpeng Fan, Steven Draikiwicz, Siddhesh A Kamat, Asif Khan, Gianluca Pirozzi, Naimish Patel, Neil M H Graham, Marcella Ruddy, Heribert Staudinger, David Weinreich, Neil Stahl, George D Yancopoulos, Leda P Mannent

Issue&Volume: 19 September 2019

Summary: 

Background

Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) generally have a high symptom burden and poor health-related quality of life, often requiring recurring systemic corticosteroid use and repeated sinus surgery. Dupilumab is a fully human monoclonal antibody that inhibits signalling of interleukin (IL)-4 and IL-13, key drivers of type 2 inflammation, and has been approved for use in atopic dermatitis and asthma. In these two studies, we aimed to assess efficacy and safety of dupilumab in patients with CRSwNP despite previous treatment with systemic corticosteroids, surgery, or both.

Methods

LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52 were two multinational, multicentre, randomised, double-blind, placebo-controlled, parallel-group studies assessing dupilumab added to standard of care in adults with severe CRSwNP. SINUS-24 was done in 67 centres in 13 countries, and SINUS-52 was done in 117 centres in 14 countries. Eligible patients were 18 years or older with bilateral CRSwNP and symptoms despite intranasal corticosteroid use, receiving systemic corticosteroids in the preceding 2 years, or having had sinonasal surgery. Patients in SINUS-24 were randomly assigned (1:1) to subcutaneous dupilumab 300 mg or placebo every 2 weeks for 24 weeks. Patients in SINUS-52 were randomly assigned (1:1:1) to dupilumab 300 mg every 2 weeks for 52 weeks, dupilumab every 2 weeks for 24 weeks and then every 4 weeks for the remaining 28 weeks, or placebo every 2 weeks for 52 weeks. All patients were randomly assigned centrally with a permuted block randomisation schedule. Randomisation was stratified by asthma or non-steroidal anti-inflammatory drug-exacerbated respiratory disease status at screening, previous surgery at screening, and country. Patients with or without comorbid asthma were included. Coprimary endpoints were changes from baseline to week 24 in nasal polyp score (NPS), nasal congestion or obstruction, and sinus Lund-Mackay CT scores (a coprimary endpoint in Japan), done in an intention-to-treat population. Safety was assessed in a pooled population of both dupilumab groups in SINUS-52 up to week 24 and the dupilumab group in SINUS-24 and the placebo groups in both studies until week 24. The trials are complete and registered at ClinicalTrials.gov, NCT02912468 and NCT02898454.

Findings

Between Dec 5, 2016, and Aug 3, 2017, 276 patients were enrolled in SINUS-24, with 143 in the dupilumab group and 133 in the placebo group receiving at least one study drug dose. Between Nov 28, 2016, and Aug 28, 2017, 448 patients were enrolled in SINUS-52, with 150 receiving at least one dose of dupilumab every 2 weeks, 145 receiving at least one dose of dupilumab every 2 weeks for 24 weeks and every 4 weeks until week 52, and 153 receiving at least one dose of placebo. Dupilumab significantly improved the coprimary endpoints in both studies. At 24 weeks, least squares mean difference in NPS of dupilumab treatment versus placebo was −2·06 (95% CI −2·43 to −1·69; p<0·0001) in SINUS-24 and −1·80 (−2·10 to −1·51; p<0·0001) in SINUS-52; difference in nasal congestion or obstruction score was −0·89 (−1·07 to −0·71; p<0·0001) in SINUS-24 and −0·87 (−1·03 to −0·71; p<0·0001) in SINUS-52; and difference in Lund-Mackay CT scores was −7·44 (−8·35 to −6·53; p<0·0001) in SINUS-24 and −5·13 (−5·80 to −4·46; p<0·0001) in SINUS-52. The most common adverse events (nasopharyngitis, worsening of nasal polyps and asthma, headache, epistaxis, and injection-site erythema) were more frequent with placebo.

Interpretation

In adult patients with severe CRSwNP, dupilumab reduced polyp size, sinus opacification, and severity of symptoms and was well tolerated. These results support the benefits of adding dupilumab to daily standard of care for patients with severe CRSwNP who otherwise have few therapeutic options.

DOI: 10.1016/S0140-6736(19)31881-1

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31881-1/fulltext