Translational Research in Inflammatory Skin Diseases, Institute for Health Services Research in Dermatology and Nursing, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
AbbVie, North Chicago, IL, USA.
Lancet. 2021 Jun 5;397(10290):2169-2181. doi: 10.1016/S0140-6736(21)00589-4. Epub 2021 May 21.
Systemic therapies are typically combined with topical corticosteroids for the management of moderate-to-severe atopic dermatitis. Upadacitinib is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2 that is being tested for atopic dermatitis. We aimed to assess the efficacy and safety of upadacitinib plus topical corticosteroids compared with placebo for the treatment of moderate-to-severe atopic dermatitis.
In this randomised, double-blind, placebo-controlled, phase 3 trial (AD Up) adults (aged 18-75 years) and adolescents (aged 12-17 years) with chronic atopic dermatitis that was moderate to severe (≥10% of body surface area affected, Eczema Area and Severity Index [EASI] score of ≥16, validated Investigator's Global Assessment for atopic dermatitis [vIGA-AD] score of ≥3, and weekly average Worst Pruritus Numerical Rating Scale score of ≥4 at baseline) were enrolled at 171 clinical centres across 22 countries in the Asia-Pacific region, Europe, the Middle East, North America, and Oceania. Patients were randomly assigned (1:1:1) to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily, all in combination with topical corticosteroids for 16 weeks. Randomisation was done using an interactive response technology system, stratified by baseline disease severity, geographical region, and age. Study investigators, study site personnel, and patients were masked to study treatment. The coprimary endpoints were the proportion of patients who had achieved at least a 75% reduction 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 improvement from baseline) at week 16. Efficacy was analysed in the intention-to-treat population and safety was analysed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03568318, and is active, but not recruiting.
Between Aug 9, 2018, and Dec 20, 2019, 901 patients were randomly assigned to receive upadacitinib 15 mg plus topical corticosteroids (n=300), upadacitinib 30 mg plus topical corticosteroids (n=297), or placebo plus topical corticosteroids (n=304). At week 16, the proportion of patients who had achieved EASI-75 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (194 [65%] of 300 patients) and the upadacitinib 30 mg plus topical corticosteroids group (229 [77%] of 297 patients) than the placebo group (80 [26%] of 304 patients; adjusted difference in EASI-75 response rate vs placebo, 38·1% [95% CI 30·8-45·4] for the upadacitinib 15 mg group and 50·6% [43·8-57·4] for the upadacitinib 30 mg group; p<0·0001 for both doses). The proportion of patients who had achieved a vIGA-AD response at week 16 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (119 [40%] patients) and upadacitinib 30 mg plus topical corticosteroid group (174 [59%] patients) than the placebo group (33 [11%] patients; adjusted difference in vIGA-AD response vs placebo, 28·5% [22·1-34·9] for the upadacitinib 15 mg group and 47·6% [41·1-54·0] for the upadacitinib 30 mg group; p<0·0001 for both doses). During the double-blind period, upadacitinib 15 and 30 mg were well tolerated in combination with topical corticosteroids. The most frequently reported treatment-emergent adverse events (≥5% in any treatment group) were acne, nasopharyngitis, upper respiratory tract infection, oral herpes, elevation of blood creatine phosphokinase levels, headache, and atopic dermatitis. The incidence of acne was higher in the upadacitinib 15 mg (30 [10%] of 300 patients) and upadacitinib 30 mg (41 [14%] of 297 patients) groups than the placebo group (six [2%] of 304 patients). The incidence of adverse events leading to discontinuation of study drug (four [1%] patients in the upadacitinib 15 mg plus topical corticosteroids group, four [1%] patients in the upadacitinib 30 mg plus topical corticosteroids group, and seven [2%] patients in the placebo plus topical corticosteroids group) and serious adverse events (seven [2%] patients, four [1%] patients, and nine [3%] patients) were similar among treatment groups. No deaths were reported in any treatment group.
Upadacitinib plus topical corticosteroids was well tolerated and superior to placebo plus topical corticosteroids. Upadacitinib as combination therapy had a positive benefit-risk profile in adults and adolescents with moderate-to-severe atopic dermatitis.
AbbVie.
