Topical tofacitinib for atopic dermatitis: a phase IIa randomized trial
Topical tofacitinib for atopic dermatitis: a phase IIa randomized trial
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DOI：
10.1111/bjd.14871
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发表时间：
2016-11-01
影响因子：
10.3
通讯作者：
Ports, W. C.
中科院分区：
文献类型：
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作者：
Bissonnette, R.;Papp, K. A.;Ports, W. C.
背景尽管特应性皮炎(AD)的需求尚未得到满足，但自一种具有新作用机制的局部疗法被批准以来，已经过去了15年。JAK抑制剂外用治疗AD的疗效尚不清楚。目的探讨小分子JAK抑制剂tofacitinib外用治疗AD的临床疗效。方法采用随机、双盲、赋形剂对照的IIa期研究方法，将69例轻、中度AD患者随机分为1：1~2%托法替尼或赋形剂软膏，每日2次，共4周。以第4周湿疹面积和严重程度指数(EASI)评分较基线的变化百分比(CFB)为主要终点。次要疗效终点包括CFB在体表面积(BSA)中的百分比、CFB在EASI临床体征严重程度总分中的百分比、医生总体评估(PGA)反应的患者比例以及CFB在患者报告的瘙痒中的比例。结果托法替尼组和赋形剂组第4周的平均CFB百分比分别为-81.7%和-29.9%，差异有统计学意义(P<；0.001)。接受托法替尼治疗的患者在第4周时，在所有预先指定的疗效终点和瘙痒症状方面，与赋形剂相比均有显著改善(P<；0.001)。第1周时，患者的体感指数、前列腺素A和血清白蛋白显著改善，第2天观察到瘙痒症状的改善。两种治疗方法的安全性/局部耐受性基本相似，尽管与赋形剂相比观察到更多的不良事件。结论：在终点处，托法替尼软膏的疗效显著优于赋形剂，起效早，安全性/局部耐受性与赋形剂相当。通过局部给药抑制JAK可能成为治疗AD的潜在靶点。
Background Despite unmet need, 15 years have passed since a topical therapy with a new mechanism of action for atopic dermatitis (AD) has been approved. Janus kinase (JAK) inhibitor treatment effect via topical application in patients with AD is unknown.Objectives Tofacitinib, a small-molecule JAK inhibitor, was investigated for the topical treatment of AD.Methods In this 4-week, phase IIa, randomized, double-blind, vehicle-controlled study (NCT02001181), 69 adults with mild-to-moderate AD were randomized 1: 1 to 2% tofacitinib or vehicle ointment twice daily. Percentage change from baseline (CFB) in Eczema Area and Severity Index (EASI) score at week 4 was the primary end point. Secondary efficacy end points included percentage CFB in body surface area (BSA), CFB in EASI Clinical Signs Severity Sum Score, proportion of patients with Physician's Global Assessment (PGA) response and CFB in patient-reported pruritus. Safety, local tolerability and pharmacokinetics were monitored.Results The mean percentage CFB at week 4 in EASI score was significantly greater (P < 0.001) for tofacitinib (-81.7%) vs. vehicle (-29.9%). Patients treated with tofacitinib showed significant (P < 0.001) improvements vs. vehicle across all pre-specified efficacy end points and for pruritus at week 4. Significant improvements in EASI, PGA and BSA were observed by week 1 and improvements in pruritus were observed by day 2. Safety/local tolerability were generally similar for both treatments, although more adverse events were observed for vehicle vs. tofacitinib.Conclusions Tofacitinib ointment showed significantly greater efficacy vs. vehicle across end points, with early onset of effect and comparable safety/local tolerability to vehicle. JAK inhibition through topical delivery is potentially a promising therapeutic target for AD.