Background

Interleukin-23 inhibition is effective in treating ulcerative colitis. Guselkumab is a dual-acting, human IgG1, interleukin-23p19 subunit inhibitor that potently neutralises interleukin-23 and can bind to CD64. We aimed to evaluate the efficacy and safety of guselkumab as induction and maintenance therapy in patients with ulcerative colitis.

Methods

The primary populations of these two phase 3, randomised, double-blind, placebo-controlled studies (QUASAR phase 3 induction and maintenance) included randomised and treated adults with moderately to severely active ulcerative colitis (induction baseline modified Mayo score from 5 to 9) with inadequate response or intolerance to conventional or advanced ulcerative colitis therapy. Patients were randomly assigned (3:2) to receive guselkumab 200 mg given intravenously or placebo at weeks 0, 4, and 8 (phase 3 induction study). All patients were randomly assigned using web-based interactive response technology. Patients in clinical response 12 weeks after guselkumab induction given intravenously (from QUASAR phase 2b and phase 3 induction studies) were randomly assigned (1:1:1) at maintenance week 0 to guselkumab 200 mg given subcutaneously every 4 weeks or 100 mg every 8 weeks or placebo for 44 weeks (maintenance). Primary endpoints were clinical remission at induction week 12 and maintenance week 44. This study is registered with ClinicalTrials.gov, NCT04033445.

Findings

The induction study primary population included 701 patients (guselkumab 200 mg given intravenously 60% [421 patients]; placebo 40% [280 patients]). The maintenance study primary population included 568 guselkumab induction responders randomly assigned to receive guselkumab 200 mg given subcutaneously every 4 weeks (190 [33%] patients) or 100 mg every 8 weeks (188 [33%] patients) or placebo (guselkumab withdrawal 190 [33%] patients). A significantly greater proportion of patients treated with guselkumab given intravenously had clinical remission at induction week 12 (23% [95 of 421 patients]) than did placebo-treated patients (8% [22 of 280 patients]; adjusted treatment difference 15%, 95% CI 10–20; p<0·0001). Clinical remission at maintenance week 44 was achieved by a significantly greater proportion of patients treated with guselkumab 200 mg given subcutaneously every 4 weeks (50% [95 of 190 patients]; adjusted treatment difference 30%, 95% CI 21–38; p<0·0001) and 100 mg every 8 weeks (45% [85 of 188 patients]; adjusted treatment difference 25%, 16–34; p<0·0001) than with placebo (19% [36 of 190 patients]). The overall safety profile was favourable and consistent with that of guselkumab in approved indications. In the induction study, adverse events were reported by 49% of patients in both groups (208 of 421 guselkumab-treated patients and 138 of 280 placebo-treated patients), serious adverse events were reported by 3% (12 of 421) of guselkumab-treated patients and 7% (20 of 280) of placebo-treated patients, and adverse events leading to treatment discontinuation were reported by 2% (seven of 421) of guselkumab-treated patients and 4% (11 of 280) of placebo-treated patients. In the maintenance study, adverse event rates were similar among groups, and the most frequently reported adverse events in all groups were ulcerative colitis, COVID-19, and arthralgia. No active tuberculosis, anaphylaxis, serum sickness, or clinically important hepatic disorders were reported in either study.

Interpretation

Guselkumab was effective and safe as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis.

Funding

Janssen Research and Development.

中文翻译：

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Guselkumab 治疗中度至重度活动性溃疡性结肠炎患者 （QUASAR）：3 期双盲、随机、安慰剂对照诱导和维持研究

 背景

白细胞介素 23 抑制对治疗溃疡性结肠炎有效。Guselkumab 是一种双作用的人 IgG1、白细胞介素-23p19 亚基抑制剂，可有效中和白细胞介素-23 并可与 CD64 结合。我们旨在评价 guselkumab 作为溃疡性结肠炎患者诱导和维持治疗的疗效和安全性。

 方法

这两项 3 期、随机、双盲、安慰剂对照研究（QUASAR 3 期诱导和维持）的主要人群包括随机和治疗的中度至重度活动性溃疡性结肠炎（诱导基线改良 Mayo 评分从 5 分到 9 分）的成人，他们对常规或晚期溃疡性结肠炎治疗反应不足或不耐受。患者被随机分配 （3：2） 在第 0 、 4 和 8 周接受 guselkumab 200 mg 静脉注射或安慰剂 （3 期诱导研究）。所有患者均使用基于 Web 的交互式响应技术随机分配。静脉内给予 guselkumab 诱导后 12 周（来自 QUASAR 2b 期和 3 期诱导研究）有临床反应的患者在维持第 0 周随机分配 （1：1：1） 接受 guselkumab 200 mg 皮下注射每 4 周一次或 100 mg 每 8 周一次或安慰剂 44 周（维持）。主要终点是诱导第 12 周和维持第 44 周的临床缓解。这项研究已在 ClinicalTrials.gov， NCT04033445 注册。

 发现

诱导研究主要人群包括 701 名患者 （guselkumab 200 mg 静脉注射 60% [421 名患者];安慰剂 40% [280 名患者]）。维持研究主要人群包括 568 名 guselkumab 诱导反应者，随机分配接受 guselkumab 200 mg 皮下注射每 4 周一次（190 名 [33%] 患者）或每 8 周 100 mg 给药（188 名 [33%] 患者）或安慰剂（guselkumab 戒断 190 名 [33%] 患者）。与安慰剂治疗的患者（8% [280 例患者中的 22 例];调整治疗差异 15%，95% CI 10-20;p<0·0001）相比，静脉注射 guselkumab 治疗的患者在诱导第 12 周获得临床缓解的比例显著更高（23% [421 例患者中的 95 例]）。在维持第 44 周接受皮下注射 guselkumab 200 mg 每 4 周一次（50% [190 例患者中的 95 例];调整后的治疗差异 30%，95% CI 21-38;p<0·0001）和 100 mg 每 8 周（45% [188 例患者中的 85 例];调整后的治疗差异 25%， 16–34;p<0·0001）比安慰剂（19% [190 名患者中的 36 名]）。在已批准的适应症中，总体安全性良好且与 guselkumab 一致。在诱导研究中，两组中 49% 的患者（421 名 guselkumab 治疗患者中的 208 名和 280 名安慰剂治疗患者中的 138 名）报告了不良事件，guselkumab 治疗患者中有 3%（421 名中的 12 名）和 7%（280 名中的 20 名）安慰剂治疗患者报告了严重不良事件，导致治疗中断的不良事件有 2%（421 名中的 7 名）和 4%（280 名中的 11 名）接受安慰剂治疗的患者。 在维持研究中，各组之间的不良事件发生率相似，所有组中报告最频繁的不良事件是溃疡性结肠炎、 COVID-19 和关节痛。两项研究均未报告活动性肺结核、过敏反应、血清病或临床上重要的肝脏疾病。

 解释

Guselkumab 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有效且安全。

 资金

杨森研发公司。