乌帕替尼诱导缓解和维持治疗克罗恩病。
Upadacitinib Induction and Maintenance Therapy for Crohn's Disease.
机构信息
From the Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN (E.V.L.); the Inflammatory Bowel Diseases Unit, Hospital Clinic Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona (J.P.); AbbVie, North Chicago, IL (A.P.L., C.P., M-E.F.M., J.L., Z.G., T.F., E.D.); the Department of Gastroenterology and INSERM Unité 1256, Nutrition-Genetics and Environmental Risk Exposure, Faculty of Medicine, University Hospital of Nancy, Lorraine University, Vandoeuvre, France (L.P.-B.); the Department of Gastroenterology, Amsterdam University Medical Centers, Amsterdam (G.D.); the Inflammatory Bowel Disease Unit, Division of Gastroenterology and Hepatology, University of Calgary, Calgary, AB, Canada (R.P.); the Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna (W.R.); the Department of Hepato-Gastroenterology and Digestive Oncology, University Hospital Centre Hospitalier Universitaire of Liège, Liège, Belgium (E.L.); the Division of Gastroenterology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (M.C.); the Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan (H.N.); the Department of Gastroenterology, Mater Hospital Brisbane, Brisbane, QLD, Australia (J.B.); the Division of Gastroenterology, University of California, San Diego, La Jolla (B.B.); and the Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York (J.-F.C.).
出版信息
N Engl J Med. 2023 May 25;388(21):1966-1980. doi: 10.1056/NEJMoa2212728.
BACKGROUND
Upadacitinib, an oral selective Janus kinase (JAK) inhibitor, is under investigation for the treatment of Crohn's disease.
METHODS
In two phase 3 induction trials (U-EXCEL and U-EXCEED), we randomly assigned patients with moderate-to-severe Crohn's disease to receive 45 mg of upadacitinib or placebo (2:1 ratio) once daily for 12 weeks. Patients who had a clinical response to upadacitinib induction therapy were randomly assigned in the U-ENDURE maintenance trial to receive 15 mg of upadacitinib, 30 mg of upadacitinib, or placebo (1:1:1 ratio) once daily for 52 weeks. The primary end points for induction (week 12) and maintenance (week 52) were clinical remission (defined as a Crohn's Disease Activity Index score of <150 [range, 0 to 600, with higher scores indicating more severe disease activity]) and endoscopic response (defined as a decrease in the Simple Endoscopic Score for Crohn's Disease [SES-CD; range, 0 to 56, with higher scores indicating more severe disease] of >50% from baseline of the induction trial [or for patients with an SES-CD of 4 at baseline, a decrease of ≥2 points from baseline]).
RESULTS
A total of 526 patients underwent randomization in U-EXCEL, 495 in U-EXCEED, and 502 in U-ENDURE. A significantly higher percentage of patients who received 45-mg upadacitinib than those who received placebo had clinical remission (in U-EXCEL, 49.5% vs. 29.1%; in U-EXCEED, 38.9% vs. 21.1%) and an endoscopic response (in U-EXCEL, 45.5% vs. 13.1%; in U-EXCEED, 34.6% vs. 3.5%) (P<0.001 for all comparisons). At week 52 in U-ENDURE, a higher percentage of patients had clinical remission with 15-mg upadacitinib (37.3%) or 30-mg upadacitinib (47.6%) than with placebo (15.1%), and a higher percentage had an endoscopic response with 15-mg upadacitinib (27.6%) or 30-mg upadacitinib (40.1%) than with placebo (7.3%) (P<0.001 for all comparisons). Herpes zoster infections occurred more frequently in the 45-mg and 30-mg upadacitinib groups than in the respective placebo groups, and hepatic disorders and neutropenia were more frequent in the 30-mg upadacitinib group than in the other maintenance groups. Gastrointestinal perforations developed in 4 patients who received 45-mg upadacitinib and in 1 patient each who received 30-mg or 15-mg upadacitinib.
CONCLUSIONS
Upadacitinib induction and maintenance treatment was superior to placebo in patients with moderate-to-severe Crohn's disease. (Funded by AbbVie; U-EXCEL, U-EXCEED, and U-ENDURE ClinicalTrials.gov numbers, NCT03345849, NCT03345836, and NCT03345823.).
背景
Upadacitinib 是一种口服选择性 Janus 激酶（JAK）抑制剂，正在研究用于治疗克罗恩病。
方法
在两项 3 期诱导试验（U-EXCEL 和 U-EXCEED）中，我们将中度至重度克罗恩病患者随机分为每日一次接受 45mg 乌帕替尼或安慰剂（2:1 比例）治疗 12 周。对乌帕替尼诱导治疗有临床反应的患者在 U-ENDURE 维持试验中被随机分为每日一次接受 15mg 乌帕替尼、30mg 乌帕替尼或安慰剂（1:1:1 比例）治疗 52 周。诱导（第 12 周）和维持（第 52 周）的主要终点是临床缓解（定义为克罗恩病活动指数评分<150[范围 0 至 600，得分越高表示疾病活动度越严重]）和内镜缓解（定义为简单克罗恩病内镜评分[SES-CD；范围 0 至 56，得分越高表示疾病越严重]从诱导试验的基线下降>50%[或对于基线 SES-CD 为 4 的患者，从基线下降≥2 分]）。
结果
共有 526 名患者在 U-EXCEL 中接受随机分组，495 名在 U-EXCEED 中，502 名在 U-ENDURE 中。接受 45mg 乌帕替尼的患者与接受安慰剂的患者相比，有临床缓解的比例显著更高（U-EXCEL 中为 49.5%比 29.1%；U-EXCEED 中为 38.9%比 21.1%）和内镜缓解（U-EXCEL 中为 45.5%比 13.1%；U-EXCEED 中为 34.6%比 3.5%）（所有比较均 P<0.001）。在 U-ENDURE 的第 52 周，与安慰剂相比，接受 15mg 乌帕替尼（37.3%）或 30mg 乌帕替尼（47.6%）的患者有临床缓解的比例更高，与安慰剂相比，接受 15mg 乌帕替尼（27.6%）或 30mg 乌帕替尼（40.1%）的患者有内镜缓解的比例更高（所有比较均 P<0.001）。与相应的安慰剂组相比，45mg 和 30mg 乌帕替尼组更常发生带状疱疹感染，与其他维持组相比，30mg 乌帕替尼组更常发生肝障碍和中性粒细胞减少症。4 名接受 45mg 乌帕替尼治疗的患者和 1 名接受 30mg 或 15mg 乌帕替尼治疗的患者发生胃肠道穿孔。
结论
在中度至重度克罗恩病患者中，乌帕替尼诱导和维持治疗优于安慰剂。（由 AbbVie 资助；U-EXCEL、U-EXCEED 和 U-ENDURE 临床试验.gov 编号，NCT03345849、NCT03345836 和 NCT03345823）。
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