Background

Upadacitinib is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, and tyrosine kinase 2. We aimed to assess the efficacy and safety of upadacitinib compared with placebo for the treatment of moderate-to-severe atopic dermatitis.

Methods

Measure Up 1 and Measure Up 2 were replicate multicentre, randomised, double-blind, placebo-controlled, phase 3 trials; Measure Up 1 was done at 151 clinical centres in 24 countries across Europe, North and South America, Oceania, and the Asia-Pacific region; and Measure Up 2 was done at 154 clinical centres in 23 countries across Europe, North America, Oceania, and the Asia-Pacific region. Eligible patients were adolescents (aged 12–17 years) and adults (aged 18–75 years) with moderate-to-severe atopic dermatitis (≥10% of body surface area affected by atopic dermatitis, Eczema Area and Severity Index [EASI] score of ≥16, validated Investigator's Global Assessment for Atopic Dermatitis [vIGA-AD] score of ≥3, and Worst Pruritus Numerical Rating Scale score of ≥4). Patients were randomly assigned (1:1:1) using an interactive response technology system to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily for 16 weeks, stratified by baseline disease severity, geographical region, and age. Coprimary endpoints were the proportion of patients who had achieved at least a 75% improvement in EASI score from baseline (EASI-75) and the proportion of patients who had achieved a vIGA-AD response (defined as a vIGA-AD score of 0 [clear] or 1 [almost clear] with ≥2 grades of reduction from baseline) at week 16. Efficacy was analysed in the intention-to-treat population and safety was analysed in all randomly assigned patients who received at least one dose of study drug. These trials are registered with ClinicalTrials.gov, NCT03569293 (Measure Up 1) and NCT03607422 (Measure Up 2), and are both active but not recruiting.

Findings

Between Aug 13, 2018, and Dec 23, 2019, 847 patients were randomly assigned to upadacitinib 15 mg (n=281), upadacitinib 30 mg (n=285), or placebo (n=281) in the Measure Up 1 study. Between July 27, 2018, and Jan 17, 2020, 836 patients were randomly assigned to upadacitinib 15 mg (n=276), upadacitinib 30 mg (n=282), or placebo (n=278) in the Measure Up 2 study. At week 16, the coprimary endpoints were met in both studies (all p<0·0001). The proportion of patients who had achieved EASI-75 at week 16 was significantly higher in the upadacitinib 15 mg (196 [70%] of 281 patients) and upadacitinib 30 mg (227 [80%] of 285 patients) groups than the placebo group (46 [16%] of 281 patients) in Measure Up 1 (adjusted difference in EASI-75 response rate vs placebo, 53·3% [95% CI 46·4–60·2] for the upadacitinib 15 mg group; 63·4% [57·1–69·8] for the upadacitinib 30 mg group) and Measure Up 2 (166 [60%] of 276 patients in the upadacitinib 15 mg group and 206 [73%] of 282 patients in the upadacitinib 30 mg group vs 37 [13%] of 278 patients in the placebo group; adjusted difference in EASI-75 response rate vs placebo, 46·9% [39·9–53·9] for the upadacitinib 15 mg group; 59·6% [53·1–66·2] for the upadacitinib 30 mg group). The proportion of patients who achieved a vIGA-AD response at week 16 was significantly higher in the upadacitinib 15 mg (135 [48%] patients) and upadacitinib 30 mg (177 [62%] patients) groups than the placebo group (24 [8%] patients) in Measure Up 1 (adjusted difference in vIGA-AD response rate vs placebo, 39·8% [33·2–46·4] for the upadacitinib 15 mg group; 53·6% [47·2–60·0] for the upadacitinib 30 mg group) and Measure Up 2 (107 [39%] patients in the upadacitinib 15 mg group and 147 [52%] patients in the upadacitinib 30 mg group vs 13 [5%] patients in the placebo group; adjusted difference in vIGA-AD response rate vs placebo, 34·0% [27·8–40·2] for the upadacitinib 15 mg group; 47·4% [41·0–53·7] for the upadacitinib 30 mg group). Both upadacitinib doses were well tolerated. The incidence of serious adverse events and adverse events leading to study drug discontinuation were similar among groups. The most frequently reported treatment-emergent adverse events were acne (19 [7%] of 281 patients in the upadacitinib 15 mg group, 49 [17%] of 285 patients in the upadacitinib 30 mg group, and six [2%] of 281 patients in the placebo group in Measure Up 1; 35 [13%] of 276 patients in the upadacitinib 15 mg group, 41 [15%] of 282 patients in the upadacitinib 30 mg group, and six [2%] of 278 patients in the placebo group in Measure Up 2), upper respiratory tract infection (25 [9%] patients, 38 [13%] patients, and 20 [7%] patients; 19 [7%] patients, 17 [16%] patients, and 12 [4%] patients), nasopharyngitis (22 [8%] patients, 33 [12%] patients, and 16 [6%] patients; 16 [6%] patients, 18 [6%] patients, and 13 [5%] patients), headache (14 [5%] patients, 19 [7%] patients, and 12 [4%] patients; 18 [7%] patients, 20 [7%] patients, and 11 [4%] patients), elevation in creatine phosphokinase levels (16 [6%] patients, 16 [6%] patients, and seven [3%] patients; nine [3%] patients, 12 [4%] patients, and five [2%] patients), and atopic dermatitis (nine [3%] patients, four [1%] patients, and 26 [9%] patients; eight [3%] patients, four [1%] patients, and 26 [9%] patients).

Interpretation

Monotherapy with upadacitinib might be an effective treatment option and had a positive benefit–risk profile in adolescents and adults with moderate-to-severe atopic dermatitis.

Funding

AbbVie.

