Efficacy and safety of enpatoran, a Toll-like receptor 7/8 inhibitor, in patients with skin manifestations of cutaneous lupus erythematosus or systemic lupus erythematosus: findings from Cohort A of a multicentre, international, double-blind, placebo-controlled, dose-finding phase 2 trial

IF 29.5 1区医学 Q1 RHEUMATOLOGY

Lancet Rheumatology Pub Date : 2026-07-01 Epub Date: 2026-05-07 DOI:10.1016/S2665-9913(25)00337-6

Prof Eric F Morand PhD, Prof Victoria P Werth MD, Prof Joerg Wenzel MD, Prof Richard Furie MD, Prof Maria Dall’Era MD, Prof Jorge Sanchez-Guerrero MD, Sanjeev Roy MD, Summer G Goodson PhD, Flavie Moreau MSc, Hans Gühring MD, Evridiki Sgouroudi PhD, Lena Klopp-Schulze PhD, David R Pearson MD

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Two participants (n=1 each from the enpatoran 25 mg and 50 mg groups) were randomly allocated to Cohort A but were subsequently found to have had BILAG scores ≥1A and 2B at screening and were therefore deemed ineligible and excluded; thus 100 participants were analysed for efficacy (placebo group n=26; enpatoran 25 mg group n=23; enpatoran 50 mg group n=25; enpatoran 100 mg group n=26). Participants in the full analysis set had a median age of 47 years (IQR 36–55); 77 (77%) were female, 23 (23%) were male, and 48 (48%) were White. At week 16, enpatoran had a significant, dose-dependent effect on CLASI-A score, with adjusted mean changes from baseline of –64 percentage points (95% CI –70 to –58) in the enpatoran 25 mg group, –68 percentage points (–75 to –61) in the enpatoran 50 mg group, and –72 percentage points (–80 to –64) in the enpatoran 100 mg group, versus –44 percentage points (–55 to –33) in the placebo group (p=0·0002 for dose–response relationship). 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引用次数: 0

Abstract

Background

Toll-like receptor (TLR)7 and TLR8 are nucleic-acid sensors involved in lupus pathogenesis. We aimed to investigate the efficacy and safety of enpatoran, an oral small-molecule TLR7/8 inhibitor, in participants with active skin manifestations of cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE).

Methods

WILLOW is a phase 2, randomised, double-blind, placebo-controlled, basket, dose-finding study conducted across 132 centres in 22 countries, enrolling patients into two cohorts (A and B) with different eligibility criteria. In Cohort A of the trial, we enrolled participants aged 18–75 years who had CLE only or SLE with mild or no extra-mucocutaneous disease activity (British Isles Lupus Assessment Group [BILAG]-2004 scores 1B, C, or D), and a Cutaneous Lupus Disease Area and Severity Index–activity (CLASI-A) score of 8 or higher. Participants were randomised (1:1:1:1) to receive placebo or enpatoran at a dose of 25 mg, 50 mg, or 100 mg twice per day for 24 weeks, in combination with standard of care. The primary objective was to evaluate the dose–response relationship of enpatoran in reducing disease activity, based on the percentage change from baseline in CLASI-A total score at week 16, analysed with a multiple comparison procedure–modelling approach. Efficacy analyses were done in the full analysis set of all randomly allocated participants. Safety was assessed in all patients who received at least one dose of study treatment. There was no involvement of people with lived experience of CLE or SLE in study design. This trial is registered with ClinicalTrials.gov (NCT05162586; completed); results from Cohort B will be reported separately.

Findings

Between May 4, 2022, and Feb 6, 2024, 463 patients were screened for eligibility across cohorts A and B; 102 participants were randomly assigned within Cohort A and received treatment (safety population). Two participants (n=1 each from the enpatoran 25 mg and 50 mg groups) were randomly allocated to Cohort A but were subsequently found to have had BILAG scores ≥1A and 2B at screening and were therefore deemed ineligible and excluded; thus 100 participants were analysed for efficacy (placebo group n=26; enpatoran 25 mg group n=23; enpatoran 50 mg group n=25; enpatoran 100 mg group n=26). Participants in the full analysis set had a median age of 47 years (IQR 36–55); 77 (77%) were female, 23 (23%) were male, and 48 (48%) were White. At week 16, enpatoran had a significant, dose-dependent effect on CLASI-A score, with adjusted mean changes from baseline of –64 percentage points (95% CI –70 to –58) in the enpatoran 25 mg group, –68 percentage points (–75 to –61) in the enpatoran 50 mg group, and –72 percentage points (–80 to –64) in the enpatoran 100 mg group, versus –44 percentage points (–55 to –33) in the placebo group (p=0·0002 for dose–response relationship). The most common treatment-emergent adverse event was upper respiratory tract infection, which occurred in two (8%) of 24 patients in the enpatoran 25 mg group, four (15%) of 26 in the enpatoran 50 mg group, five (19%) of 26 in the enpatoran 100 mg group, and two (8%) of 26 in the placebo group. Overall, one (4%) participant in the placebo group, one (4%) in the enpatoran 100 mg group, and two (8%) in the enpatoran 25 mg group had serious adverse events; none were reported with enpatoran 50 mg.

