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.

Funding

AbbVie.

中文翻译：

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Upadacitinib 作为中度至重度活动性溃疡性结肠炎的诱导和维持治疗：来自三个 3 期、多中心、双盲、随机试验的结果

背景

对能够为溃疡性结肠炎患者提供快速、稳健和持续的疾病控制的先进疗法存在巨大的未满足需求。我们评估了 upadacitinib（一种口服选择性 Janus 激酶 1 抑制剂）作为中度至重度活动性溃疡性结肠炎患者的诱导和维持治疗的疗效和安全性。

方法

该 3 期、多中心、随机、双盲、安慰剂对照临床项目包括两项重复诱导研究（U-ACHIEVE 诱导 [UC1] 和 U-ACCOMPLISH [UC2]）和一项维持研究（U-ACHIEVE 维持 [UC2]）。 UC3]）。这些研究在欧洲、北美和南美、澳大拉西亚、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 个临床中心进行(UC3)。患有中度至重度活动性溃疡性结肠炎（适应 Mayo 评分 5-9；内镜评分 2 或 3 分）至少 90 天的 16-75 岁患者被随机分配（2:1）接受口服 upadacitinib 45 mg 每天一次或安慰剂治疗8 周（诱导研究）。在 8 周 upadacitinib 诱导后达到临床反应的患者被重新随机分配（1:1:1）至 upadacitinib 15 mg、upadacitinib 30 mg 或安慰剂治疗 52 周（维持研究）。所有患者均使用基于网络的交互式响应技术随机分配。主要终点是第 8 周（诱导）和第 52 周（维持）时每个 Adapted Mayo 评分的临床缓解。两项诱导研究中的疗效分析基于意向治疗人群，其中包括所有接受至少一剂治疗的随机患者。在维持研究中，本手稿中报告的主要疗效分析是基于前 450 名（计划的）临床反应者对 upadacitinib 45 mg 每天一次的 8 周诱导治疗的反应。诱导研究中的安全性分析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，该人群包括作为主要分析人群的一部分接受至少一剂治疗的所有患者。这些研究已在 ClinicalTrials.gov、NCT02819635 (U-ACHIEVE) 和 NCT03653026 (U-ACCOMPLISH) 注册。

发现

在 2018 年 10 月 23 日至 2020 年 9 月 7 日期间，474 名患者在 UC1 中被随机分配接受 45 mg 每日一次（n=319）或安慰剂（n=155）的 upadacitinib。在 2018 年 12 月 6 日至 2021 年 1 月 14 日期间，522 名患者在 UC2 中被随机分配接受 45 mg 每日一次（n=345）或安慰剂（n=177）的 upadacitinib。在 UC3 中，共有 451 名患者（21 名来自 2b 期研究，278 名来自 UC1，152 名来自 UC2）在 upadacitinib 诱导治疗 8 周后达到临床反应，再次随机分配到 upadacitinib 15 mg (n=148) 、 upadacitinib 30 mg (n=154) 和安慰剂 (n=149) 在主要分析人群中。与安慰剂组（UC1 154 名患者中的 7 名 [5%]和 174 名患者中的 7 名 [4%]；p<0·0001；调整后的治疗差异为 21·6% [95% CI 15·8–27·4] UC1 和 29·0% [23·2–34·7 ] 对于 UC2)。在维持研究中，接受 upadacitinib 的患者（148 名中的 15 mg 63 [42%]；154 名中的 30 mg 80 [52%]）比接受安慰剂的患者（149 名中的 18 [12%]； p<0·0001；upadacitinib 15 mg 调整后的治疗差异为 30·7% [21·7–39·8]与安慰剂相比，upadacitinib 30 mg与安慰剂相比为 39·0% [29·7–48·2]）。UC1 中最常报告的不良事件是鼻咽炎（upadacitinib 45 mg 组 319 例中的 15 [5%] vs安慰剂组 155 例中的 6 [4%]）、肌酸磷酸激酶升高（15 [4%] vs 3 [ 2%]）和痤疮（15 [5%]对1 [1%]）。在 UC2 中，最常报告的不良事件是痤疮（upadacitinib 45 mg 组 344 例中的 24 例 [7%]与安慰剂组 177 例中的 3 例 [2%]）。在两项诱导研究中，upadacitinib 45 mg 组的严重不良事件和导致停止治疗的不良事件发生率低于安慰剂组（严重不良事件 8 [3%]与UC1 中的 9 (6%) 和 UC2 中的 11 [3%]与8 [5%]；导致停药的不良事件在 UC1 中有6 [2%]对14 [9%]，在 UC2中有 6 [2%]对9 [5%]）。在 UC3 中，最常报告的不良事件 (≥5%) 是溃疡性结肠炎恶化（乌帕替尼 15 mg 组 148 例中的 19 [13%] vs upadacitinib 30 mg 组 154 例中的 11 [7%] vs 45 [安慰剂组 149 人中的 30%），鼻咽炎（18 [12%] vs 22 [14%] vs 15 [10%]），肌酸磷酸激酶升高（9 [6%] vs 13 [8%] vs 3 [ 2%]），关节痛（9 [6%] vs 5 [3%] vs15 [10%]）和上呼吸道感染（7 [5%] vs 9 [6%] vs 6 [4%]）。严重不良事件（10 [7%] vs 9 [6%] vs 19 [13%]）和导致停药的不良事件（6 [4%] vs 10 [6%] vs 17 [11%]）的比例两个 upadacitinib 组均低于安慰剂组。癌症事件、经裁定的主要不良心脏事件或静脉血栓栓塞的报道很少。没有与治疗相关的死亡。

解释

Upadacitinib 表现出积极的疗效和安全性，可能是中度至重度活动性溃疡性结肠炎患者的有效治疗选择。

资金

艾伯维。