Rubin David T, Dotan Iris, DuVall Aaron, Bouhnik Yoram, Radford-Smith Graham, Higgins Peter D R, Mishkin Daniel S, Arrisi Pablo, Scalori Astrid, Oh Young S, Tole Swati, Chai Akiko, Chamberlain-James Kirsten, Lacey Stuart, McBride Jacqueline, Panés Julian
Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA.
Rabin Medical Center, Petah Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Lancet Gastroenterol Hepatol. 2022 Jan;7(1):17-27. doi: 10.1016/S2468-1253(21)00338-1. Epub 2021 Nov 17.
Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In an earlier phase 2 induction study, etrolizumab significantly improved clinical remission relative to placebo in patients with moderately to severely active ulcerative colitis. The HIBISCUS studies aimed to compare the efficacy and safety of etrolizumab to adalimumab and placebo for induction of remission in patients with moderately to severely active ulcerative colitis.
HIBISCUS I and HIBISCUS II were identically designed, multicentre, phase 3, randomised, double-blind, placebo-controlled and active-controlled studies of etrolizumab, adalimumab, and placebo in adult (18-80 years) patients with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. All patients had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. In both studies, patients were randomly assigned (2:2:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks; subcutaneous adalimumab 160 mg on day 1, 80 mg at week 2, and 40 mg at weeks 4, 6, and 8; or placebo. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants, and baseline disease activity. All patients and study site personnel were masked to treatment assignment. The primary endpoint was induction of remission at week 10 (defined as MCS of 2 or lower, with individual subscores of 1 or lower, and rectal bleeding subscore of 0) with etrolizumab compared with placebo. Pooled analyses of both studies comparing etrolizumab and adalimumab were examined for several clinical and endoscopic endpoints. Efficacy was analysed using a modified intent-to-treat population, defined as all randomly assigned patients who received at least one dose of study drug. These trials are registered with ClinicalTrials.gov, NCT02163759 (HIBISCUS I), NCT02171429 (HIBISCUS II).
Between Nov 4, 2014, and May 25, 2020, each study screened 652 patients (HIBISCUS I) and 613 patients (HIBISCUS II). Each study enrolled and randomly assigned 358 patients (HIBISCUS I etrolizumab n=144, adalimumab n=142, placebo n=72; HIBISCUS II etrolizumab n=143; adalimumab n=143; placebo n=72). In HIBISCUS I, 28 (19·4%) of 144 patients in the etrolizumab group and five (6·9%) of 72 patients in the placebo group were in remission at week 10, with an adjusted treatment difference of 12·3% (95% CI 1·6 to 20·6; p=0·017) in favour of etrolizumab. In HIBISCUS II, 26 (18·2%) of 143 patients in the etrolizumab group and eight (11·1%) of 72 patients in the placebo group were in remission at week 10, with an adjusted treatment difference of 7·2% (95% CI -3·8 to 16·1; p=0·17). In the pooled analysis, etrolizumab was not superior to adalimumab for induction of remission, endoscopic improvement, clinical response, histological remission, or endoscopic remission; however, similar numerical results were observed in both groups. In HIBISCUS I, 50 (35%) of 144 patients in the etrolizumab group reported any adverse event, compared with 61 (43%) of 142 in the adalimumab group and 26 (36%) of 72 in the placebo group. In HIBISCUS II, 63 (44%) of 143 patients in the etrolizumab group reported any adverse event, as did 62 (43%) of 143 in the adalimumab group and 33 (46%) in the placebo group. The most common adverse event in all groups was ulcerative colitis flare. The incidence of serious adverse events in the pooled patient population was similar for etrolizumab (15 [5%] of 287) and placebo (seven [5%] of 144) and lower for adalimumab (six [2%] of 285). Two patients in the etrolizumab group died; neither death was deemed to be treatment related.
Etrolizumab was superior to placebo for induction of remission in HIBISCUS I, but not in HIBISCUS II. Etrolizumab was well tolerated in both studies.
F Hoffmann-La Roche.
艾托珠单抗是一种靶向肠道的抗β7整合素单克隆抗体。在一项早期2期诱导研究中，相对于安慰剂，艾托珠单抗显著改善了中度至重度活动性溃疡性结肠炎患者的临床缓解情况。“木槿花”（HIBISCUS）研究旨在比较艾托珠单抗与阿达木单抗及安慰剂在中度至重度活动性溃疡性结肠炎患者诱导缓解方面的疗效和安全性。
“木槿花I”和“木槿花II”研究设计相同，为多中心、3期、随机、双盲、安慰剂对照及活性药物对照研究，纳入18 - 80岁、中度至重度活动性溃疡性结肠炎（梅奥诊所总评分[MCS]为6 - 12，内镜亚评分为≥2，直肠出血亚评分为≥1，大便频率亚评分为≥1）且未使用过肿瘤坏死因子抑制剂的成年患者。所有患者经临床和内镜证据确诊溃疡性结肠炎至少3个月，且疾病累及距肛缘至少20 cm。在两项研究中，患者按2:2:1随机分组，分别接受皮下注射艾托珠单抗105 mg，每4周1次；皮下注射阿达木单抗，第1天160 mg，第2周80 mg，第4、6、8周各40 mg；或安慰剂。随机分组按基线时是否同时使用皮质类固醇、免疫抑制剂以及基线疾病活动度进行分层。所有患者及研究站点人员均对治疗分配情况不知情。主要终点为第10周时艾托珠单抗与安慰剂相比诱导缓解情况（定义为MCS为2或更低，各亚评分为1或更低，直肠出血亚评分为0）。对两项研究中比较艾托珠单抗和阿达木单抗的合并分析考察了多个临床和内镜终点。疗效分析采用改良意向性治疗人群，定义为所有随机分组且接受至少一剂研究药物的患者。这些试验已在ClinicalTrials.gov注册，注册号分别为NCT02163759（“木槿花I”）、NCT02171429（“木槿花II”）。
在2014年11月4日至2020年5月25日期间，每项研究分别筛查了652例患者（“木槿花I”）和613例患者（“木槿花II”）。每项研究均纳入并随机分配了358例患者（“木槿花I”：艾托珠单抗组n = 144，阿达木单抗组n = 142，安慰剂组n = 72；“木槿花II”：艾托珠单抗组n = 143，阿达木单抗组n = 143，安慰剂组n = 72）。在“木槿花I”中，艾托珠单抗组144例患者中有28例（19.4%）在第10周达到缓解，安慰剂组72例患者中有5例（6.9%）达到缓解，调整后的治疗差异为12.3%（95%CI 1.6至20.6；p = 0.017），支持艾托珠单抗。在“木槿花II”中，艾托珠单抗组143例患者中有26例（18.2%）在第10周达到缓解，安慰剂组72例患者中有8例（11.1%）达到缓解，调整后的治疗差异为7.2%（95%CI -3.8至16.1；p = 0.17）。在合并分析中，艾托珠单抗在诱导缓解、内镜改善、临床反应、组织学缓解或内镜缓解方面并不优于阿达木单抗；然而，两组观察到类似的数值结果。在“木槿花I”中，艾托珠单抗组144例患者中有50例（35%）报告了任何不良事件，阿达木单抗组142例患者中有61例（43%），安慰剂组72例患者中有26例（36%）。在“木槿花II”中，艾托珠单抗组