Interpretation

Enpatoran showed a significant and dose-dependent effect on disease activity in participants with active cutaneous manifestations of CLE or SLE, and was well tolerated.

Funding

Merck Healthcare KGaA, Darmstadt, Germany.

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一种toll样受体7/8抑制剂enpatoran在皮肤表现为皮肤红斑狼疮或系统性红斑狼疮患者中的疗效和安全性：来自一项多中心、国际、双盲、安慰剂对照、剂量寻找的2期试验的a队列研究结果。

背景：toll样受体（TLR）7和TLR8是参与狼疮发病的核酸传感器。本研究旨在研究口服小分子TLR7/8抑制剂enpatoran在皮肤表现为皮肤红斑狼疮（CLE）或系统性红斑狼疮（SLE）的患者中的疗效和安全性。柳树是一项2期、随机、双盲、安慰剂对照、篮子、剂量发现研究，在22个国家的132个中心进行，将患者纳入具有不同资格标准的两个队列（a和B）。在试验的队列A中，我们招募了年龄在18-75岁的参与者，他们只有CLE或SLE，轻度或无皮肤外的疾病活动（不列颠群岛狼疮评估组[BILAG]-2004评分为1B， C或D），皮肤狼疮疾病面积和严重程度指数-活动（CLASI-A）评分为8或更高。参与者随机（1:1:1:1）接受安慰剂或恩帕托兰，剂量为25mg， 50mg或100mg，每天两次，持续24周，并结合标准治疗。主要目的是评估enpatoran在降低疾病活动性方面的剂量-反应关系，基于第16周时CLASI-A总分与基线的百分比变化，并通过多重比较程序建模方法进行分析。在所有随机分配的参与者的完整分析集中进行疗效分析。对所有接受至少一剂研究治疗的患者进行安全性评估。在研究设计中没有让有CLE或SLE生活经验的人参与。该试验已在ClinicalTrials.gov注册（NCT05162586；已完成）；队列B的结果将单独报告。研究结果：在2022年5月4日至2024年2月6日期间，463名患者在队列A和B中进行了合格筛选；在队列A中随机分配102名参与者并接受治疗（安全人群）。2名参与者（恩帕托兰25 mg组和50 mg组各n=1名）被随机分配到队列A，但随后发现筛查时BILAG评分≥1A和2B，因此被认为不合格并被排除；因此，对100名参与者进行了疗效分析（安慰剂组n=26；恩patoran 25 mg组n=23；恩patoran 50 mg组n=25；恩patoran 100 mg组n=26）。完整分析组参与者的中位年龄为47岁（IQR 36-55）；女性77例（77%），男性23例（23%），白人48例（48%）。在第16周，enpatoran对CLASI-A评分有显著的剂量依赖性影响，enpatoran 25 mg组从基线调整后的平均变化为-64个百分点（95% CI为-70至-58），enpatoran 50 mg组为-68个百分点（-75至-61），enpatoran 100 mg组为-72个百分点（-80至-64），而安慰剂组为-44个百分点（-55至-33）（剂量反应关系p= 0.0002）。最常见的治疗不良事件是上呼吸道感染，在enpatoran 25mg组中，24例患者中有2例（8%）发生上呼吸道感染，在enpatoran 50mg组中，26例患者中有4例（15%）发生上呼吸道感染，在enpatoran 100mg组中，26例患者中有5例（19%）发生上呼吸道感染，在安慰剂组中，26例患者中有2例（8%）发生上呼吸道感染。总体而言，安慰剂组有1名（4%）参与者，enpatoran 100 mg组有1名（4%）参与者，enpatoran 25 mg组有2名（8%）参与者发生严重不良事件；50mg恩帕妥兰无报告。解释：Enpatoran对CLE或SLE皮肤表现活跃的参与者的疾病活动性表现出显著的剂量依赖性作用，并且耐受性良好。资助：Merck Healthcare KGaA， Darmstadt, Germany。

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来源期刊

Lancet Rheumatology RHEUMATOLOGY-

CiteScore

34.70

自引率

3.10%

发文量

279

期刊介绍： The Lancet Rheumatology, an independent journal, is dedicated to publishing content relevant to rheumatology specialists worldwide. It focuses on studies that advance clinical practice, challenge existing norms, and advocate for changes in health policy. The journal covers clinical research, particularly clinical trials, expert reviews, and thought-provoking commentary on the diagnosis, classification, management, and prevention of rheumatic diseases, including arthritis, musculoskeletal disorders, connective tissue diseases, and immune system disorders. Additionally, it publishes high-quality translational studies supported by robust clinical data, prioritizing those that identify potential new therapeutic targets, advance precision medicine efforts, or directly contribute to future clinical trials. With its strong clinical orientation, The Lancet Rheumatology serves as an independent voice for the rheumatology community, advocating strongly for the enhancement of patients' lives affected by rheumatic diseases worldwide.