Metz Martin, Giménez-Arnau Ana, Hide Michihiro, Lebwohl Mark, Mosnaim Giselle, Saini Sarbjit, Sussman Gordon, Szalewski Robert, Haemmerle Sibylle, Lheritier Karine, Martzloff El-Djouher, Seko Noriko, Wang Pengpeng, Zharkov Artem, Maurer Marcus
Urticaria Center of Reference and Excellence, Institute of Allergology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin.
Fraunhofer Institute for Translational Medicine and Pharmacology, Immunology and Allergology, Berlin.
N Engl J Med. 2025 Mar 6;392(10):984-994. doi: 10.1056/NEJMoa2408792.
Chronic spontaneous urticaria is an idiopathic syndrome defined by recurring itch, hives, or angioedema (or a combination of these symptoms) for more than 6 weeks. Remibrutinib, an oral, highly selective Bruton's tyrosine kinase inhibitor, showed efficacy and favorable safety in phase 2b trials. Data from phase 3 trials are needed.
In the identical, multicenter, double-blind, randomized, placebo-controlled REMIX-1 and REMIX-2 trials, we evaluated the efficacy and safety of remibrutinib in patients with symptomatic chronic spontaneous urticaria after treatment with second-generation H-antihistamines. Patients were randomly assigned in a 2:1 ratio to receive oral remibrutinib at a dose of 25 mg twice daily or placebo. The primary end point was the change from baseline to week 12 in the urticaria activity score during a 7-day period (UAS7), which comprises severity scores for itch and hives during 1 week (scores range from 0 to 42, with higher scores indicating greater severity). Key secondary end points included adverse events and a UAS7 of 6 or lower at weeks 2 and 12 and a UAS7 of 0 at week 12.
A total of 470 patients in REMIX-1 and 455 in REMIX-2 were randomly assigned to receive either remibrutinib (313 and 300 patients, respectively) or placebo (157 and 155 patients, respectively). The remibrutinib group had a significantly greater decrease in the UAS7 at week 12 than the placebo group (least-squares mean [±SE] change, -20.0±0.7 vs. -13.8±1.0 [P<0.001] in REMIX-1 and -19.4±0.7 vs. -11.7±0.9 [P<0.001] in REMIX-2), which appeared to be sustained through week 24. At week 12, significantly more patients in the remibrutinib group than in the placebo group had a UAS7 of 6 or lower (REMIX-1, 49.8% vs. 24.8% [P<0.001]; REMIX-2, 46.8% vs. 19.6% [P<0.001]) and a UAS7 of 0 (REMIX-1, 31.1% vs. 10.5% [P<0.001]; REMIX-2, 27.9% vs. 6.5% [P<0.001]). The percentages of patients with any adverse event and with serious adverse events were similar in the remibrutinib group and the placebo group, although a higher percentage of patients in the remibrutinib group than in the placebo group had petechiae (3.8% vs. 0.3% in the combined groups).
Treatment with oral remibrutinib resulted in a significant improvement in a composite measure of itching and hives at week 12. (Funded by Novartis Pharmaceuticals; REMIX-1 and REMIX-2 ClinicalTrials.gov numbers, NCT05030311 and NCT05032157, respectively.).
慢性自发性荨麻疹是一种特发性综合征，其定义为反复出现瘙痒、风团或血管性水肿（或这些症状的组合）超过6周。瑞帕替尼是一种口服的、高度选择性的布鲁顿酪氨酸激酶抑制剂，在2b期试验中显示出疗效和良好的安全性。需要3期试验的数据。
在相同的多中心、双盲、随机、安慰剂对照的REMIX-1和REMIX-2试验中，我们评估了瑞帕替尼在第二代H1抗组胺药治疗后有症状的慢性自发性荨麻疹患者中的疗效和安全性。患者以2:1的比例随机分配，接受每日两次25mg的口服瑞帕替尼或安慰剂。主要终点是从基线到第12周的7天内荨麻疹活动评分（UAS7）的变化，该评分包括1周内瘙痒和风团的严重程度评分（评分范围为0至42，分数越高表明严重程度越高）。关键次要终点包括不良事件以及在第2周和第12周时UAS7为6或更低，以及在第12周时UAS7为0。
REMIX-1试验中有470名患者，REMIX-2试验中有455名患者被随机分配接受瑞帕替尼（分别为313名和300名患者）或安慰剂（分别为157名和155名患者）。在第12周时，瑞帕替尼组的UAS7下降幅度明显大于安慰剂组（最小二乘均值[±SE]变化，REMIX-1中为-20.0±0.7 vs. -13.8±1.0[P<0.001]，REMIX-2中为-19.4±0.7 vs. -11.7±0.9[P<0.001]），这种改善似乎持续到第24周。在第12周时，瑞帕替尼组UAS7为6或更低的患者明显多于安慰剂组（REMIX-1中为49.8% vs. 24.8%[P<0.001]；REMIX-2中为46.8% vs. 19.6%[P<0.001]），且UAS7为0的患者也明显多于安慰剂组（REMIX-1中为31.1% vs. 10.5%[P<0.001]；REMIX-2中为27.9% vs. 6.5%[P<0.001]）。瑞帕替尼组和安慰剂组中出现任何不良事件和严重不良事件的患者百分比相似，尽管瑞帕替尼组中出现瘀点的患者百分比高于安慰剂组（合并组中分别为3.8%和0.3%）。
口服瑞帕替尼治疗在第12周时使瘙痒和风团的综合指标有显著改善。（由诺华制药公司资助；REMIX-1和REMIX-2的临床试验注册号分别为NCT05030311和NCT05032157。）
