Cendakimab in Patients With Moderate to Severe Atopic Dermatitis: A Randomized Clinical Trial.

IF 11.5 1区医学 Q1 DERMATOLOGY JAMA dermatology Pub Date : 2024-08-01 DOI:10.1001/jamadermatol.2024.2131

Andrew Blauvelt, Emma Guttman-Yassky, Charles Lynde, Saakshi Khattri, Joel Schlessinger, Shinichi Imafuku, Yayoi Tada, Akimichi Morita, Marni Wiseman, Bartlomiej Kwiek, Martina Machkova, Peijin Zhang, Misti Linaberry, Jie Li, Sandra Zhang, Giovanni Franchin, Edgar D Charles, Claudia H M C De Oliveira, Jonathan I Silverberg

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Abstract

Importance: Cendakimab selectively targets interleukin (IL)-13, a type 2 cytokine implicated in atopic dermatitis (AD) pathogenesis, by inhibiting binding to its receptors (IL13R-α1 and IL13R-α2). Proof-of-concept work in AD supports using cendakimab for type 2 inflammatory diseases.

Objective: To evaluate the efficacy and safety of cendakimab compared with placebo in patients with moderate to severe AD.

Design, setting, and participants: This phase 2, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging clinical trial was conducted from May 2021 to November 2022. Adult patients with moderate to severe AD and inadequate response to topical medications were enrolled at 69 sites in 5 countries (US [n = 26], Japan [n = 17], Canada [n = 9], Poland [n = 9], and Czech Republic [n = 8]). Data were analyzed between April 25, 2023, and October 16, 2023.

Interventions: Patients were randomized (1:1:1:1) to receive subcutaneous cendakimab, 360 mg, every 2 weeks; 720 mg, every 2 weeks; 720 mg, once weekly; or placebo.

Main outcome and measure: Mean percentage change in Eczema Area and Severity Index scores from baseline to week 16. Hierarchical testing with multiplicity adjustment was performed for 720 mg, once weekly vs placebo, then 720 mg, every 2 weeks vs placebo, and then 360 mg, every 2 weeks vs placebo.

Results: Overall, 221 patients were randomized, and 220 received study drug (95 women [43%]; mean [SD] age, 37.7 [13.9] years; 720 mg, once weekly [54 (24%)]; 720 mg, every 2 weeks [55 (25%)]; 360 mg, every 2 weeks [55 (25%)]; placebo [56 (26%)]). The primary efficacy end point was met for cendakimab, 720 mg, once weekly vs placebo (-84.4 vs -62.7; P = .003) but missed statistical significance for 720 mg, every 2 weeks (-76.0 vs -62.7; P = .06). The treatment effect for 360 mg, every 2 weeks (-16.3; nominal P = .03 vs placebo) was comparable with 720 mg, once weekly (-21.8); however, significance was not claimed because the hierarchical testing sequence was interrupted. Of patients with treatment-emergent adverse events leading to discontinuation, 4 (7.4%) received 720 mg, once weekly; 2 (3.6%) 720 mg, every 2 weeks; 1 (1.8%) 360 mg, every 2 weeks; and 2 (3.6%) placebo.

Conclusions and relevance: The results of this randomized clinical trial indicated that cendakimab was effective, generally safe, and well-tolerated in patients with moderate to severe AD. The primary end point was met with a significant reduction in Eczema Area and Severity Index scores with 720 mg, once weekly at week 16. Cendakimab demonstrated progressive AD improvement at all doses during 16 weeks of treatment.

Trial registration: ClinicalTrials.gov Identifier: NCT04800315.

