爱尔兰都柏林大学Alan D Irvine团队比较了每日一次乌帊替尼与安慰剂治疗中重度特应性皮炎青少年和成人的疗效。2021年5月20日，该成果发表在《柳叶刀》杂志上。
乌帊替尼是一种口服Janus激酶（JAK）抑制剂，对JAK1的抑制效力大于JAK2、JAK3和酪氨酸激酶2。为了评估乌帊替尼与安慰剂治疗中重度特应性皮炎的疗效和安全性，研究组进行了两项重复的多中心、随机、双盲、安慰剂对照、3期临床试验，其中队列1在欧洲、北美、南美、大洋洲和亚太地区的24个国家的151个临床中心进行；队列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。
研究组招募青少年（12-17岁）和成人（18-75岁）中重度特应性皮炎患者，将其按1：1：1随机分配，分别接受乌帊替尼15 mg、乌帊替尼30 mg、或安慰剂治疗，每天一次，持续16周，按基线疾病严重程度、地理区域和年龄进行分层。主要终点为16周时EASI评分较基线至少改善75%的患者比例（EASI-75）和达到vIGA AD缓解的患者比例（定义为vIGA AD评分为0[清除]或1[几乎清除]，且比基线至少改善两级）。在意向治疗人群中分析疗效。
2018年8月13日至2019年12月23日，队列1共招募了847名患者，其中乌帊替尼15 mg组281例，乌帊替尼30 mg组285例，安慰剂组281例。2018年7月27日至2020年1月17日，队列2共招募了836名患者，其中乌帊替尼15 mg组276例，乌帊替尼30 mg组282例，安慰剂组278例。
第16周时，在队列1中，乌帊替尼15 mg组有70%的患者达到EASI-75，乌帊替尼30 mg组有80%，均显著高于安慰剂组的16%；在队列2中，乌帊替尼15 mg组有60%的患者达到EASI-75，乌帊替尼30 mg组有73%，亦显著高于安慰剂组的13%。16周时，在队列1中，乌帊替尼15 mg组有48%的患者达到vIGA AD缓解，乌帊替尼30 mg组有62%，均显著高于安慰剂组的8%；在队列2中，乌帊替尼15 mg组有39%的患者达到vIGA AD缓解，乌帊替尼30 mg组有52%，亦均显著高于安慰剂组的5%。
两种剂量的乌帊替尼都具有良好的耐受性。组间严重不良事件和导致研究药物停药的不良事件发生率相似。最常报告的因治疗引起的不良事件是痤疮（队列1中乌帊替尼15 mg组的发生率为7%，乌帊替尼30 mg组为17%，安慰剂组仅为2%；队列2中乌帊替尼15 mg组的发生率为13%，乌帊替尼30 mg组为15%，安慰剂组为2%）、上呼吸道感染（9%、13%、7%、7%、16%、4%）、鼻咽炎（8%、12%、6%、6%、6%、5%）、头痛（5%、7%、4%、7%、7%、4%）、肌酸磷酸激酶水平升高（6%、6%、3%、3%、4%、2%）和过敏性皮炎（3%、1%、9%、3%、1%、9%）。
研究结果表明，乌帊替尼单药治疗中重度特应性皮炎青少年和成人疗效显著，具有较好的临床益处。
附：英文原文
Title: Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomised controlled phase 3 trials
Author: Emma Guttman-Yassky, Henrique D Teixeira, Eric L Simpson, Kim A Papp, Aileen L Pangan, Andrew Blauvelt, Diamant Thai, Chia-Yu Chu, H Chih-ho Hong, Norito Kato, Amy S Paller, Brian Calimlim, Yihua Gu, Xiaofei Hu, Meng Liu, Yang Yang, John Liu, Allan R Tenorio, Alvina D Chu, Alan D Irvine
Issue&Volume: 2021-05-20
Abstract:
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.
DOI: 10.1016/S0140-6736(21)00588-2
Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00588-2/fulltext
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