Faculty of Medicine, Upper Airways Research Laboratory, Ghent University, Ghent, Belgium; CLINTEC, Karolinska Institutet, Stockholm, Sweden.
Division of Allergy, Eastern Virginia Medical School, Norfolk, VA, USA.
Lancet. 2019 Nov 2;394(10209):1638-1650. doi: 10.1016/S0140-6736(19)31881-1. Epub 2019 Sep 19.
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.
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.
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.
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.
Sanofi and Regeneron Pharmaceuticals.
患有慢性鼻-鼻窦炎伴鼻息肉（CRSwNP）的患者通常具有较高的症状负担和较差的健康相关生活质量，经常需要反复使用全身性皮质类固醇和鼻窦手术。度普利尤单抗是一种全人源单克隆抗体，可抑制白细胞介素（IL）-4 和 IL-13 的信号传导，这是 2 型炎症的关键驱动因素，已被批准用于特应性皮炎和哮喘。在这两项研究中，我们旨在评估度普利尤单抗在既往接受全身性皮质类固醇、手术或两者联合治疗的 CRSwNP 患者中的疗效和安全性。
LIBERTY NP SINUS-24 和 LIBERTY NP SINUS-52 是两项多中心、多国、随机、双盲、安慰剂对照、平行组研究，评估了在严重 CRSwNP 成年患者中添加标准治疗药物的度普利尤单抗。SINUS-24 在 13 个国家的 67 个中心进行，SINUS-52 在 14 个国家的 117 个中心进行。符合条件的患者年龄在 18 岁或以上，双侧 CRSwNP，尽管使用了鼻内皮质类固醇，但仍有症状，在过去 2 年内接受过全身性皮质类固醇治疗，或曾接受过鼻窦手术。SINUS-24 中的患者被随机分配（1:1）接受皮下注射度普利尤单抗 300mg 或安慰剂，每 2 周一次，共 24 周。SINUS-52 中的患者被随机分配（1:1:1）接受度普利尤单抗 300mg 每 2 周一次，共 52 周，每 2 周一次，共 24 周，然后每 4 周一次，共 28 周，或安慰剂每 2 周一次，共 52 周。所有患者均通过中心随机化进行随机分组，采用随机区组随机化方案。随机化按筛选时的哮喘或非甾体抗炎药加重的呼吸道疾病状态、筛选时的手术情况和国家进行分层。包括有或没有合并哮喘的患者。主要终点是在 24 周时从基线到鼻息肉评分（NPS）、鼻塞或阻塞、鼻窦 Lund-Mackay CT 评分（日本的主要终点）的变化，在意向治疗人群中进行评估。安全性在 SINUS-52 中至第 24 周的度普利尤单抗组和 SINUS-24 中的度普利尤单抗组以及这两项研究中安慰剂组的汇总人群中进行评估，直至第 24 周。这些试验已经完成并在 ClinicalTrials.gov 上注册，NCT02912468 和 NCT02898454。
2016 年 12 月 5 日至 2017 年 8 月 3 日期间，276 名患者入组 SINUS-24，其中度普利尤单抗组 143 名，安慰剂组 133 名，至少接受了一次研究药物剂量。2016 年 11 月 28 日至 2017 年 8 月 28 日期间，448 名患者入组 SINUS-52，其中 150 名患者接受了每 2 周一次的度普利尤单抗至少一次剂量，145 名患者接受了每 2 周一次的度普利尤单抗 24 周剂量，然后每 4 周一次，直至第 52 周，153 名患者接受了至少一次安慰剂剂量。度普利尤单抗在两项研究中均显著改善了主要终点。在 24 周时，与安慰剂相比，度普利尤单抗治疗的最小二乘均数差值在 NPS 方面为 -2.06（95%CI -2.43 至 -1.69；p<0.0001），在 SINUS-52 中为 -1.80（-2.10 至 -1.51；p<0.0001）；鼻塞或阻塞评分的差值为 -0.89（-1.07 至 -0.71；p<0.0001），在 SINUS-52 中为 -0.87（-1.03 至 -0.71；p<0.0001）；Lund-Mackay CT 评分的差值为 -7.44（-8.35 至 -6.53；p<0.0001），在 SINUS-52 中为 -5.13（-5.80 至 -4.46；p<0.0001）。最常见的不良事件（鼻咽炎、鼻息肉恶化、哮喘加重、头痛、鼻出血和注射部位红斑）在安慰剂组中更为常见。
在患有严重 CRSwNP 的成年患者中，度普利尤单抗可缩小息肉大小、鼻窦混浊程度，并改善症状严重程度，且具有良好的耐受性。这些结果支持在严重 CRSwNP 患者中添加度普利尤单抗作为每日标准治疗的益处，这些患者否则治疗选择有限。
赛诺菲和再生元制药公司。