中文翻译：

---

在患有中度至重度特应性皮炎的青少年和成人中每日一次 upadacitinib 与安慰剂（Measure Up 1 和 Measure Up 2）：来自两项重复双盲、随机对照 3 期试验的结果

背景

Upadacitinib 是一种口服 Janus 激酶 (JAK) 抑制剂，对 JAK1 的抑制效力高于 JAK2、JAK3 和酪氨酸激酶 2。我们旨在评估 upadacitinib 与安慰剂相比治疗中度至重度特应性皮炎的疗效和安全性.

方法

Measure Up 1 和 Measure Up 2 是重复的多中心、随机、双盲、安慰剂对照、3 期试验；Measure Up 1 在欧洲、南北美洲、大洋洲和亚太地区的 24 个国家的 151 个临床中心进行；Measure Up 2 在欧洲、北美、大洋洲和亚太地区的 23 个国家的 154 个临床中心进行。符合条件的患者是患有中度至重度特应性皮炎（≥10% 的体表面积受特应性皮炎、湿疹面积和严重程度指数 [EASI] 评分的青少年（12-17 岁）和成人（18-75 岁） ≥ 16，经验证的特应性皮炎调查员总体评估 [vIGA-AD] 评分≥3，最严重瘙痒数值评定量表评分≥4）。患者被随机分配（1：1：1) 使用交互式反应技术系统接受 upadacitinib 15 mg、upadacitinib 30 mg 或安慰剂，每天一次，持续 16 周，按基线疾病严重程度、地理区域和年龄分层。共同主要终点是 EASI 评分较基线提高至少 75% 的患者比例 (EASI-75) 和达到 vIGA-AD 反应的患者比例（定义为 vIGA-AD 评分为 0 [清除] 或 1 [几乎清除] 且比基线降低 ≥ 2 级）。在意向治疗人群中分析了疗效，并在所有接受至少一剂研究药物的随机分配患者中分析了安全性. 这些试验已在 ClinicalTrials.gov、NCT03569293（Measure Up 1）和 NCT03607422（Measure Up 2）注册，并且都处于活跃状态但未招募。

发现

在 2018 年 8 月 13 日至 2019 年 12 月 23 日期间，847 名患者在 Measure Up 1 研究中被随机分配至 upadacitinib 15 mg（n=281）、upadacitinib 30 mg（n=285）或安慰剂（n=281）。在 Measure Up 2 研究中，2018 年 7 月 27 日至 2020 年 1 月 17 日期间，836 名患者被随机分配到 upadacitinib 15 mg（n=276）、upadacitinib 30 mg（n=282）或安慰剂（n=278）组。在第 16 周，两项研究都达到了共同主要终点（所有 p<0·0001）。在第 16 周达到 EASI-75 的患者比例在 upadacitinib 15 mg（281 名患者中的 196 [70%]）和 upadacitinib 30 mg（285 名患者中的 227 [80%]）组中显着高于安慰剂组（281 名患者中的 46 名 [16%]）在 Measure Up 1（调整后的 EASI-75 响应率与安慰剂，upadacitinib 15 mg 组为 53·3% [95% CI 46·4–60·2]；upadacitinib 30 mg 组为 63·4% [57·1–69·8]）和 Measure Up 2（upadacitinib 15 mg 组 276 名患者中的 166 [60%] 和 upadacitinib 15 mg 组中 282 名患者中的 206 [73%] upadacitinib 30 mg 组vs安慰剂组 278 名患者中的 37 [13%]；调整后的 EASI-75 响应率与安慰剂差异，upadacitinib 15 mg 组为 46·9% [39·9–53·9]；59 ·6% [53·1–66·2]（upadacitinib 30 mg 组）。在 upadacitinib 15 mg（135 [48%] 名患者）和 upadacitinib 30 mg（177 [62%] 名患者）组中，在第 16 周达到 vIGA-AD 反应的患者比例显着高于安慰剂组（24 [48%] 名患者）。 8%] 患者）在 Measure Up 1（调整后的 vIGA-AD 反应率与安慰剂，upadacitinib 15 mg 组为 39·8% [33·2–46·4]；upadacitinib 30 mg 组为 53·6% [47·2–60·0]）和 Measure Up 2（upadacitinib 15 mg 组中有 107 名 [39%] 患者和 upadacitinib 30 mg 组中有 147 名 [52%] 患者与安慰剂组中的 13 [5%] 名患者相比；调整后的 vIGA-AD 反应率与安慰剂，upadacitinib 15 mg 组为 34·0% [27·8–40·2]；upadacitinib 30 mg 组为 47·4% [41·0–53·7]）。两种 upadacitinib 剂量均具有良好的耐受性。严重不良事件和导致研究药物停药的不良事件发生率在各组中相似。最常报告的治疗出现的不良事件是痤疮（upadacitinib 15 mg 组 281 名患者中的 19 [7%]、upadacitinib 30 mg 组 285 名患者中的 49 [17%] 和 281 名患者中的 6 [2%] Measure Up 1 中安慰剂组的患者；upadacitinib 15 mg 组 276 名患者中有 35 名 [13%]，upadacitinib 30 mg 组 282 名患者中有 41 [15%] 名，upadacitinib 30 mg 组 278 名患者中有 6 名 [2%] Measure Up 2 中的安慰剂组，上呼吸道感染（25 [9%] 名患者，38 [13%] 名患者和 20 [7%] 名患者；19 [7%] 名患者，17 [16%] 名患者，

解释

upadacitinib 单药治疗可能是一种有效的治疗选择，并且在患有中度至重度特应性皮炎的青少年和成人中具有积极的获益-风险特征。

资金

艾伯维。