<br>使用 izuforant 靶向胆碱能荨麻疹中的组胺受体 4 （LEO 152020）：一项 IIa 期随机双盲安慰剂对照多中心交叉试验的结果。,British Journal of Dermatology

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使用 izuforant 靶向胆碱能荨麻疹中的组胺受体 4 （LEO 152020）：一项 IIa 期随机双盲安慰剂对照多中心交叉试验的结果。
British Journal of Dermatology ( IF 11.0 ) Pub Date : 2024-05-17 , DOI: 10.1093/bjd/ljae038
Eva Grekowitz _{1,

2} , Martin Metz _{1,

2} , Sabine Altrichter _{1,

2,

3} , Andrea Bauer ₄ , Knut Brockow ₅ , Guido Heine ₆ , Leonard Lionnet ₇ , Kadriye Kaplan Saday ₈ , Thomas Hultsch ₈ , Ole E Søerensen ₈ , Marcus Maurer _{1,

2}

Affiliation

背景胆碱能性荨麻疹（CholU）是慢性诱发性荨麻疹的常见亚型，其体征和症状（例如瘙痒性风团和血管性水肿）是由体育锻炼出汗、被动变暖和其他出汗情况引发的。虽然指南建议使用第二代 H1 抗组胺药进行治疗，但大约 90% 的患者报告疾病不受控制。靶向组胺 4 受体（H4R）已在过敏/炎症性疾病的临床前/临床研究中显示出前景。Izuforant （LEO 152020）是一种选择性口服 H4R 拮抗剂，具有预期的双重止痒和抗炎作用。目的评估 izuforant 对 CholU 成人的影响，CholU 是一种由组胺驱动的常见慢性荨麻疹，其特征是皮肤 H4R 表达水平高。方法这是一项 IIa 期、随机、双盲、安慰剂对照、多中心交叉试验，其中对 1 标准剂量的 H1 抗组胺药反应不足≥ CholU 患者接受 izuforant 100 mg，每天两次或安慰剂（EUCTR2020-004961-38-DE;NCT04853992）。主要终点是荨麻疹活动评分相对于基线的变化。探索性终点包括 7 天内的 CholU 活动评分、荨麻疹控制试验、医师整体评估、患者严重程度整体评估（PGA-S）、激发试验、皮肤病学生活质量指数和 CholU 生活质量（CholU-QoL）。评估了药代动力学和药效学参数、血清生物标志物以及安全性和耐受性。结果 19 例患者被随机分组并纳入完整分析集;18 例完成治疗 [平均（SD）年龄 29.5 （9.8）岁;平均（SD） CholU 持续时间 8.0 （6.3）岁]。未达到主要和大多数预先指定的探索性终点;与安慰剂相比，izuforant 的 PGA-S 有显著改善（P = 0.02），而生活质量和组胺皮肤点刺试验的其他终点没有显著改善。使用 izuforant 发生的所有不良事件（AEs）都被认为是轻微的。最常报告的（> 1 名患者）是恶心（3 名患者）和上腹痛（2 名患者），与安慰剂（各 1 名患者）相比，izuforant 更常见。没有与治疗相关的严重 AE，也没有接受 izuforant 治疗的患者停止研究。用 izuforant 治疗不会导致 H4R 下调。结论这是第一项探讨 H4R 作为荨麻疹治疗靶点作用的研究。用 izuforant 靶向 H4R 耐受性良好，但与安慰剂相比，在主要终点和 CholU 中除一个预先指定的探索终点外，所有终点均未显示出显著改善。

"点击查看英文标题和摘要"

Targeting histamine receptor 4 in cholinergic urticaria with izuforant (LEO 152020): results from a phase IIa randomized double-blind placebo-controlled multicentre crossover trial.

BACKGROUND Cholinergic urticaria (CholU) is a common subtype of chronic inducible urticaria, where signs and symptoms (e.g. pruritic wheals and angioedema) are triggered by sweating due to physical exercise, passive warming and by other sweat-inducing situations. While guidelines recommend treatment with second-generation H1 antihistamines, approximately 90% of patients report uncontrolled disease. Targeting the histamine 4 receptor (H4R) has shown promise in preclinical/clinical studies of allergic/inflammatory diseases. Izuforant (LEO 152020) is a selective oral H4R antagonist with expected dual antipruritic and anti-inflammatory effects. OBJECTIVES To assess the effects of izuforant in adults with CholU, a common type of chronic urticaria driven by histamine and characterized by high skin levels of H4R expression. METHODS This was a phase IIa randomized double-blind placebo-controlled multicentre crossover trial where patients with CholU with an inadequate response to ≥ 1 standard dose of H1 antihistamine received izuforant 100 mg twice daily or placebo (EUCTR2020-004961-38-DE; NCT04853992). The primary endpoint was change from baseline in Urticaria Activity Score. Exploratory endpoints included CholU activity score over 7 days, urticaria control test, Physician Global Assessment, patient global assessment of severity (PGA-S), provocation tests, Dermatology Life Quality Index and CholU quality of life (CholU-QoL). Pharmacokinetic and pharmacodynamic parameters, and serum biomarkers were assessed, as well as safety and tolerability. RESULTS Nineteen patients were randomized and included in the full analysis set; 18 completed treatment [mean (SD) age 29.5 (9.8) years; mean (SD) CholU duration 8.0 (6.3) years]. The primary and most of prespecified exploratory endpoints were not met; there were significant improvements in PGA-S for izuforant vs. placebo (P = 0.02), and nonsignificant improvements for other endpoints in quality of life and histamine skin prick test. All adverse events (AEs) experienced with izuforant were considered mild. The most frequently reported (> 1 patient) were nausea (three patients) and upper abdominal pain (two patients), occurring more frequently with izuforant vs. placebo (one patient each). There were no treatment-related serious AEs and no patient receiving izuforant discontinued the study. Treatment with izuforant did not cause downregulation of H4R. CONCLUSIONS This is the first study to explore the role of H4R as a therapeutic target in urticaria. Targeting H4R with izuforant was well tolerated but did not demonstrate significant improvements vs. placebo in the primary endpoint and all but one prespecified exploratory endpoint in CholU.

更新日期：2024-05-17

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