对于中重度特应性皮炎，通常将全身性治疗与局部皮质类固醇联合使用。Upadacitinib 是一种口服 Janus 激酶（JAK）抑制剂，对 JAK1 的抑制作用强于 JAK2、JAK3 和酪氨酸激酶 2，目前正在进行特应性皮炎的研究。本研究旨在评估与安慰剂相比，Upadacitinib 联合局部皮质类固醇治疗中重度特应性皮炎的疗效和安全性。
在这项随机、双盲、安慰剂对照、3 期试验（AD Up）中，年龄在 18-75 岁的成人和年龄在 12-17 岁的青少年患有慢性特应性皮炎，病情为中重度（受影响的身体表面积≥10%，Eczema Area and Severity Index[EASI]评分≥16，验证性研究者全球评估特应性皮炎[vIGA-AD]评分≥3，每周平均最差瘙痒数字评定量表评分≥4），在亚洲-太平洋地区、欧洲、中东、北美和大洋洲的 171 个临床中心入组。患者以 1:1:1 的比例随机分配（15mg Upadacitinib、30mg Upadacitinib 或安慰剂），每天一次，均与局部皮质类固醇联合使用 16 周。随机化使用交互式响应技术系统进行，根据基线疾病严重程度、地理位置和年龄进行分层。研究调查人员、研究现场人员和患者对研究治疗均设盲。主要终点是达到 EASI 评分至少下降 75%（EASI-75）的患者比例和达到 vIGA-AD 应答（定义为 vIGA-AD 评分 0[清除]或 1[几乎清除]，且与基线相比至少改善 2 级）的患者比例，均在第 16 周时评估。疗效在意向治疗人群中进行分析，安全性在接受至少一剂研究药物的所有患者中进行分析。这项研究在 ClinicalTrials.gov 上注册，编号为 NCT03568318，正在进行中，但不招募患者。
在 2018 年 8 月 9 日至 2019 年 12 月 20 日期间，901 名患者被随机分配接受 Upadacitinib 15mg 联合局部皮质类固醇（n=300）、Upadacitinib 30mg 联合局部皮质类固醇（n=297）或安慰剂联合局部皮质类固醇（n=304）。在第 16 周时，与安慰剂组（304 名患者中有 80 名[26%]）相比，Upadacitinib 15mg 联合局部皮质类固醇组（300 名患者中有 194 名[65%]）和 Upadacitinib 30mg 联合局部皮质类固醇组（297 名患者中有 229 名[77%]）达到 EASI-75 的患者比例显著更高；Upadacitinib 15mg 组和 Upadacitinib 30mg 组 EASI-75 应答率与安慰剂组的差异分别为 38.1%（95%CI 30.8-45.4）和 50.6%（43.8-57.4）（两组均 p<0.0001）。在第 16 周时，与安慰剂组（304 名患者中有 33 名[11%]）相比，Upadacitinib 15mg 联合局部皮质类固醇组（300 名患者中有 119 名[40%]）和 Upadacitinib 30mg 联合局部皮质类固醇组（297 名患者中有 174 名[59%]）达到 vIGA-AD 应答的患者比例显著更高；Upadacitinib 15mg 组和 Upadacitinib 30mg 组 vIGA-AD 应答与安慰剂组的差异分别为 28.5%（22.1-34.9）和 47.6%（41.1-54.0）（两组均 p<0.0001）。在双盲期间，Upadacitinib 15mg 和 30mg 联合局部皮质类固醇治疗耐受性良好。报告的最常见治疗后出现的不良事件（任何治疗组发生率≥5%）为痤疮、鼻咽炎、上呼吸道感染、单纯疱疹、血肌酸磷酸激酶水平升高、头痛和特应性皮炎。Upadacitinib 15mg（300 名患者中有 30 名[10%]）和 Upadacitinib 30mg（297 名患者中有 41 名[14%]）组的痤疮发生率高于安慰剂组（304 名患者中有 6 名[2%]）。因不良事件而停止研究药物治疗的发生率（Upadacitinib 15mg 加局部皮质类固醇组 4 名[1%]患者、Upadacitinib 30mg 加局部皮质类固醇组 4 名[1%]患者和安慰剂加局部皮质类固醇组 7 名[2%]患者）和严重不良事件（Upadacitinib 15mg 加局部皮质类固醇组 7 名[2%]患者、Upadacitinib 30mg 加局部皮质类固醇组 4 名[1%]患者和安慰剂加局部皮质类固醇组 9 名[3%]患者）在各组间相似。各组均无死亡报告。
Upadacitinib 联合局部皮质类固醇治疗对成人和青少年中重度特应性皮炎的耐受性良好，优于安慰剂联合局部皮质类固醇治疗。在特应性皮炎患者中，Upadacitinib 联合治疗具有良好的获益风险比。
艾伯维。
