意大利圣拉斐尔大学Silvio Danese团队研究了乌帕替尼作为中度至重度活动性溃疡性结肠炎的诱导和维持治疗的效果与安全性。2022年5月26日出版的《柳叶刀》发表了这项成果。

对于为溃疡性结肠炎患者提供快速、有力和持续的疾病控制的先进疗法，还有很大需求未被满足。研究组评估了口服选择性Janus激酶1抑制剂乌帕替尼作为诱导和维持治疗中度至重度活动性溃疡性结肠炎患者的有效性和安全性。

这一临床3期、多中心、随机、双盲、安慰剂对照临床计划包括两项重复诱导研究（U-ACHIEVE诱导[UC1]和U-ACHIEVE[UC2]）和一项单一维持研究（U-ACHIEVE维持[UC3]）。这项研究在欧洲、北美和南美、澳大利亚、非洲和亚太地区的39个国家的199个临床中心（UC1）、40个国家的204个临床中心（UC2）和35个国家的195个临床中心（UC3）进行。

招募年龄在16-75岁之间、患有中度至重度活动性溃疡性结肠炎至少90天的患者（适应梅奥评分5-9；内窥镜评分2或3），将其随机分配（2:1），每日一次口服45 mg乌帕替尼或安慰剂，为期8周（诱导研究）。在8周的乌帕替尼诱导后取得临床疗效的患者被重新随机分配（1:1:1）至乌帕替尼15 mg、乌帕替尼30 mg或安慰剂组，为期52周（维持研究）。

所有患者均采用基于网络的交互反应技术随机分配。主要终点是第8周（诱导期）和第52周（维持期）的临床缓解率。两项诱导研究中的疗效分析基于意向治疗人群，包括所有接受至少一剂治疗的随机患者。

在维持研究中，课题组报道的主要疗效分析基于首批450名（计划中）临床缓解者，他们接受了为期8周的乌帕替尼诱导治疗，每日一次，每次45 mg。诱导研究中的安全性分析人群包括接受至少一剂治疗的所有随机患者；在维持研究中，作为主要分析人群的一部分，包括所有接受至少一剂治疗的患者。

2018年10月23日至2020年9月7日，474名患者被随机分配到UC1中，其中319例每日服用一次45 mg乌帕替尼，155例服用安慰剂。2018年12月6日至2021年1月14日，522名患者被随机分配到UC2中，其中345例每日服用一次45 mg乌帕替尼，177例服用安慰剂。在UC3中，共有451名患者（21名来自临床2b期研究，278名来自UC1，152名来自UC2）在8周的乌帕替尼诱导治疗后取得临床疗效，再次随机分配，其中乌帕替尼15 mg组148例，乌帕替尼30 mg组154例，安慰剂组149例。

45 mg乌帕替尼队列中UC1组319名患者中有83名（26%）获得临床缓解，UC2组341名患者中有114名（34%），均显著高于安慰剂队列，即UC1组154名患者中有7名（5%），UC2组174名患者中有7名（4%），UC1组校正治疗差异为21.6%，UC2组为29.0%。在维持研究中，乌帕替尼15 mg组148名患者中有63名（42%）获得临床缓解，乌帕替尼30 mg组154名患者中有80名（52%），均显著高于安慰剂队列，即149名患者中有18名（12%），校正后的治疗差异分别30.7%和39.0%。

UC1中最常见的不良事件是鼻咽炎（乌帕替尼45 mg组319例中有15例[5%]，安慰剂组155例中有6例[4%]）、肌酸磷酸激酶升高（分别为15例[4%]与3例[2%]）和痤疮（分别为15例[5%]与1例[1%]）。UC2中最常报告的不良事件是痤疮（乌帕替尼45 mg组344例中有24例[7%]，安慰剂组177例中有3例[2%]）。

在这两项诱导研究中，乌帕替尼45 mg组的严重不良事件（UC1组8例[3%]，安慰剂组9例[6%]；UC2组11例[3%]，安慰剂组8例[5%]）和导致停药的不良事件发生率（UC1组6例[2%]，安慰剂组14例[9%]；UC2组6例[2%]，安慰剂组9例[5%]）均低于安慰剂组。

UC3中最常报告的不良事件（≥5%）为溃疡性结肠炎恶化（乌帕替尼15 mg组148例中有19例[13%]、乌帕替尼30 mg组154例中有11例[7%]、安慰剂组149例中有45例[30%]）、鼻咽炎（18例[12%]、22例[14%]、15例[10%]）、肌酸磷酸激酶升高（9例[6%]、13例[8%]、3例[2%]）、关节痛（9例[6%]、5例[3%]、15例[10%]），上呼吸道感染（7例[5%]、9例[6%]、6例[4%]）。

两个乌帕替尼组的严重不良事件（乌帕替尼15 mg组有10例[7%]、乌帕替尼30 mg组有9例[6%]、安慰剂组有19例[13%]）和导致停药的不良事件（分别为6例[4%]、10例[6%]、17例[11%]）发生率均低于安慰剂组。很少报告癌症事件、判定的重大心脏不良事件或静脉血栓栓塞。没有治疗相关死亡。

研究结果表明，乌帕替尼显示出积极的疗效和安全性，可能是中重度活动性溃疡性结肠炎患者的有效治疗选择。

附：英文原文

Title: Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials

Author: Silvio Danese, Séverine Vermeire, Wen Zhou, Aileen L Pangan, Jesse Siffledeen, Susan Greenbloom, Xavier Hébuterne, Geert DHaens, Hiroshi Nakase, Julian Panés, Peter D R Higgins, Pascal Juillerat, James O Lindsay, Edward V Loftus, William J Sandborn, Walter Reinisch, Min-Hu Chen, Yuri Sanchez Gonzalez, Bidan Huang, Wangang Xie, John Liu, Michael A Weinreich, Remo Panaccione

Issue&Volume: 2022-05-26

Abstract:

Background

There is a great unmet need for advanced therapies that provide rapid, robust, and sustained disease control for patients with ulcerative colitis. We assessed the efficacy and safety of upadacitinib, an oral selective Janus kinase 1 inhibitor, as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis.

