近日，美国强生公司Gulam Khan团队研究了克罗恩病患者使用古塞库单抗进行静脉注射诱导和皮下维持治疗的疗效和安全性。相关论文于2025年7月17日发表在《柳叶刀》杂志上。

尽管有生物疗法，但克罗恩病患者的疾病控制欠佳仍然是一个问题。研究组报告了GALAXI-2和GALAXI-3研究的结果，这些研究旨在评估中度至重度活动性克罗恩病成人患者静脉诱导后皮下使用古塞库单抗维持治疗超过48周的有效性和安全性。

GALAXI-2和GALAXI-3是设计相同的3期随机、双盲试验，有活性对照和安慰剂对照。患有中度至重度活动性克罗恩病（病程≥3个月）的成年患者在40个国家的257个地点入组。通过使用集中计算机生成的时间表，将符合条件的参与者随机分配（2:2:2:1）到以下四个治疗组之一：(1)在第0、4和8周静脉注射200毫克古塞库单抗，然后从第12周到第44周每4周皮下注射200毫克古塞库单抗（200毫克组）；(2)在第0、4、8周静脉注射200 mg古塞库单抗，然后从第16周至第40周每8周皮下注射100 mg古塞库单抗（古塞库单抗100 mg组）；(3)在第0周静脉注射约6mg /kg的ustekinumab，然后从第8周至第40周每8周皮下注射90mg ustekinumab （ustekinumab组）；(4)在第0、4、8周每4周静脉注射一次安慰剂（安慰剂组）。

在第12周，对安慰剂无临床缓解的参与者接受了ustekinumab的掩盖挽救治疗；所有其他参与者在第12周无论反应状态如何，仍按随机方案进行治疗。受试者、调查人员、现场工作人员和资助者被屏蔽以研究治疗，直到所有受试者在第48周完成随访或在第48周之前终止研究参与。主要的复合终点（将每个古塞库单抗方案与安慰剂进行比较）是(1)第12周的临床反应和第48周的临床缓解；(2)第12周的临床反应和第48周的内镜反应。在初始分析人群中测量所有随机分配的受试者，这些受试者接受了至少一剂研究药物，并满足根据卫生当局要求引入的第三项方案修正案引入的克罗恩病简单内窥镜评分（SES-CD）资格标准。对接受至少一剂研究治疗的参与者（全治疗分析人群）进行安全性评估。

从2020年1月8日至2023年10月20日，1048名参与者被随机分配、治疗并随访至第48周，其中1021名参与者被纳入主要分析人群：508名（49.8%）参与者被纳入GALAXI-2，513名（50.2%）参与者被纳入GALAXI-3。在第12周的临床缓解终点和第48周的临床缓解终点方面，两种古塞库单抗方案均优于安慰剂，在146名受试者中，200 mg古塞库单抗组有80名（55%），100 mg古塞库单抗组有70名（49%），76名安慰剂组有9名（12%）(调整治疗差异，200 mg古塞库单抗组为43%，100 mg古塞库单抗为38% [27-49]；（p< 0.0001），在GALAXI-3中，150名受试者中有72名（48%）在200 mg古塞库单抗组，143名受试者中有67名（47%）在100 mg古塞库单抗组，72名受试者中有9名（13%）在安慰剂组（35%[24-46]和34% [23-45]）；0·0001)。

同样，在第12周的临床反应终点和第48周的内镜反应终点方面，两种古塞库单抗方案都优于安慰剂，在古塞库单抗200 mg组中有56名（38%）参与者，在古塞库单抗100 mg组中有56名（39%）参与者，在安慰剂组中有4名（5%）参与者(古塞库单抗200 mg组中有33%[24-42]，在古塞库单抗100 mg组中有34% [24-43]；（p . lt; 0.0001），在GALAXI-3中，古塞库单抗200 mg组中有54名（36%）参与者，古塞库单抗100 mg组中有48名（34%）参与者，安慰剂组中有4名（6%）参与者(31%[21-40]和28% [19-37]；0·0001)。在古塞库单抗200 mg组中，有21名（7%）参与者发生了严重不良事件（发生率为每100参与者年9.7件），在古塞库单抗100 mg组中有32名（11%）参与者发生了严重不良事件（发生率为每100参与者年14.9件），在ustekinumab组中有35名（12%）参与者发生了严重不良事件（发生率为每100参与者年18.4件），在安慰剂组中有23名（15%）参与者发生了严重不良事件（发生率为每100参与者年23.8件）。没有死亡报告。

