抗 OX40 抗体治疗中重度特应性皮炎：一项多中心、双盲、安慰剂对照的 2b 期研究。

An anti-OX40 antibody to treat moderate-to-severe atopic dermatitis: a multicentre, double-blind, placebo-controlled phase 2b study.

机构信息

Department of Dermatology and Department of Allergy and Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Department of Dermatology, Oregon Health & Science University, Portland, OR, USA.

出版信息

Lancet. 2023 Jan 21;401(10372):204-214. doi: 10.1016/S0140-6736(22)02037-2. Epub 2022 Dec 9.

DOI:10.1016/S0140-6736(22)02037-2

PMID:36509097

Abstract

BACKGROUND

OX40 is crucial for T-cell differentiation and memory induction. The anti-OX40 antibody, rocatinlimab inhibits the OX40 pathway. We evaluated the efficacy and safety of rocatinlimab in adults with moderate-to-severe atopic dermatitis.

METHODS

This multicentre, double-blind, placebo-controlled phase 2b study was done at 65 secondary and tertiary sites in the USA, Canada, Japan, and Germany. Eligible patients were adults (aged 18 years or older) with confirmed atopic dermatitis (American Academy of Dermatology Consensus Criteria or local diagnostic criteria) with moderate-to-severe disease activity, as defined by an Eczema Area and Severity Index (EASI) score of 16 or more, validated Investigator's Global Assessment for Atopic Dermatitis score of 3 (moderate) or 4 (severe), and affected body surface area 10% or higher at both screening and baseline, with documented history (within 1 year) of inadequate response to topical medications or if topical treatments were medically inadvisable. Patients were randomly assigned (1:1:1:1:1) to receive subcutaneous rocatinlimab every 4 weeks (150 mg or 600 mg) or every 2 weeks (300 mg or 600 mg) or subcutaneous placebo up to week 18, with an 18-week active-treatment extension and 20-week follow-up. Percentage change from baseline in EASI score was assessed as the primary endpoint at week 16 and during the active extension and follow-up in all randomly assigned patients exposed to study drug with a post-baseline EASI score at week 16 or earlier according to the group they were randomly assigned to. Safety was assessed in all randomly assigned patients exposed to study drug; patients were analysed according to the group they were randomly assigned to. The study is registered with ClinicalTrials.gov, NCT03703102.

FINDINGS

Between Oct 22, 2018, and Oct 21, 2019, 274 patients (114 [42%] women, 160 [58%] men; mean age 38·0 years [SD 14·5]) were randomly assigned to one of the rocatinlimab groups (217 [79%] patients) or to the placebo group (57 [21%] patients). Compared with placebo (-15·0 [95% CI -28·6 to -1·4]), significant least-squares mean percent reductions in EASI score at week 16 were observed in all rocatinlimab groups (rocatinlimab 150 mg every 4 weeks -48·3 [-62·2 to -34·0], p=0·0003; rocatinlimab 600 mg every 4 weeks -49·7 [-64·3 to -35·2], p=0·0002; rocatinlimab 300 mg every 2 weeks -61·1 [-75·2 to -47·0], p<0·0001; and rocatinlimab 600 mg every 2 weeks -57·4 [-71·3 to -43·4], p<0·0001). The most common adverse events during the double-blind period in patients receiving rocatinlimab (adverse events ≥5% of patients in the total rocatinlimab group and more common than the placebo group) were pyrexia (36 [17%] patients), nasopharyngitis (30 [14%] patients), chills (24 [11%] patients), headache (19 [9%] patients), aphthous ulcer (15 [7%] patients), and nausea (13 [6%] patients). There were no deaths.

INTERPRETATION

Patients treated with rocatinlimab had progressive improvements in atopic dermatitis, which was maintained in most patients after treatment discontinuation. Treatment was well tolerated.

FUNDING

Kyowa Kirin.

摘要

背景

OX40 对于 T 细胞分化和记忆诱导至关重要。抗 OX40 抗体罗卡替林单抗抑制 OX40 通路。我们评估了罗卡替林单抗在中重度特应性皮炎成人患者中的疗效和安全性。

方法

这是一项多中心、双盲、安慰剂对照的 2b 期研究，在美国、加拿大、日本和德国的 65 个二级和三级中心进行。符合条件的患者为年龄在 18 岁或以上、经美国皮肤病学会共识标准或当地诊断标准确诊的特应性皮炎患者（中度至重度疾病活动，定义为 Eczema Area and Severity Index[EASI]评分≥16 分，经验证的研究者全球评估特应性皮炎[IGA]评分为 3 分（中度）或 4 分（重度），且在筛选和基线时受累体表面积≥10%，且有病史（1 年内）表明对局部药物治疗反应不足或局部治疗不适合。患者随机（1:1:1:1:1）接受每 4 周（150mg 或 600mg）、每 2 周（300mg 或 600mg）皮下注射罗卡替林单抗或安慰剂，最多至第 18 周，然后进行 18 周的活性治疗扩展和 20 周的随访。所有接受研究药物治疗且在第 16 周或更早时基线后 EASI 评分的随机分组患者（根据其随机分组情况）的 EASI 评分与基线相比的百分比变化被评估为主要终点，同时在所有接受研究药物治疗且在第 16 周或更早时基线后 EASI 评分的随机分组患者（根据其随机分组情况）中进行活性扩展和随访期间评估。所有接受研究药物治疗的随机分组患者均进行安全性评估；患者根据其随机分组情况进行分析。该研究在 ClinicalTrials.gov 注册，NCT03703102。

结果

2018 年 10 月 22 日至 2019 年 10 月 21 日，274 名患者（114 名[42%]女性，160 名[58%]男性；平均年龄 38.0 岁[14.5]岁）被随机分配至罗卡替林单抗组（217 名[79%]患者）或安慰剂组（57 名[21%]患者）。与安慰剂组（-15.0[95%CI-28.6 至-1.4]）相比，所有罗卡替林单抗组在第 16 周时 EASI 评分的最小二乘均值百分比下降均有显著统计学意义（罗卡替林单抗 150mg 每 4 周组-48.3[-62.2 至-34.0]，p=0.0003；罗卡替林单抗 600mg 每 4 周组-49.7[-64.3 至-35.2]，p=0.0002；罗卡替林单抗 300mg 每 2 周组-61.1[-75.2 至-47.0]，p<0.0001；和罗卡替林单抗 600mg 每 2 周组-57.4[-71.3 至-43.4]，p<0.0001）。在接受罗卡替林单抗治疗的患者中，在双盲期间最常见的不良反应（在总罗卡替林单抗组中发生频率≥5%的不良反应，且比安慰剂组更常见）为发热（36[17%]例患者）、鼻咽炎（30[14%]例患者）、寒战（24[11%]例患者）、头痛（19[9%]例患者）、阿弗他溃疡（15[7%]例患者）和恶心（13[6%]例患者）。无死亡病例。