Methods

This phase 3, multicentre, randomised, double-blind, placebo-controlled clinical programme consisted of two replicate induction studies (U-ACHIEVE induction [UC1] and U-ACCOMPLISH [UC2]) and a single maintenance study (U-ACHIEVE maintenance [UC3]). The studies were conducted across Europe, North and South America, Australasia, Africa, and the Asia-Pacific region at 199 clinical centres in 39 countries (UC1), 204 clinical centres in 40 countries (UC2), and 195 clinical centres in 35 countries (UC3). Patients aged 16–75 years with moderately to severely active ulcerative colitis (Adapted Mayo score 5–9; endoscopic subscore 2 or 3) for at least 90 days were randomly assigned (2:1) to oral upadacitinib 45 mg once daily or placebo for 8 weeks (induction studies). Patients who achieved clinical response following 8-week upadacitinib induction were re-randomly assigned (1:1:1) to upadacitinib 15 mg, upadacitinib 30 mg, or placebo for 52 weeks (maintenance study). All patients were randomly assigned using web-based interactive response technology. The primary endpoints were clinical remission per Adapted Mayo score at week 8 (induction) and week 52 (maintenance). The efficacy analyses in the two induction studies were based on the intent-to-treat population, which included all randomised patients who received at least one dose of treatment. In the maintenance study, the primary efficacy analyses reported in this manuscript were based on the first 450 (planned) clinical responders to 8-week induction therapy with upadacitinib 45 mg once daily. The safety analysis population in the induction studies consisted of all randomised patients who received at least one dose of treatment; in the maintenance study, this population included all patients who received at least one dose of treatment as part of the primary analysis population. These studies are registered at ClinicalTrials.gov, NCT02819635 (U-ACHIEVE) and NCT03653026 (U-ACCOMPLISH).

Findings

Between Oct 23, 2018, and Sept 7, 2020, 474 patients were randomly assigned to upadacitinib 45 mg once daily (n=319) or placebo (n=155) in UC1. Between Dec 6, 2018, and Jan 14, 2021, 522 patients were randomly assigned to upadacitinib 45 mg once daily (n=345) or placebo (n=177) in UC2. In UC3, a total of 451 patients (21 from the phase 2b study, 278 from UC1, and 152 from UC2) who achieved a clinical response after 8 weeks of upadacitinib induction treatment were randomly assigned again to upadacitinib 15 mg (n=148), upadacitinib 30 mg (n=154), and placebo (n=149) in the primary analysis population. Statistically significantly more patients achieved clinical remission with upadacitinib 45 mg (83 [26%] of 319 patients in UC1 and 114 [34%] of 341 patients in UC2) than in the placebo group (seven [5%] of 154 patients in UC1 and seven [4%] of 174 patients; p<0·0001; adjusted treatment difference 21·6% [95% CI 15·8–27·4] for UC1 and 29·0% [23·2–34·7] for UC2). In the maintenance study, clinical remission was achieved by statistically significantly more patients receiving upadacitinib (15 mg 63 [42%] of 148; 30 mg 80 [52%] of 154) than those receiving placebo (18 [12%] of 149; p<0·0001; adjusted treatment difference 30·7% [21·7–39·8] for upadacitinib 15 mg vs placebo and 39·0% [29·7–48·2] for upadacitinib 30 mg vs placebo). The most commonly reported adverse events in UC1 were nasopharyngitis (15 [5%] of 319 in the upadacitinib 45 mg group vs six [4%] of 155 in the placebo group), creatine phosphokinase elevation (15 [4%] vs three [2%]), and acne (15 [5%] vs one [1%]). In UC2, the most frequently reported adverse event was acne (24 [7%] of 344 in the upadacitinib 45 mg group vs three [2%] of 177 in the placebo group). In both induction studies, serious adverse events and adverse events leading to discontinuation of treatment were less frequent in the upadacitinib 45 mg group than in the placebo group (serious adverse events eight [3%] vs nine (6%) in UC1 and 11 [3%] vs eight [5%] in UC2; adverse events leading to discontinuation six [2%] vs 14 [9%] in UC1 and six [2%] vs nine [5%] in UC2). In UC3, the most frequently reported adverse events (≥5%) were worsening of ulcerative colitis (19 [13%] of 148 in the upadacitinib 15 mg group vs 11 [7%] of 154 in the upadacitinib 30 mg group vs 45 [30%] of 149 in the placebo group), nasopharyngitis (18 [12%] vs 22 [14%] vs 15 [10%]), creatine phosphokinase elevation (nine [6%] vs 13 [8%] vs three [2%]), arthralgia (nine [6%] vs five [3%] vs 15 [10%]), and upper respiratory tract infection (seven [5%] vs nine [6%] vs six [4%]). The proportion of serious adverse events (ten [7%] vs nine [6%] vs 19 [13%]) and adverse events leading to discontinuation (six [4%] vs ten [6%] vs 17 [11%]) was lower in both upadacitinib groups than in the placebo group. Events of cancer, adjudicated major adverse cardiac events, or venous thromboembolism were reported infrequently. There were no treatment-related deaths.

Interpretation

Upadacitinib demonstrated a positive efficacy and safety profile and could be an effective treatment option for patients with moderately to severely active ulcerative colitis.

DOI: 10.1016/S0140-6736(22)00581-5

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)00581-5/fulltext