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用于中度至重度特应性皮炎患者的仙达昔单抗：随机临床试验

重要意义仙达单抗通过抑制白细胞介素（IL）-13受体（IL13R-α1和IL13R-α2）的结合，选择性地靶向白细胞介素（IL）-13，这是一种与特应性皮炎（AD）发病机制有关的2型细胞因子。AD的概念验证工作支持将仙达单抗用于2型炎症性疾病：评估仙达单抗与安慰剂相比对中重度AD患者的疗效和安全性：该2期随机、双盲、安慰剂对照、平行组、剂量范围临床试验于2021年5月至2022年11月进行。5个国家（美国[n = 26]、日本[n = 17]、加拿大[n = 9]、波兰[n = 9]和捷克共和国[n = 8]）的69个研究机构招募了中度至重度AD且对局部药物反应不充分的成人患者。数据分析时间为 2023 年 4 月 25 日至 2023 年 10 月 16 日：患者随机（1:1:1:1:1）接受皮下注射仙达单抗，360 毫克，每两周一次；720 毫克，每两周一次；720 毫克，每周一次；或安慰剂。主要结果和测量：湿疹面积和严重程度指数评分从基线到第 16 周的平均百分比变化。对720毫克（每周1次）与安慰剂、720毫克（每2周1次）与安慰剂、360毫克（每2周1次）与安慰剂进行了多重性调整的层次测试：共有 221 名患者接受了随机治疗，其中 220 人接受了研究药物（95 名女性 [43%]；平均 [SD] 年龄 37.7 [13.9] 岁；720 毫克，每周一次 [54 (24%)]；720 毫克，每两周一次 [55 (25%)]；360 毫克，每两周一次 [55 (25%)]；安慰剂 [56 (26%)]）。仙达单抗（720 毫克，每周一次 vs 安慰剂）达到了主要疗效终点（-84.4 vs -62.7；P = .003），但 720 毫克，每两周一次（-76.0 vs -62.7；P = .06）未达到统计学意义。360毫克，每两周一次的治疗效果（-16.3；与安慰剂相比，标称P = .03）与720毫克，每周一次的治疗效果（-21.8）相当；但是，由于分层测试序列中断，因此未获得显著性。在出现导致停药的治疗突发不良事件的患者中，4 人（7.4%）接受了每周一次的 720 毫克治疗；2 人（3.6%）接受了每两周一次的 720 毫克治疗；1 人（1.8%）接受了每两周一次的 360 毫克治疗；2 人（3.6%）接受了安慰剂治疗：这项随机临床试验的结果表明，仙达单抗对中度至重度AD患者有效、总体安全且耐受性良好。在第16周时，720毫克（每周一次）的湿疹面积和严重程度指数评分显著降低，达到了主要终点。在16周的治疗中，所有剂量的Cendakimab都能逐步改善AD：试验注册：ClinicalTrials.gov Identifier：试验注册：ClinicalTrials.gov Identifier：NCT04800315。

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来源期刊

JAMA dermatology DERMATOLOGY-

CiteScore

14.10

自引率

5.50%

发文量

300

期刊介绍： JAMA Dermatology is an international peer-reviewed journal that has been in continuous publication since 1882. It began publication by the American Medical Association in 1920 as Archives of Dermatology and Syphilology. The journal publishes material that helps in the development and testing of the effectiveness of diagnosis and treatment in medical and surgical dermatology, pediatric and geriatric dermatology, and oncologic and aesthetic dermatologic surgery. JAMA Dermatology is a member of the JAMA Network, a consortium of peer-reviewed, general medical and specialty publications. It is published online weekly, every Wednesday, and in 12 print/online issues a year. The mission of the journal is to elevate the art and science of health and diseases of skin, hair, nails, and mucous membranes, and their treatment, with the aim of enabling dermatologists to deliver evidence-based, high-value medical and surgical dermatologic care. The journal publishes a broad range of innovative studies and trials that shift research and clinical practice paradigms, expand the understanding of the burden of dermatologic diseases and key outcomes, improve the practice of dermatology, and ensure equitable care to all patients. It also features research and opinion examining ethical, moral, socioeconomic, educational, and political issues relevant to dermatologists, aiming to enable ongoing improvement to the workforce, scope of practice, and the training of future dermatologists. JAMA Dermatology aims to be a leader in developing initiatives to improve diversity, equity, and inclusion within the specialty and within dermatology medical publishing.

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