研究结果表明，静脉诱导后皮下使用古塞库单抗维持治疗在中度至重度活动性克罗恩病患者中是有效的，在第48周的多个终点显示优于安慰剂和ustekinumab。安全性结果是有利的，并且与古塞库单抗在批准适应症中的已知概况一致。

附：英文原文

Title: Efficacy and safety of intravenous induction and subcutaneous maintenance therapy with guselkumab for patients with Crohn's disease (GALAXI-2 and GALAXI-3): 48-week results from two phase 3, randomised, placebo and active comparator-controlled, double-blind, triple-dummy trials

Author: Remo Panaccione, Brian G Feagan, Anita Afzali, David T Rubin, Walter Reinisch, Julián Panés, Silvio Danese, Tadakazu Hisamatsu, Natalie A Terry, Leonardo Salese, Rian Van Rampelbergh, Aparna Sahoo, Marion L Vetter, Jacqueline Yee, Chenglong Han, Mary Ellen Frustaci, Kitty Y Y Wan, Zijiang Yang, Jewel Johanns, Jane M Andrews, Geert R DHaens, Bruce E Sands, Mohamed Nabil Abdelli, Niazy Abu Farsakh, Abdullah Al Omary, Sharara Ala, Olga Alexeeva, Reza Allamehzadeh, Vito Annese, Tomasz Arlukowicz, Naveen Arya, Monika Augustyn, Niaz Ausaf, Irit Avni-Biron, Marcelo Bacci, Jozef Balaz, Michael Barker, Khalil Bedran, Jakob Begun, Ekaterina Beloborodova, Charles Bernstein, Pintu Bhakhar, Amit Bhanvadia, Leonid Bilianskyi, Irina Blumenstein, Sandra Boratto, Aleksey Borsuk, Martin Bortlik, Fabrizio Bossa, Jalel Boubaker, Jeff Bullock, Melvin Bullock, Elena Bunkova, Guillaume Cadiot, Qian Cao, Daniel Carpio López, Rute Cerqueira, Marek Cesarz, Patrick Chamouard, Baili Chen, Hong Chen, Xiangrong Chen, Yan Chen, Adeeti Chiplunker, Cheng-Tang Chiu, Jaeyoung Chun, Roberto da Silva Junior, Wei Jie Dai, Wit Danilkiewicz, Olena Datsenko, Peter-Philip De Cruz, Gjorgi Deriban, Shigang Ding, Yijuan Ding, Malgorzata Duszynska, George DuVall, Ana Echarri Piudo, Otaviano Felicio, Daniela Ferreira, Rafal Filip, Yulia Fominykh, James Fon, Carlos Francesconi, Keith Friedenberg, Bernadetta Frysna, Toshimitsu Fujii, Ewa Furmanowska-Ladorska, Xiang Gao, Antonio Gasbarrini, Beata Gawdis-Wojnarska, Richard Gearry, Paolo Gionchetti, Jadwiga Gniady-Jastrzebska, Eran Goldin, Oleksandr Golovchenko, Srdjan Gornjakovic, Oleksiy Gridnyev, Luis Guevara Casallas, William Harlan, Xavier Hébuterne, Sonja Heeren, Vicent Hernández Ramírez, Ida Normiha Hilmi, Norkiyuki Horiki, Namiko Hoshi, Bilal Hotayt, Xiaohua Hou, Naizhong Hu, Vivian Huang, Aleksei Iakovlev, Takahiro Ikeda, Keisuke Ishigami, Yoh Ishiguro, Hiroaki Ito, Ferenc Izbéki, Animesh Jain, Vipul Jairath, Zofia Jamrozik-Kruk, Konrad Janik, Christof Jochum, Ivana Jovicic, Roberto Luiz Kaiser Junior, Takashi Kagaya, Toshihiro Kanda, Ben Kang, Sang Bum Kang, Gulam Khan

Issue&Volume: 2025-07-17

Abstract:

Background

Despite the availability of biological therapies, suboptimal disease control remains a problem for patients with Crohn's disease. We report the results of the GALAXI-2 and GALAXI-3 studies, which aimed to assess the efficacy and safety of intravenous induction followed by subcutaneous maintenance therapy with guselkumab over 48 weeks in adults with moderately to severely active Crohn's disease.

