Incyte Corp, Wilmington, Delaware 19880, USA.
J Am Acad Dermatol. 2012 Oct;67(4):658-64. doi: 10.1016/j.jaad.2011.12.018. Epub 2012 Jan 24.
Janus-associated kinases (JAKs) are involved in signal transduction from a variety of cytokines implicated in the pathogenesis of psoriasis, including interleukin (IL)-12, IL-23, and interferon-γ. INCB018424, a small molecule inhibitor of JAK1 and JAK2, inhibits cytokine-induced JAK/signal transducers and activators of transcription signaling and the resultant production of inflammatory proteins (eg, IL-17).
We sought to demonstrate proof of concept in patients with stable plaque psoriasis.
Patients were dosed with vehicle, 0.5% or 1.0% INCB018424 phosphate cream once a day or 1.5% twice a day for 28 days. Additional groups included two active comparators (calcipotriene 0.005% cream or betamethasone dipropionate 0.05% cream).
Both the 1% and the 1.5% cream improved lesion thickness, erythema, and scaling and reduced lesion area compared with placebo. A composite lesion score decreased by greater than 50% with the efficacious doses of INCB018424 compared with 32% for vehicle controls. Topical application of INCB018424 was well tolerated with few mild adverse events noted. Mean plasma concentrations of INCB018424 after topical application of 0.5% to 1.5% cream were in the low nanomolar range, representing a fraction (<1%) of the half maximal inhibitory concentration (IC(50)) in whole blood for inhibition of cytokine-stimulated signal transducers and activators of transcription-3 phosphorylation.
This study was limited by the relatively short study duration and small sample size.
Topical INCB018424 is safe, is well tolerated, and exhibits clinical activity in the topical treatment of psoriasis.
Janus 相关激酶（JAK）参与多种细胞因子的信号转导，这些细胞因子与银屑病的发病机制有关，包括白细胞介素（IL）-12、IL-23 和干扰素-γ。INCB018424 是一种小分子 JAK1 和 JAK2 抑制剂，可抑制细胞因子诱导的 JAK/信号转导和转录激活因子信号，以及由此产生的炎症蛋白（如 IL-17）的产生。
我们旨在稳定斑块型银屑病患者中证明概念验证。
患者每天一次接受载体、0.5%或 1.0% INCB018424 磷酸酯乳膏，或每天两次接受 1.5% INCB018424 磷酸酯乳膏治疗，共 28 天。其他组包括两种活性对照剂（卡泊三醇 0.005%乳膏或倍他米松二丙酸酯 0.05%乳膏）。
与安慰剂相比，1%和 1.5%乳膏均改善了病变厚度、红斑和鳞屑，并减少了病变面积。与载体对照组的 32%相比，INCB018424 的有效剂量使复合病变评分降低了超过 50%。INCB018424 局部应用具有良好的耐受性，仅观察到少数轻度不良反应。局部应用 0.5%至 1.5%乳膏后，INCB018424 的平均血浆浓度处于低纳摩尔范围，代表全血中细胞因子刺激的信号转导和转录激活因子-3 磷酸化的半数最大抑制浓度（IC50）的一小部分（<1%）。
本研究受到研究持续时间相对较短和样本量较小的限制。
局部 INCB018424 安全、耐受良好，并在银屑病的局部治疗中表现出临床疗效。
