Efficacy and Safety of Zabedosertib, an Interleukin-1 Receptor-Associated Kinase 4 Inhibitor, in Patients with Moderate-to-Severe Atopic Dermatitis: A Phase II Randomized Study.
Stefan J Jodl, Margitta Worm, Frauke Friedrichs, Ulrike Heinzel-Pleines, Andrea Wagenfeld, Maximilian Feldmüller, Stefan Klein, Ruiping Zhang, Kaweh Shakery, Ruth D Holzmann, Beate Rohde, Vidya Perera
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引用次数: 0
Abstract
Introduction: Interleukin-1 receptor-associated kinase 4 (IRAK4) is expressed in various immune cells and regulates proinflammatory cytokine production. Its inhibition represents a novel, promising therapeutic option in the treatment of atopic dermatitis (AD). Zabedosertib (BAY1834845) is a potent, selective IRAK4 inhibitor that suppresses markers of local and systemic immune responses. This study aimed to evaluate the efficacy and safety of zabedosertib in adults with moderate-to-severe AD.
Methods: DAMASK was a randomized, double-blind, 12-week, placebo-controlled, phase 2a, proof-of-concept study. Patients were randomized 2:1 to receive oral zabedosertib 120 mg twice daily or placebo. The primary efficacy endpoint was a composite of 75% reduction from baseline on the Eczema Area and Severity Index (EASI-75), no discontinuation of study medication for lack of efficacy, no rescue medication during the 4 weeks before Day 84, and no initiation of systemic AD treatment. Other efficacy assessments included validated Investigator's Global Assessment for Atopic Dermatitis (vIGA-AD), Peak Pruritus numerical rating scale score, and affected body surface area (BSA); for safety, it included frequency and severity of treatment-emergent adverse events (TEAEs).
Results: Of 77 randomized patients, 69 were included in the primary efficacy analysis (zabedosertib, n = 47; placebo, n = 22); 55 patients completed treatment. At Week 12, there was no significant difference between zabedosertib and placebo in the primary efficacy endpoint (32.3% vs. 37.4%) or percentage change in EASI from baseline (- 44.6% vs. - 55.9%). There were also no significant differences between zabedosertib and placebo at Week 12 in vIGA-AD response (15.9% vs. 28.5%), Peak Pruritus response (16.4% vs. 25.0%), percentage change in Peak Pruritus (- 20.7% vs. - 27.3%), or percentage change in BSA affected by AD (- 13.3% vs. - 20.3%). No severe or serious TEAEs were reported throughout the study.
Conclusions: Zabedosertib was safe and well tolerated in adults with moderate-to-severe AD but showed no evidence of efficacy in reducing disease severity or pruritus in this placebo-controlled study.
白细胞介素-1受体相关激酶4 （Interleukin-1 receptor-associated kinase 4, IRAK4）在多种免疫细胞中表达，调节促炎细胞因子的产生。它的抑制是治疗特应性皮炎（AD）的一种新的、有前途的治疗选择。Zabedosertib （BAY1834845）是一种有效的选择性IRAK4抑制剂，可抑制局部和全身免疫反应的标志物。本研究旨在评估zabedosertib治疗成人中重度AD的有效性和安全性。方法：DAMASK是一项随机，双盲，12周，安慰剂对照，2a期，概念验证研究。患者按2:1随机分配，接受口服zabedosertib 120 mg，每日两次或安慰剂。主要疗效终点是湿疹面积和严重程度指数（EASI-75）较基线减少75%，在第84天之前的4周内没有因缺乏疗效而停止研究药物，没有开始全身AD治疗。其他疗效评估包括验证的研究者特应性皮炎总体评估（vIGA-AD）、峰值瘙痒数值评定量表评分和受影响的体表面积（BSA）；在安全性方面，它包括治疗中出现的不良事件（teae）的频率和严重程度。结果：在77例随机患者中，69例纳入主要疗效分析（zabedosertib, n = 47；安慰剂，n = 22）；55例患者完成治疗。在第12周，zabedosertib和安慰剂在主要疗效终点（32.3% vs. 37.4%）或EASI从基线的百分比变化（- 44.6% vs. - 55.9%）方面没有显著差异。在第12周，zabedosertib和安慰剂在vIGA-AD反应（15.9% vs. 28.5%）、瘙痒峰反应（16.4% vs. 25.0%）、瘙痒峰变化百分比（- 20.7% vs. - 27.3%）或受AD影响的BSA变化百分比（- 13.3% vs. - 20.3%）方面也没有显著差异。在整个研究过程中没有严重或严重的teae报告。结论：在这项安慰剂对照研究中，Zabedosertib在中度至重度AD成人患者中是安全且耐受性良好的，但没有证据表明Zabedosertib在降低疾病严重程度或瘙痒方面有效。试验注册：ClinicalTrials.gov识别码，NCT05656911。
期刊介绍：
Dermatology and Therapy is an international, open access, peer-reviewed, rapid publication journal (peer review in 2 weeks, published 3–4 weeks from acceptance). The journal is dedicated to the publication of high-quality clinical (all phases), observational, real-world, and health outcomes research around the discovery, development, and use of dermatological therapies. Studies relating to diagnosis, pharmacoeconomics, public health and epidemiology, quality of life, and patient care, management, and education are also encouraged.
Areas of focus include, but are not limited to all clinical aspects of dermatology, such as skin pharmacology; skin development and aging; prevention, diagnosis, and management of skin disorders and melanomas; research into dermal structures and pathology; and all areas of aesthetic dermatology, including skin maintenance, dermatological surgery, and lasers.
The journal is of interest to a broad audience of pharmaceutical and healthcare professionals and publishes original research, reviews, case reports/case series, trial protocols, and short communications. Dermatology and Therapy will consider all scientifically sound research be it positive, confirmatory or negative data. Submissions are welcomed whether they relate to an International and/or a country-specific audience, something that is crucially important when researchers are trying to target more specific patient populations. This inclusive approach allows the journal to assist in the dissemination of quality research, which may be considered of insufficient interest by other journals. The journal appeals to a global audience and receives submissions from all over the world.
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