Rubin David T, Allegretti Jessica R, Panés Julián, Shipitofsky Nicole, Yarandi Shadi S, Huang Kuan-Hsiang Gary, Germinaro Matthew, Wilson Rebbecca, Zhang Hongyan, Johanns Jewel, Feagan Brian G, Hisamatsu Tadakazu, Lichtenstein Gary R, Bressler Brian, Peyrin-Biroulet Laurent, Sands Bruce E, Dignass Axel
University of Chicago Medicine Inflammatory Bowel Disease Centre, Chicago, IL, USA.
Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Lancet. 2025 Jan 4;405(10472):33-49. doi: 10.1016/S0140-6736(24)01927-5. Epub 2024 Dec 17.
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.
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.
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.
Guselkumab was effective and safe as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis.
Janssen Research and Development.
白细胞介素-23抑制疗法在治疗溃疡性结肠炎方面有效。古塞库单抗是一种双效人IgG1白细胞介素-23p19亚基抑制剂，可有效中和白细胞介素-23并能与CD64结合。我们旨在评估古塞库单抗作为溃疡性结肠炎患者诱导和维持治疗的疗效及安全性。
这两项3期随机、双盲、安慰剂对照研究（QUASAR 3期诱导和维持研究）的主要人群包括随机分组并接受治疗的中度至重度活动性溃疡性结肠炎成年患者（诱导期基线改良梅奥评分5至9分），这些患者对传统或先进的溃疡性结肠炎治疗反应不佳或不耐受。患者被随机分配（3:2）在第0、4和8周接受静脉注射200mg古塞库单抗或安慰剂（3期诱导研究）。所有患者均使用基于网络的交互式应答技术进行随机分配。静脉注射古塞库单抗诱导治疗12周后出现临床缓解的患者（来自QUASAR 2b期和3期诱导研究）在维持期第0周被随机分配（1:1:1），分别接受每4周皮下注射200mg古塞库单抗、每8周皮下注射100mg古塞库单抗或安慰剂，为期44周（维持期）。主要终点为诱导期第12周和维持期第44周的临床缓解。本研究已在ClinicalTrials.gov注册，注册号为NCT04033445。
诱导研究的主要人群包括701例患者（静脉注射200mg古塞库单抗组占60% [421例患者]；安慰剂组占40% [280例患者]）。维持研究的主要人群包括568例古塞库单抗诱导治疗有反应的患者，他们被随机分配接受每4周皮下注射200mg古塞库单抗（190例[33%]患者）、每8周皮下注射100mg古塞库单抗（188例[33%]患者）或安慰剂（停止使用古塞库单抗组190例[33%]患者）。静脉注射古塞库单抗治疗的患者在诱导期第12周临床缓解的比例（23% [421例患者中的95例]）显著高于安慰剂治疗的患者（8% [280例患者中的22例]；调整后的治疗差异为15%，95%置信区间为10 - 20；p<0.0001）。每4周皮下注射200mg古塞库单抗（50% [190例患者中的95例]；调整后的治疗差异为30%，95%置信区间为21 - 38；p<0.0001）和每8周皮下注射100mg古塞库单抗（45% [188例患者中的85例]；调整后的治疗差异为25%，16 - 34；p<0.0001）的患者在维持期第44周临床缓解的比例显著高于安慰剂组（19% [190例患者中的36例]）。总体安全性良好，与古塞库单抗在已批准适应症中的情况一致。在诱导研究中，两组均有49%的患者报告了不良事件（4个21例接受古塞库单抗治疗的患者中有208例，280例接受安慰剂治疗的患者中有138例），接受古塞库单抗治疗的患者中有3%（421例中的12例）报告了严重不良事件，接受安慰剂治疗的患者中有7%（280例中的20例）报告了严重不良事件，接受古塞库单抗治疗的患者中有2%（421例中的7例）和接受安慰剂治疗的患者中有4%（280例中的11例）报告了导致治疗中断的不良事件。在维持研究中，各组不良事件发生率相似，所有组中最常报告的不良事件为溃疡性结肠炎、COVID - 19和关节痛。两项研究均未报告活动性结核病、过敏反应、血清病或具有临床意义的肝脏疾病。
古塞库单抗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。
杨森研发公司。