Methods

GALAXI-2 and GALAXI-3 were identically designed, phase 3, randomised, double-blind, triple-dummy, treat-through trials with active and placebo comparators. Adult patients with moderately to severely active Crohn's disease (≥3 months duration) were enrolled at 257 sites across 40 countries. Eligible participants were randomly assigned (2:2:2:1) by use of a centralised computer-generated schedule to one of four treatment groups: (1) 200 mg intravenous guselkumab at weeks 0, 4, and 8, then 200 mg subcutaneous guselkumab every 4 weeks from week 12 to week 44 (guselkumab 200 mg group); (2) 200 mg intravenous guselkumab at weeks 0, 4, and 8, then 100 mg subcutaneous guselkumab every 8 weeks from week 16 to week 40 (guselkumab 100 mg group); (3) approximately 6 mg/kg intravenous ustekinumab at week 0, then 90 mg subcutaneous ustekinumab every 8 weeks from week 8 to week 40 (ustekinumab group); or (4) intravenous placebo every 4 weeks at weeks 0, 4, and 8 (placebo group). At week 12, participants without a clinical response to placebo received masked rescue therapy with ustekinumab; all other participants remained on their randomised regimen irrespective of response status at week 12. Participants, investigators, site personnel, and the funder were masked to study treatment until all participants had either completed the follow-up visit at week 48 or terminated study participation before week 48. Coprimary composite endpoints (comparing each guselkumab regimen with placebo) were (1) clinical response at week 12 and clinical remission at week 48 and (2) clinical response at week 12 and endoscopic response at week 48, measured in the primary analysis population of all randomly assigned participants who received at least one dose of the study agent and satisfied the Simple Endoscopic Score for Crohn's Disease (SES-CD) eligibility criteria introduced with the third protocol amendment as per health authority request. Safety was assessed in participants who received at least one dose of study treatment (all-treated analysis population). These trials are registered with ClinicalTrials.gov (NCT03466411).

Findings

From Jan 8, 2020, to Oct 20, 2023, 1048 participants were randomly assigned, treated, and followed up until week 48, of whom 1021 participants were included in the primary analysis population: 508 (49·8%) in GALAXI-2 and 513 (50·2%) in GALAXI-3. Both guselkumab regimens were superior to placebo for the endpoint of clinical response at week 12 and clinical remission at week 48 in GALAXI-2, which was observed in 80 (55%) of 146 participants in the guselkumab 200 mg group, 70 (49%) of 143 in the guselkumab 100 mg group, and nine (12%) of 76 in the placebo group (adjusted treatment difference 43% [95% CI 32–54] in the guselkumab 200 mg group and 38% [27–49] in the guselkumab 100 mg group; p<0·0001), and in GALAXI-3, observed in 72 (48%) of 150 participants in the guselkumab 200 mg group, 67 (47%) of 143 in the guselkumab 100 mg group, and nine (13%) of 72 in the placebo group (35% [24–46] and 34% [23–45]; p<0·0001). Similarly, both guselkumab regimens were superior to placebo for the endpoint of clinical response at week 12 and endoscopic response at week 48 in GALAXI-2, observed in 56 (38%) participants in the guselkumab 200 mg group, 56 (39%) in the guselkumab 100 mg group, and four (5%) in the placebo group (33% [24–42] in the guselkumab 200 mg group and 34% [24–43] in the guselkumab 100 mg group; p<0·0001), and in GALAXI-3, observed in 54 (36%) participants in the guselkumab 200 mg group, 48 (34%) in the guselkumab 100 mg group, and four (6%) in the placebo group (31% [21–40] and 28% [19–37]; p<0·0001). Serious adverse events occurred in 21 (7%) participants in the guselkumab 200 mg group (incidence rate 9·7 events per 100 participant-years), 32 (11%) in the guselkumab 100 mg group (14·9 events per 100 participant-years), 35 (12%) in the ustekinumab group (18·4 events per 100 participant-years), and 23 (15%) in the placebo group (23·8 events per 100 participant-years). No deaths were reported.

Interpretation

Intravenous induction followed by subcutaneous maintenance therapy with guselkumab was efficacious in participants with moderately to severely active Crohn's disease, showing superiority to placebo and ustekinumab at week 48 across multiple endpoints. Safety outcomes were favourable and consistent with the known profile of guselkumab in approved indications.

DOI: 10.1016/S0140-6736(25)00681-6

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)00681-6/abstract